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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Webvision: The Organization of the Retina and Visual System [Internet]" /><meta name="citation_title" content="Regeneration in the Visual System of Adult Mammals" /><meta name="citation_publisher" content="University of Utah Health Sciences Center" /><meta name="citation_date" content="2007/06/21" /><meta name="citation_author" content="Yves Sauve" /><meta name="citation_author" content="Frederic Gaillard" /><meta name="citation_pmid" content="21413374" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK11507/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Regeneration in the Visual System of Adult Mammals" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Utah Health Sciences Center" /><meta name="DC.Contributor" content="Yves Sauve" /><meta name="DC.Contributor" content="Frederic Gaillard" /><meta name="DC.Date" content="2007/06/21" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK11507/" /><meta name="description" content="Over 90 years after Ramon y Cajal's farsighted work (1) (Fig. 1), we are still unable to solve the great mystery of regeneration in the adult mammalian central nervous system (CNS). Retinal degeneration leading to loss of photoreceptors and retinal ganglion cells (RGCs) is still largely untreatable, although recent experimental work is beginning to provide possible solutions to these devastating conditions. Other untreatable pathologies leading to loss of sight involve lesions to the CNS visual centers or projection pathways. There are two fundamental experimental approaches presently used to tackle both these problems. One involves reconstructing lost circuitry by replacement with (usually fetal) neuronal tissue, and the other is attempting to slow the rate of the degeneration." /><meta name="og:title" content="Regeneration in the Visual System of Adult Mammals" /><meta name="og:type" content="book" /><meta name="og:description" content="Over 90 years after Ramon y Cajal's farsighted work (1) (Fig. 1), we are still unable to solve the great mystery of regeneration in the adult mammalian central nervous system (CNS). Retinal degeneration leading to loss of photoreceptors and retinal ganglion cells (RGCs) is still largely untreatable, although recent experimental work is beginning to provide possible solutions to these devastating conditions. Other untreatable pathologies leading to loss of sight involve lesions to the CNS visual centers or projection pathways. There are two fundamental experimental approaches presently used to tackle both these problems. One involves reconstructing lost circuitry by replacement with (usually fetal) neuronal tissue, and the other is attempting to slow the rate of the degeneration." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK11507/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-webvision-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/webvision/ch33regeneration1/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK11507/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Kolb H, Fernandez E, Jones B, et al., editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/webvision/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-webvision-lrg.png" alt="Cover of Webvision" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Webvision: The Organization of the Retina and Visual System [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK11507_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK11507_dtls__"><div>Kolb H, Fernandez E, Jones B, et al., editors.</div><div>Salt Lake City (UT): <a href="http://webvision.med.utah.edu/" ref="pagearea=page-banner&amp;targetsite=external&amp;targetcat=link&amp;targettype=publisher">University of Utah Health Sciences Center</a>; 1995-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/webvision/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/webvision/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/webvision/ch32nona/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/webvision/ch34regeneration2/" title="Next page in this title">Next &gt;</a></div></div></div></div></div>
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK11507_"><span class="title" itemprop="name">Regeneration in the Visual System of Adult Mammals</span></h1><p class="contrib-group"><span itemprop="author">Yves Sauve</span> and <span itemprop="author">Frederic Gaillard</span>.</p><p class="small">Created: <span itemprop="datePublished">May 1, 2005</span>; Last Update: <span itemprop="dateModified">June 21, 2007</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ch33regeneration1.Introduction"><h2 id="_ch33regeneration1_Introduction_">Introduction</h2><blockquote><p>"...once development was ended, the founts of growth and regeneration of the
axons and dendrites dried up irrevocably. In adult centres the nerve paths are
something fixed, ended, immutable. Everything may die, nothing may be
regenerated. It is for the science of the future to change, if possible, this
harsh decree. Inspired with high ideals, it must work to impede or moderate
gradual decay of neurons, to overcome the almost invincible rigidity of their
connections, and to re-establish normal nerve paths, when disease has severed
centres that were intimately associated." (Santiago Ramon y Cajal, 1913-14).</p></blockquote><p>Over 90 years after Ramon y Cajal's farsighted work (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.1">1</a>) (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F1/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F1" rid-ob="figobch33regeneration1F1">Fig. 1</a>), we
are still unable to solve the great mystery of regeneration in the adult mammalian
central nervous system (CNS). Retinal degeneration leading to loss of photoreceptors
and retinal ganglion cells (RGCs) is still largely untreatable, although recent
experimental work is beginning to provide possible solutions to these devastating
conditions. Other untreatable pathologies leading to loss of sight involve lesions
to the CNS visual centers or projection pathways. There are two fundamental
experimental approaches presently used to tackle both these problems. One involves
reconstructing lost circuitry by replacement with (usually fetal) neuronal tissue,
and the other is attempting to slow the rate of the degeneration.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F1" co-legend-rid="figlgndch33regeneration1F1"><a href="/books/NBK11507/figure/ch33regeneration1.F1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F1" rid-ob="figobch33regeneration1F1"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f1.gif" src-large="/books/NBK11507/bin/regeneration1f1.jpg" alt="Figure 1. Santiago Ramon y Cajal at work." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F1"><h4 id="ch33regeneration1.F1"><a href="/books/NBK11507/figure/ch33regeneration1.F1/?report=objectonly" target="object" rid-ob="figobch33regeneration1F1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Santiago Ramon y Cajal at work. From the Cajal Institute (http://www.cajal.csic.es/). </p></div></div></div><div id="ch33regeneration1.Reconstruction_of_Pr"><h2 id="_ch33regeneration1_Reconstruction_of_Pr_">Reconstruction of Primary Visual Pathways</h2><p>Without any experimental intervention, nerve lesions in the adult CNS of mammals
produce only a limited and brief period of abortive sprouting and then to the death
of axotomized neurons. In sharp contrast, the peripheral nervous system (PNS) and
the immature CNS of mammals, as well as the mature CNS of cold-blooded vertebrates,
all display varying levels of successful spontaneous regeneration after injury. The
development of experimental repair strategies has relied on lessons learned from
these systems. Combined with advances in anatomical tracing and immunohistochemical
methods, these strategies have revealed the surprising capacity for regeneration and
synapse formation in the adult mammalian CNS. For instance, Dr. Albert Aguayo and
colleagues have used an experimental approach (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.2">2-4</a>)
based on the concept that regeneration in the PNS is dependent on the permissive
environment provided by Schwann cells present in the nerve tube. They suggested that
the absence of this permissive environment in the mature CNS was the reason for
failure of regeneration. Thus, they postulate that damaged neurons from the mature
CNS might be able to regenerate axons if placed in close proximity to Schwann cells.
In fact, this hypothesis was suggested by Ramon y Cajal (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.1">1</a>) over a century ago and was later
tested by Tello in 1907 (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.5">5</a>) (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F2/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F2" rid-ob="figobch33regeneration1F2">Fig. 2</a>) in a series of experiments on
rabbits. There was a suggestion that retinal axons could regenerate after axotomy if
the cut optic nerve end was anastomosed to a sciatic nerve graft (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.5">5</a>). The lack of
anatomical tracers at that time did not allow us to see whether such regenerating
axons were indeed of CNS origin, namely from RGCs. The indisputable proof that some
CNS neurons do have this regenerative potential had to wait until specific axonal
tracing techniques became available in the late 1970s (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.6">6</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.7">7</a>).
Further work applied to primary visual pathways showed that if directed into the
brain (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F3/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F3" rid-ob="figobch33regeneration1F3">Fig. 3</a>), regenerating RGC axons were
able to re-establish connections in visual centers of the brainstem (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>). These
connections appeared capable of transmitting visual information (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.8">8</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.9">9</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F2" co-legend-rid="figlgndch33regeneration1F2"><a href="/books/NBK11507/figure/ch33regeneration1.F2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F2" rid-ob="figobch33regeneration1F2"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f2.gif" src-large="/books/NBK11507/bin/regeneration1f2.jpg" alt="Figure 2. Sciatic nerve graft (B) anastomosed on the optic nerve stump (A) in an adult rabbit." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F2"><h4 id="ch33regeneration1.F2"><a href="/books/NBK11507/figure/ch33regeneration1.F2/?report=objectonly" target="object" rid-ob="figobch33regeneration1F2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Sciatic nerve graft (B) anastomosed on the optic nerve stump (A) in
an adult rabbit. Axons can be seen to cross the anastomosis site (D). A scar
has formed at the anastomosis site (C). Letters in lowercase indicate a vein
in the optic nerve (a), "neurilema" <a href="/books/NBK11507/figure/ch33regeneration1.F2/?report=objectonly" target="object" rid-ob="figobch33regeneration1F2">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F3" co-legend-rid="figlgndch33regeneration1F3"><a href="/books/NBK11507/figure/ch33regeneration1.F3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F3" rid-ob="figobch33regeneration1F3"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f3.gif" src-large="/books/NBK11507/bin/regeneration1f3.jpg" alt="Figure 3. Schematic of peripheral nerve graft bridging the retinofugal pathways." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F3"><h4 id="ch33regeneration1.F3"><a href="/books/NBK11507/figure/ch33regeneration1.F3/?report=objectonly" target="object" rid-ob="figobch33regeneration1F3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Schematic of peripheral nerve graft bridging the retinofugal
pathways. A, normal optic pathway projecting to superior colliculus (SC),
pretectum (PT), and dorsal lateral geniculate nucleus (dLGN). B,
regeneration of optic axons through a peripheral nerve <a href="/books/NBK11507/figure/ch33regeneration1.F3/?report=objectonly" target="object" rid-ob="figobch33regeneration1F3">(more...)</a></p></div></div><p>The concept that neural regeneration depends on a permissive environment does not
alone explain why most mature mammalian CNS neurons do not regenerate an axon. For
instance, in the absence of axonal myelin-associated growth inhibitors such as Nogo,
axonal sprouting itself is not improved (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.10">10</a>). The role of
axonal growth inhibitors in axonal regeneration remains a controversial issue (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.11">11</a>). When
developing experimental strategies, other factors have to be considered, such as
axotomy-induced cell death and secondary degeneration (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.12">12</a>), scar
formation (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.13">13</a>), and factors
intrinsic to neurons themselves. We know that most CNS neurons loose their capacity
for axonal regeneration at a specific point in early development, even before
myelination (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.14">14-16</a>).</p><p>The abundant and diverse experiments directed at reconstructing visual circuitry
(several will be discussed below) have all uncovered a range of difficulties, such
as: 1) establishing a permissive interface between sprouting and/or regenerating
axons, or between graft and host; 2) providing the optimal conditions for
appropriately directed axon outgrowth; 3) achieving sufficient amount of axon
outgrowth for proper function; and 4) limiting or controlling the local neural
responses to initial injury, such as cell death, which may in itself mitigate
against effective recovery. A central point to all such work is that visual function
should be used as the yardstick for success (see <a href="#ch33regeneration1.Generation_of_Action">Generation of Action Potentials in
Target Neurons</a>).</p></div><div id="ch33regeneration1.Requirements_for_Rec"><h2 id="_ch33regeneration1_Requirements_for_Rec_">Requirements for Recovery of Function following Lesions of CNS Pathways</h2><p>The recovery of lost function following axonal interruption in any neuronal system
depends on the fulfillment of the following prerequisites:</p><ul><li id="A4248" class="half_rhythm"><div>survival of axotomized neurons and prevention of secondary degeneration</div></li><li id="A4249" class="half_rhythm"><div>axonal extension of the neurons surviving axotomy</div></li><li id="A4250" class="half_rhythm"><div>guidance of regenerating axons toward their appropriate target(s)</div></li><li id="A4251" class="half_rhythm"><div>target innervation and synapse formation onto recipient neurons</div></li><li id="A4252" class="half_rhythm"><div>supra-threshold activation in target neurons caused by regenerated
afferents</div></li><li id="A4253" class="half_rhythm"><div>restoration of ordered functional connections</div></li><li id="A4254" class="half_rhythm"><div>preservation of local and downstream circuitry</div></li></ul><p>The retinocollicular pathway is particularly suitable for addressing the
above-mentioned points for at least three reasons: 1) RGC axons project to the
superior colliculus (SC) through the optic nerve, which can be easily lesioned,
replaced, and anatomically traced; 2) because RGCs are excited by light, they can be
selectively stimulated in a physiological manner without the use of less selective
electrical pulses, which would concomitantly excite other pathways; 3) intact RGC
axons arborize preferentially in the superficial layers of the SC, onto which they
form a point-to-point representation of the retina (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.17">17-19</a>)
and which allows comparison of the regenerated pathway with those intact, using
either morphological or physiological approaches.</p><p>We will review the extent to which these requirements can be achieved by using the
example of the interrupted retinocollicular pathway and attempts for reconstruction
using PN grafts replacing the optic nerve. In brief, the potential for regeneration
of optic axons after being damaged was first indicated by studying hamsters in which
the optic nerve was cut and a peripheral nerve graft placed in association with the
retinal optic fiber layer (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.3">3</a>) (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F3/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F3" rid-ob="figobch33regeneration1F3">Fig. 3</a>). Optic axons grew into
this nerve graft, and studies in cat, in this instance, showed that the major
classes characterized, both anatomically and physiologically, contribute to this
regenerative growth (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.20">20</a>).
Subsequent experiments (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.21">21</a>) refined
the approach and were able to show that up to 10% or so of the normal optic
projection was able to regenerate into the nerve graft. If the other end of the
nerve graft was placed in an appropriate brain region, a proportion of these axons
could reach regions normally innervated by them (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.22">22</a>).
If the central stump was placed in close proximity to a visual center, the axons
formed terminal ramifications and synapses within that region (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>). If placed at
a distance from a visual center, axons were able to grow as much as 6 mm through the
brainstem to specific targets of optic input, ignoring in the process other brain
regions, including ones that had lost their primary input during the surgical
procedure (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.22">22</a>). Although an
anatomical study of topological representation of the regenerated axons has not been
done, physiological experiments (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>) have indicated
that although the precise map encountered in the normal retinotectal projection was
not seen, there was indication of a tendency for the naso-temporal representation of
the visual field to be appropriately arrayed along the rostrocaudal SC axis. Whether
this would be sufficient for an animal to be able to perform a behavior requiring
topographically encoded information, such as head tracking, is not clear. The
further possibility that some sort of training regimen might improve the tightness
of the map has not been explored either, but this preparation does lend itself to
such exploration.</p></div><div id="ch33regeneration1.Promoting_the_Surviv"><h2 id="_ch33regeneration1_Promoting_the_Surviv_">Promoting the Survival of Axotomized RGCs</h2><div id="ch33regeneration1.RGCs_Die_after_Optic"><h3>RGCs Die after Optic Nerve Transection</h3><p>After a complete intraorbital lesion of the adult mammalian optic nerve, the
majority of RGCs are lost within 2 weeks (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.21">21</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.25">25-27</a>).
Axotomized RGCs start dying after 1 week post-lesion, via programmed cell death.
This process, known as apoptosis, is also responsible for the naturally
occurring cell death of RGCs during development. Cells undergoing apoptosis,
such as axotomized RGCs, are characterized by the condensation of their nucleus,
DNA fragmentation, and the formation of apoptotic bodies (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.25">25</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.28">28</a>).
The pathways responsible for the apoptotic death of axotomized RGCs involve the
activation of caspases types 3, 8, 9, and CPP32-like (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.29">29-33</a>),
and the p38 mitogen-activated protein kinase p38MAPK (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.34">34</a>). The
inhibition of either or all of these caspases (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.30">30</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.32">32</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.35">35</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.36">36</a>)
or of p38MAPK (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.34">34</a>)
enhances the survival of axotomized RGCs. Furthermore, optic nerve transection
leads to the elevation of proapoptotic protein Bax and the decrease of the
antiapoptotic proteins Bcl-2 and Bcl-X (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.37">37</a>). The
overexpression of Bcl-2 in transgenic mice has been shown to protect RGCs for
axotomy-induced death (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.38">38</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.39">39</a>).
Finally, transfection of RGCs with the X-linked inhibitor of apoptosis or with
the caspase inhibitor p35 can both protect RGCs from axotomy-induced cell death
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.40">40</a>). The
conclusion from these findings is that axotomy-induced death of RGCs involves
the activation of not only one but several apoptotic pathways. Therefore,
strategies aimed at preventing the death of axotomized RGCs would have to target
multiple pathways.</p></div><div id="ch33regeneration1.Strategies_to_Preven"><h3>Strategies to Prevent the Death of Axotomized RGCs</h3><p>Most strategies developed to prevent RGC death involve the supply of various
trophic factors either exogenously, through cell-based therapy, or via gene
transfection (for reviews, see Yip and So (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.41">41</a>), Cui et al (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.42">42</a>), Weishaupt and
Bahr (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.43">43</a>), and
Koeberle and Bahr (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.44">44</a>)). The
rationale for supplying neurotrophins to axotomized RGCs is that their death
might be related to the loss of retrogradely supplied trophic factors, such as
brain-derived neurotrophic factor (BDNF), from their targets in the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.45">45-47</a>).
Axotomized RGCs can be rescued by experimentally supplying the retina with BDNF,
either via intravitreal injections (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.26">26</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.48">48-50</a>)
or via gene transfection of retinal cells (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.51">51</a>).
Furthermore, transfection of retinal cells with the high-affinity BDNF receptor
TrkB also enhances the survival of axotomized RGCs (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.52">52</a>).
Axotomized RGCs have also been rescued by the experimental addition of several
other neurotrophic factors (some of which having additive effects with each
other): neurotrophin NT-4/5 (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.26">26</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.53">53</a>);
NGF (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.54">54</a>); GDNF
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.55">55</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.56">56</a>);
Neurturin (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.57">57</a>); and CNTF
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.50">50</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.58">58-60</a>).
Several growth factors mediate their action by binding to their specific
receptors and activating the mitogen-activated protein kinase (MAPK) and
phosphatidylinositide-3-kinase (PI3K) transduction cascade pathways. For details
on secondary messengers and factors interfering with these cascades, see reviews
by Kaplan and Miller (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.61">61</a>),
Patapoutian and
Reichardt (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.62">62</a>), and
Koeberle and Bahr (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.44">44</a>). In
brief, neurotrophic factors may prevent axotomy-induced RGC death by interfering
with caspase pathways and by promoting the expression of pro-survival genes.</p><p>The neurotrophic factors tested to date for their survival effect on axotomized
RGCs all have only short-term effects, suggesting that trophic withdrawal is not
the only trigger for the apoptosis of axotomized RGCs. Blockade of axonal
transport (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.63">63</a>) has
minimal effects on the death of RGCs in neonatal rats. Other factors have been
identified, among them, the up-regulation of inducible nitric oxide synthase
(iNOS) by Muller cells after RGC axotomy (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.64">64</a>).
Inhibition of NOS has been shown to promote the survival of axotomized RGCs
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.64">64</a>), and when
done in combination with BDNF, it potentiates the effect of this neurotrophin
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.48">48</a>).
Modulation of microglial cells and macrophage activity has also been shown to
have an effect on the survival of axotomized RGCs (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.65">65-67</a>).</p><p>Finally, the prevention of axotomy-induced RGC death has been explored using a
vaccination approach known as "protective autoimmunity" (for a review, see
Schwartz (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.68">68</a>)). Dr.
Michal Schwartz and colleagues recently demonstrated that T cells specific to
self-proteins residing in the site of the CNS insult can be neuroprotective.
With the aim of boosting autoimmunity for neuroprotection without risking the
induction of an autoimmune disease, Dr. Schwartz's group has developed the use
of Cop-1 (an FDA-approved drug for the treatment of multiple sclerosis) as an
active vaccination for neuroprotection. This approach is currently under
investigation as a potential preventive treatment for glaucoma.</p></div></div><div id="ch33regeneration1.Promoting_the_Growth"><h2 id="_ch33regeneration1_Promoting_the_Growth_">Promoting the Growth of Axotomized RGC Axons</h2><p>Anastomosis of a PN graft onto the optic nerve stump has been shown to have a
survival effect on RGCs (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.21">21</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.69">69</a>)
as well as acting as an environment permissive to RGC axonal regeneration (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.3">3</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>).
A maximum of 10% of the total RGC population in rodents (10,000 of 100,000 in rats
and hamsters) (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F4a/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F4a" rid-ob="figobch33regeneration1F4a">Fig. 4a</a>, <a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F4b/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F4b" rid-ob="figobch33regeneration1F4b">Fig. 4b</a>,
<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F4c/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F4c" rid-ob="figobch33regeneration1F4c">Fig. 4c</a>) can regenerate an axon as far
as the distal end of an autologous PN graft, covering a distance of up to 2.5 cm.
This allows them to reach areas of the primary visual targets, such as the
contralateral superior colliculus. The RGCs that have regenerated an axon along the
PN graft appear to survive longer than the RGCs that have failed to do so (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.21">21</a>). Whether some
RGCs have intrinsic survival or axonal regenerative capacities or whether some RGCs
simply randomly succeed to regenerate an axon by chance (for instance, proximity to
the PN graft stump before retrograde degeneration beyond the optic disc) remains to
be clarified.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F4a" co-legend-rid="figlgndch33regeneration1F4a"><a href="/books/NBK11507/figure/ch33regeneration1.F4a/?report=objectonly" target="object" title="Figure 4a" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F4a" rid-ob="figobch33regeneration1F4a"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f4a.gif" src-large="/books/NBK11507/bin/regeneration1f4a.jpg" alt="Figure 4a. Demonstration of hamster RGC axonal regeneration in PN grafts." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F4a"><h4 id="ch33regeneration1.F4a"><a href="/books/NBK11507/figure/ch33regeneration1.F4a/?report=objectonly" target="object" rid-ob="figobch33regeneration1F4a">Figure 4a</a></h4><p class="float-caption no_bottom_margin">Demonstration of hamster RGC axonal regeneration in PN grafts.
Photomicrographic montage of a flattened retinal whole-mount from an animal
with a PN graft attached to the ON. The montages were prepared from 24
overlapping photographs printed at a magnification <a href="/books/NBK11507/figure/ch33regeneration1.F4a/?report=objectonly" target="object" rid-ob="figobch33regeneration1F4a">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F4b" co-legend-rid="figlgndch33regeneration1F4b"><a href="/books/NBK11507/figure/ch33regeneration1.F4b/?report=objectonly" target="object" title="Figure 4b" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F4b" rid-ob="figobch33regeneration1F4b"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f4b.gif" src-large="/books/NBK11507/bin/regeneration1f4b.jpg" alt="Figure 4b. Same retina as in A, incubated with the monoclonal antibody, RT 97, the immunofluorescent axons of retinal ganglion cells converge toward the central optic disk." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F4b"><h4 id="ch33regeneration1.F4b"><a href="/books/NBK11507/figure/ch33regeneration1.F4b/?report=objectonly" target="object" rid-ob="figobch33regeneration1F4b">Figure 4b</a></h4><p class="float-caption no_bottom_margin">Same retina as in A, incubated with the monoclonal antibody, RT
97, the immunofluorescent axons of retinal ganglion cells converge toward
the central optic disk. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F4c" co-legend-rid="figlgndch33regeneration1F4c"><a href="/books/NBK11507/figure/ch33regeneration1.F4c/?report=objectonly" target="object" title="Figure 4c" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F4c" rid-ob="figobch33regeneration1F4c"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f4c.gif" src-large="/books/NBK11507/bin/regeneration1f4c.jpg" alt="Figure 4c. Diagram, drawn from a photographic montage of a flattened retinal whole-mount from a different retina, indicating the location of 9451 neurons (dots) retrogradely labeled with HRP applied to the unconnected, extracranial end of the graft." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F4c"><h4 id="ch33regeneration1.F4c"><a href="/books/NBK11507/figure/ch33regeneration1.F4c/?report=objectonly" target="object" rid-ob="figobch33regeneration1F4c">Figure 4c</a></h4><p class="float-caption no_bottom_margin">Diagram, drawn from a photographic montage of a flattened retinal
whole-mount from a different retina, indicating the location of 9451 neurons
(dots) retrogradely labeled with HRP applied to the unconnected,
extracranial end of the graft. The montage <a href="/books/NBK11507/figure/ch33regeneration1.F4c/?report=objectonly" target="object" rid-ob="figobch33regeneration1F4c">(more...)</a></p></div></div><p>The promotion of RGC axonal regeneration seems to involve different mechanisms than
the ones promoting their axonal extension: most trophic factors shown to promote RGC
survival fail to promote their axonal regeneration. The discovery of new candidate
molecules promoting axonal extension comes in part from the observation that lens
scratching induces the production of low molecular weight molecules that can promote
both RGC survival and axonal regeneration within the intracranially lesioned optic
nerve (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.70">70</a>). Furthermore,
macrophage stimulation, which is associated with the release of similarly acting
molecules (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.71">71</a>) can also
promote RGC axonal extension within the lesioned optic nerve. The neutralization of
myelin-associated growth inhibitors can promote RGC axonal regeneration within
lesioned optic nerves, but only if RGCs are in an "active growth state", such as
stimulated by the small molecules mentioned above (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.72">72</a>).</p><p>The ability of RGCs to regenerate an axon does not only depend on their environment
but also on their intrinsic state. As mentioned in the introduction, most CNS
neurons such as RGCs appear to loose their capacity for axonal regeneration during
maturation (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.15">15</a>,
<a class="bk_pop" href="#ch33regeneration1.EXTYLES.16">16</a>).
Some recent experimental manipulations have showed that it might be possible to
reverse, at least to some extent, this state. Dr Lisa McKerracher and colleagues
have shown that inactivation of the small GTPase Rho can promote RGC axonal
regeneration after micro-lesions of the optic nerve in adult rats (for a review, see
Ellezam et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.73">73</a>). Another
approach, investigated by Dr. Mary Filbin and colleagues, involves elevating the
intracellular level of cyclic AMP in neurons (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.74">74</a>) (for a review,
see Spencer and Filbin (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.75">75</a>)).</p></div><div id="ch33regeneration1.Guidance_of_Regenera"><h2 id="_ch33regeneration1_Guidance_of_Regenera_">Guidance of Regenerating RGC Axons Toward Their Appropriate Target</h2><p>On the basis of what we know about developmental events, the challenges for
regenerating RGC axons to successfully reach their appropriate targets are severe.
First, as during development (for a review, see Oster et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.76">76</a>)), regenerating
axons have to navigate within the retina, find their way to the optic disc, exit it,
and finally enter into the optic nerve. After PN grafting (anastomosed on the
intraorbitally cut optic nerve stump) combined with intravitreal BDNF (to increase
the survival of axotomized RGCs), a minority of RGC axons do successfully regenerate
an axon into a peripheral nerve graft. However, many regenerating RGC axons never
actually exit the optic disc (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.77">77</a>). Several axons
from surviving RGCs appear to turn sharply just before the optic disc, growing in
the opposite direction, forming numerous collateral branches and loops, with erratic
growing patterns (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F5/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F5" rid-ob="figobch33regeneration1F5">Fig. 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F5" co-legend-rid="figlgndch33regeneration1F5"><a href="/books/NBK11507/figure/ch33regeneration1.F5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F5" rid-ob="figobch33regeneration1F5"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f5.gif" src-large="/books/NBK11507/bin/regeneration1f5.jpg" alt="Figure 5. Camera lucida drawings of neurobiotin-labeled RGC axons in flat-mounted retinas 2 weeks after optic nerve (ON) transection alone (A) or with the intravitreal administration of BDNF (B) or NT-3 (C) at the time of transection." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F5"><h4 id="ch33regeneration1.F5"><a href="/books/NBK11507/figure/ch33regeneration1.F5/?report=objectonly" target="object" rid-ob="figobch33regeneration1F5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Camera lucida drawings of neurobiotin-labeled RGC axons in
flat-mounted retinas 2 weeks after optic nerve (ON) transection alone (A) or
with the intravitreal administration of BDNF (B) or NT-3 (C) at the time of
transection. The broken lines indicate <a href="/books/NBK11507/figure/ch33regeneration1.F5/?report=objectonly" target="object" rid-ob="figobch33regeneration1F5">(more...)</a></p></div></div><p>A second challenge facing the regenerating RGC axon consists of navigating across the
optic chiasma by crossing or not crossing the midline, again depending on the RGC
type and/or location in the retina (for a review, see Williams et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.78">78</a>)). After which,
regenerating RGC axons, again depending on their types, have to extend all the way
into their appropriate target(s); some individual RGCs even have to send collaterals
to multiple targets, such as both the SC and the dorsolateral geniculate nucleus
(dLGN), and even more as shown in <a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F6/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F6" rid-ob="figobch33regeneration1F6">Fig. 6</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F6" co-legend-rid="figlgndch33regeneration1F6"><a href="/books/NBK11507/figure/ch33regeneration1.F6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F6" rid-ob="figobch33regeneration1F6"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f6.gif" src-large="/books/NBK11507/bin/regeneration1f6.jpg" alt="Figure 6. Retinal projections to the primary visual centers (white arrows) and their major links with homolateral secondary subcortical areas." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F6"><h4 id="ch33regeneration1.F6"><a href="/books/NBK11507/figure/ch33regeneration1.F6/?report=objectonly" target="object" rid-ob="figobch33regeneration1F6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Retinal projections to the primary visual centers (white arrows)
and their major links with homolateral secondary subcortical areas. Double
arrows indicate reciprocal connectivity. For abbreviations, see later.
Cortical connections are given in Fig. 28. <a href="/books/NBK11507/figure/ch33regeneration1.F6/?report=objectonly" target="object" rid-ob="figobch33regeneration1F6">(more...)</a></p></div></div><p>By using PN grafts, it has been possible to guide regenerating RGC axons into their
appropriate targets such as the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.8">8</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.9">9</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.22">22</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.79">79</a>),
the dLGN (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.80">80</a>), the pretectal
nuclei (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F7/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F7" rid-ob="figobch33regeneration1F7">Fig. 7</a>) (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>), or
deliberately into inappropriate targets such as the inferior colliculus or
cerebellum (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.81">81</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F7" co-legend-rid="figlgndch33regeneration1F7"><a href="/books/NBK11507/figure/ch33regeneration1.F7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F7" rid-ob="figobch33regeneration1F7"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f7.gif" src-large="/books/NBK11507/bin/regeneration1f7.jpg" alt="Figure 7. Light micrographs of 40-&#x003bc;m-thick cryostat coronal sections illustrating CTB-labeled retinal axons in the pretectum 16 weeks after grafting a segment of peripheral nerve between the left retina and the lateral side of the left diencephalon." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F7"><h4 id="ch33regeneration1.F7"><a href="/books/NBK11507/figure/ch33regeneration1.F7/?report=objectonly" target="object" rid-ob="figobch33regeneration1F7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Light micrographs of 40-&#x003bc;m-thick cryostat coronal
sections illustrating CTB-labeled retinal axons in the pretectum 16 weeks
after grafting a segment of peripheral nerve between the left retina and the
lateral side of the left diencephalon. A, <a href="/books/NBK11507/figure/ch33regeneration1.F7/?report=objectonly" target="object" rid-ob="figobch33regeneration1F7">(more...)</a></p></div></div><p>However, in some animals following insertion of the distal end of the PN graft into a
chosen target, only a minority or even none of the regenerating RGC axons can enter
a target (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>). In such
cases, several RGC axons (anterogradely labeled with a tracer from the eye) are
confined to a neuroma-like formation at the interface between the graft and the CNS
target (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F8/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F8" rid-ob="figobch33regeneration1F8">Fig. 8</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F8" co-legend-rid="figlgndch33regeneration1F8"><a href="/books/NBK11507/figure/ch33regeneration1.F8/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F8" rid-ob="figobch33regeneration1F8"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f8.gif" src-large="/books/NBK11507/bin/regeneration1f8.jpg" alt="Figure 8. Light micrographs of a 40-&#x003bc;m-thick cryostat coronal section illustrating retinal axons 24 weeks after connecting the left eye and the ipsilateral brainstem with a segment of peripheral nerve and 5 days after intraocular injection of CTB." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F8"><h4 id="ch33regeneration1.F8"><a href="/books/NBK11507/figure/ch33regeneration1.F8/?report=objectonly" target="object" rid-ob="figobch33regeneration1F8">Figure 8</a></h4><p class="float-caption no_bottom_margin">Light micrographs of a 40-&#x003bc;m-thick cryostat coronal
section illustrating retinal axons 24 weeks after connecting the left eye
and the ipsilateral brainstem with a segment of peripheral nerve and 5 days
after intraocular injection of CTB. A, interface <a href="/books/NBK11507/figure/ch33regeneration1.F8/?report=objectonly" target="object" rid-ob="figobch33regeneration1F8">(more...)</a></p></div></div><p>The cause of the formation of the neuroma-like endings is unclear. Three main factors
have to be considered: 1) glial reactions that might be associated with the lack of
axonal penetration into the CNS target; 2) the presence of inhibitory molecules,
which may also be responsible for the curtailed growth observed in CNS targets, and
that are known to be expressed in the damaged CNS (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.82">82</a>) and at the
PNS-CNS interface (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.83">83-88</a>);
and 3) the perturbation, due to graft insertion procedure, of the tri-dimensional
structure of the extracellular matrix that might act as "guiding railways" coated
with molecules that have growth-inhibitory or -promoting properties such as laminin,
vimentin, and chondroitin sulfate proteoglycans (CSPGs).</p><p>In some instances, PN grafts cannot be directly inserted into appropriate targets
because of the small size of the nucleus. In the study of Aviles-Trigueros et al.
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>), successful
innervation of the olivary pretectal nucleus (OPN) and the nucleus of the optic
tract (NOT) was achieved by inserting the distal end of a PN graft into the
superficial aspect of the midbrain, between these two nuclei, by carefully avoiding
touching them. Under such circumstances, some axons were seen crossing the midline
to innervate the contralateral nuclei. This led the investigators to insert the
nerves some distance further away from the nuclei. Axons, although coursing for long
distances through the brainstem, still showed selectivity for optic target regions
(<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F9/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F9" rid-ob="figobch33regeneration1F9">Fig. 9</a>, <a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F10/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F10" rid-ob="figobch33regeneration1F10">Fig. 10</a>,
<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F11/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F11" rid-ob="figobch33regeneration1F11">Fig. 11</a>). This occurred even though
some nuclei within their trajectory were deafferented by the surgery associated with
graft insertion.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F9" co-legend-rid="figlgndch33regeneration1F9"><a href="/books/NBK11507/figure/ch33regeneration1.F9/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F9" rid-ob="figobch33regeneration1F9"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f9.gif" src-large="/books/NBK11507/bin/regeneration1f9.jpg" alt="Figure 9. Drawings of alternate 40-&#x003bc;m-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 16 weeks after grafting a peripheral nerve segment between the left retina and the lateral aspect of the left diencephalon." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F9"><h4 id="ch33regeneration1.F9"><a href="/books/NBK11507/figure/ch33regeneration1.F9/?report=objectonly" target="object" rid-ob="figobch33regeneration1F9">Figure 9</a></h4><p class="float-caption no_bottom_margin">Drawings of alternate 40-&#x003bc;m-thick cryostat coronal
sections through the brainstem, from caudal (top left) to rostral (bottom
right), of a rat 16 weeks after grafting a peripheral nerve segment between
the left retina and the lateral aspect of <a href="/books/NBK11507/figure/ch33regeneration1.F9/?report=objectonly" target="object" rid-ob="figobch33regeneration1F9">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F10" co-legend-rid="figlgndch33regeneration1F10"><a href="/books/NBK11507/figure/ch33regeneration1.F10/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F10" rid-ob="figobch33regeneration1F10"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f10.gif" src-large="/books/NBK11507/bin/regeneration1f10.jpg" alt="Figure 10. Drawings of consecutive 40-&#x003bc;m-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 46 weeks after grafting a peripheral nerve segment between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F10"><h4 id="ch33regeneration1.F10"><a href="/books/NBK11507/figure/ch33regeneration1.F10/?report=objectonly" target="object" rid-ob="figobch33regeneration1F10">Figure 10</a></h4><p class="float-caption no_bottom_margin">Drawings of consecutive 40-&#x003bc;m-thick cryostat coronal
sections through the brainstem, from caudal (top left) to rostral (bottom
right), of a rat 46 weeks after grafting a peripheral nerve segment between
the left retina and the dorsal aspect of <a href="/books/NBK11507/figure/ch33regeneration1.F10/?report=objectonly" target="object" rid-ob="figobch33regeneration1F10">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F11" co-legend-rid="figlgndch33regeneration1F11"><a href="/books/NBK11507/figure/ch33regeneration1.F11/?report=objectonly" target="object" title="Figure 11" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F11" rid-ob="figobch33regeneration1F11"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f11.gif" src-large="/books/NBK11507/bin/regeneration1f11.jpg" alt="Figure 11. Light micrographs of 40-&#x003bc;m-thick cryostat coronal sections illustrating regenerated retinal fibers in the pretectum 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT and 5 days after intraocular injection of CTB." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F11"><h4 id="ch33regeneration1.F11"><a href="/books/NBK11507/figure/ch33regeneration1.F11/?report=objectonly" target="object" rid-ob="figobch33regeneration1F11">Figure 11</a></h4><p class="float-caption no_bottom_margin">Light micrographs of 40-&#x003bc;m-thick cryostat coronal
sections illustrating regenerated retinal fibers in the pretectum 46 weeks
after grafting a segment of peripheral nerve between the left retina and the
dorsal aspect of the left midbrain between <a href="/books/NBK11507/figure/ch33regeneration1.F11/?report=objectonly" target="object" rid-ob="figobch33regeneration1F11">(more...)</a></p></div></div><p>The specificity of innervation of visual and non-visual targets would appear to be at
odds with the observation of Zwimpfer et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.81">81</a>) showing
innervation of the cerebellum by optic axons regenerating through PN grafts. There
is, however, a significant difference in experimental design in that in the study of
Aviles-Trigueros et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>), the axons
have a "choice" of optic or non-optic targets, whereas in the cerebellum study, no
choice is available. To complicate the issue, there is evidence that when two of the
principal targets of retinofugal axons, the SC and dLGN, are ablated in newborn
hamsters and the somatosensory (ventrobasal) or auditory (medial geniculate)
thalamic nuclei are partially deafferented, the optic axons form permanent, abnormal
connections in the latter nuclei (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.89">89</a>). The mechanisms responsible for
"apparent" preference of appropriate target in studies such as by Aviles-Trigueros
et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>) are still
unclear.</p><p>In addition to PN grafting, several studies have reported successful RGC axonal
regeneration within the severed optic nerve (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.70">70</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.73">73</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.90">90-93</a>).
However, it remains unclear as to what is the growth pattern of individual
regenerating RGC axons, especially at the level of the optic chiasm, and
distally.</p></div><div id="ch33regeneration1.Arborization_and_Syn"><h2 id="_ch33regeneration1_Arborization_and_Syn_">Arborization and Synapse Formation by RGC Axons Regenerating into Their CNS
Targets</h2><p>Studies involving PN grafting to bridge the retinofugal pathways have shown that
regenerating RGC axons can form distinct arborizations in the target which they
reinnervate (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.94">94</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.95">95</a>).
The study of Aviles-Trigueros et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>) suggests that
regenerated retinal axons adopt distinctive patterns of terminal arborizations,
depending on the target they reinnervate. For instance, while axons entering the OPN
show little ramification and swellings reminiscent of the typical retinal
innervation of this nucleus, in the NOT axons tend to show more profuse
ramifications and arborizations with terminal swellings (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F12/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F12" rid-ob="figobch33regeneration1F12">Fig. 12</a> and
<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F13/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F13" rid-ob="figobch33regeneration1F13">Fig. 13</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F12" co-legend-rid="figlgndch33regeneration1F12"><a href="/books/NBK11507/figure/ch33regeneration1.F12/?report=objectonly" target="object" title="Figure 12" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F12" rid-ob="figobch33regeneration1F12"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f12.gif" src-large="/books/NBK11507/bin/regeneration1f12.jpg" alt="Figure 12. Drawings of retinal fibers 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT and 5 days after intraocular injection of CTB." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F12"><h4 id="ch33regeneration1.F12"><a href="/books/NBK11507/figure/ch33regeneration1.F12/?report=objectonly" target="object" rid-ob="figobch33regeneration1F12">Figure 12</a></h4><p class="float-caption no_bottom_margin">Drawings of retinal fibers 46 weeks after grafting a segment of
peripheral nerve between the left retina and the dorsal aspect of the left
midbrain between the OPN and NOT and 5 days after intraocular injection of
CTB. A, retinal fibers divide into fine <a href="/books/NBK11507/figure/ch33regeneration1.F12/?report=objectonly" target="object" rid-ob="figobch33regeneration1F12">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F13" co-legend-rid="figlgndch33regeneration1F13"><a href="/books/NBK11507/figure/ch33regeneration1.F13/?report=objectonly" target="object" title="Figure 13" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F13" rid-ob="figobch33regeneration1F13"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f13.gif" src-large="/books/NBK11507/bin/regeneration1f13.jpg" alt="Figure 13. Light micrograph of a 40-&#x003bc;m-thick cryostat coronal section of the midbrain illustrating retinal fibers in the superficial gray 40 weeks after grafting a peripheral nerve segment between the left eye and the lateral aspect of the ipsilateral SC and 5 days after intraocular injection of CTB." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F13"><h4 id="ch33regeneration1.F13"><a href="/books/NBK11507/figure/ch33regeneration1.F13/?report=objectonly" target="object" rid-ob="figobch33regeneration1F13">Figure 13</a></h4><p class="float-caption no_bottom_margin">Light micrograph of a 40-&#x003bc;m-thick cryostat coronal
section of the midbrain illustrating retinal fibers in the superficial gray
40 weeks after grafting a peripheral nerve segment between the left eye and
the lateral aspect of the ipsilateral SC <a href="/books/NBK11507/figure/ch33regeneration1.F13/?report=objectonly" target="object" rid-ob="figobch33regeneration1F13">(more...)</a></p></div></div><p>These types of terminals are reminiscent of the terminals previously described for
such retinorecipient nuclei in another rodent (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.96">96</a>). In this
context, what is also remarkable, is the similarity of the morphology of the
elaborate arborizations found in the superficial layers of the superior colliculus
(<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F14/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F14" rid-ob="figobch33regeneration1F14">Fig. 14</a>) with that described in normal
animals (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.96">96</a>). This
indicates further specificity of terminal arborization within the retinorecipient
reinnervated target. Thus, it appears that the morphology of the arborization is
dictated by the recipient region, more than by the type of retinal fiber arriving to
target (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.80">80</a>), and that
regenerating axons modify their arbors to adapt to the local conditions of the
target nucleus.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F14" co-legend-rid="figlgndch33regeneration1F14"><a href="/books/NBK11507/figure/ch33regeneration1.F14/?report=objectonly" target="object" title="Figure 14" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F14" rid-ob="figobch33regeneration1F14"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f14.gif" src-large="/books/NBK11507/bin/regeneration1f14.jpg" alt="Figure 14. Light micrographs and drawing illustrating regenerated retinal fibers in the stratum griseum superficiale of 40-&#x003bc;m-thick cryostat sections of the midbrain 48 weeks after grafting a segment of PN between the left eye and the lateral side of the ipsilateral SC and 5 days after intraocular injection of CTB." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F14"><h4 id="ch33regeneration1.F14"><a href="/books/NBK11507/figure/ch33regeneration1.F14/?report=objectonly" target="object" rid-ob="figobch33regeneration1F14">Figure 14</a></h4><p class="float-caption no_bottom_margin">Light micrographs and drawing illustrating regenerated retinal
fibers in the stratum griseum superficiale of 40-&#x003bc;m-thick
cryostat sections of the midbrain 48 weeks after grafting a segment of PN
between the left eye and the lateral side of the <a href="/books/NBK11507/figure/ch33regeneration1.F14/?report=objectonly" target="object" rid-ob="figobch33regeneration1F14">(more...)</a></p></div></div><p>In 1987, Vidal-Sanz et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>) provided experimental evidence that regenerating RGC axons were able
to re-establish connections in visual centers of the brainstem (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F15/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F15" rid-ob="figobch33regeneration1F15">Fig.
15</a>). These
connections appear to persist for the life span of the rodent, i.e., up to 2 years
of age (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.97">97</a>). The type of
synaptic contacts formed, the ratios of contacts to terminal perimeter, and the
domains of the postsynaptic neurons contacted are similar to those of intact
retinofugal pathways (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.22">22</a>).
Therefore, regenerated RGC axons can establish well-differentiated synapses with
neurons in the SC. On the basis of their results, Carter et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.22">22</a>) concluded
that, "The synaptic differentiation attained by such reformed retinocollicular
projections suggests that regenerating CNS axons and their target neurons in the
adult mammalian brain may retain or reexpress certain molecular determinants of
normal connectivity". There are, however, morphological differences between the
regenerated and control synapses: 1) larger size of some regenerated terminals; 2)
greater mean length of the regenerated synapses; and 3) higher proportion of
contacts with dendrites that contain vesicles in regenerated <i>versus</i>
intact synapses.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F15" co-legend-rid="figlgndch33regeneration1F15"><a href="/books/NBK11507/figure/ch33regeneration1.F15/?report=objectonly" target="object" title="Figure 15" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F15" rid-ob="figobch33regeneration1F15"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f15.gif" src-large="/books/NBK11507/bin/regeneration1f15.jpg" alt="Figure 15. Electron micrographs of presynaptic profiles in the superficial SC (strata zonale and griseum superficiale) lightly labeled with HRP injected in the PN-grafted eyes of group IIb rats." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F15"><h4 id="ch33regeneration1.F15"><a href="/books/NBK11507/figure/ch33regeneration1.F15/?report=objectonly" target="object" rid-ob="figobch33regeneration1F15">Figure 15</a></h4><p class="float-caption no_bottom_margin">Electron micrographs of presynaptic profiles in the superficial SC
(strata zonale and griseum superficiale) lightly labeled with HRP injected
in the PN-grafted eyes of group IIb rats. D, dendrites. The presynaptic
terminals contain vesicles that are predominantly <a href="/books/NBK11507/figure/ch33regeneration1.F15/?report=objectonly" target="object" rid-ob="figobch33regeneration1F15">(more...)</a></p></div></div></div><div id="ch33regeneration1.Generation_of_Action"><h2 id="_ch33regeneration1_Generation_of_Action_">Generation of Action Potentials in Target Neurons</h2><p>Dr. Sue Keirstead and colleagues (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.8">8</a>) provided electrophysiological
evidence that the synapses, such as the ones described at the electron-microscopic
level by Vidal-Sanz et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>), could
mediate the transynaptic activation of neurons in the superior colliculus of adult
mammals. Extracellular
recordings in the superior colliculus, 15 to 18 weeks after PN graft insertion into
the SC, revealed excitatory and inhibitory postsynaptic responses to visual
stimulation of the eye that had received PN anastomosis onto its completely cut
optic nerve (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F16/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F16" rid-ob="figobch33regeneration1F16">Fig. 16</a>). Specific stimulation
protocols (involving paired electrical stimulation of the PN graft) were used to
verify that postsynaptic activity could be elicited in the reinnervated SC.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F16" co-legend-rid="figlgndch33regeneration1F16"><a href="/books/NBK11507/figure/ch33regeneration1.F16/?report=objectonly" target="object" title="Figure 16" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F16" rid-ob="figobch33regeneration1F16"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f16.gif" src-large="/books/NBK11507/bin/regeneration1f16.jpg" alt="Figure 16. A, 10 successive responses to light flash (at arrow) recorded at a depth of 250 &#x003bc;m in the SC." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F16"><h4 id="ch33regeneration1.F16"><a href="/books/NBK11507/figure/ch33regeneration1.F16/?report=objectonly" target="object" rid-ob="figobch33regeneration1F16">Figure 16</a></h4><p class="float-caption no_bottom_margin">A, 10 successive responses to light flash (at arrow) recorded at a
depth of 250 &#x003bc;m in the SC. The large unit responds with a single
spike on 4 of 10 iterations. B, the same unit responds erratically with
inconsistent latency to (traces 1) single <a href="/books/NBK11507/figure/ch33regeneration1.F16/?report=objectonly" target="object" rid-ob="figobch33regeneration1F16">(more...)</a></p></div></div><p>Additional studies by Sauve et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.9">9</a>), using the same
experimental preparation, indicated that each element of a typical bursting response
to light (excitatory type of response; <a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F17/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F17" rid-ob="figobch33regeneration1F17">Fig. 17</a>)
consists of a terminal potential (TP) arising from a regenerated RGC axon terminal
arborization, followed by a longer duration focal synaptic potential (FSP) that is
selectively blocked by GABA. FSPs are extracellular changes in potential that
reflect summation of excitatory postsynaptic potentials (EPSPs) in neurons within
the terminal field of the regenerated RGC axon (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F18/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F18" rid-ob="figobch33regeneration1F18">Fig. 18</a>).
In some instances, superimposed on these FSPs are spikes (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F19/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F19" rid-ob="figobch33regeneration1F19">Fig. 19</a>),
which arise after three to four consecutive closely spaced impulses from RGS (as
inferred from the TPs).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F17" co-legend-rid="figlgndch33regeneration1F17"><a href="/books/NBK11507/figure/ch33regeneration1.F17/?report=objectonly" target="object" title="Figure 17" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F17" rid-ob="figobch33regeneration1F17"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f17.gif" src-large="/books/NBK11507/bin/regeneration1f17.jpg" alt="Figure 17. Unitary response to static illumination of a spot 4&quot; in diameter recorded at a depth of 190 &#x003bc;m in a reinnervated SC 37 weeks after graft insertion." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F17"><h4 id="ch33regeneration1.F17"><a href="/books/NBK11507/figure/ch33regeneration1.F17/?report=objectonly" target="object" rid-ob="figobch33regeneration1F17">Figure 17</a></h4><p class="float-caption no_bottom_margin">Unitary response to static illumination of a spot 4" in diameter
recorded at a depth of 190 &#x003bc;m in a reinnervated SC 37 weeks
after graft insertion. Bandpass 100 Hz to 5 kHz. From Sauve et al. (9). </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F18" co-legend-rid="figlgndch33regeneration1F18"><a href="/books/NBK11507/figure/ch33regeneration1.F18/?report=objectonly" target="object" title="Figure 18" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F18" rid-ob="figobch33regeneration1F18"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f18.gif" src-large="/books/NBK11507/bin/regeneration1f18.jpg" alt="Figure 18. Successive OFF responses to repetitive light stimuli every 3." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F18"><h4 id="ch33regeneration1.F18"><a href="/books/NBK11507/figure/ch33regeneration1.F18/?report=objectonly" target="object" rid-ob="figobch33regeneration1F18">Figure 18</a></h4><p class="float-caption no_bottom_margin">Successive OFF responses to repetitive light stimuli every 3.1 sec
from the same unit as in Fig. 1. Traces begin 125 msec after offset of
light. Band pass 10 Hz to 5 kHz. After application of GABA between traces 3
and 4, the second component of each unitary <a href="/books/NBK11507/figure/ch33regeneration1.F18/?report=objectonly" target="object" rid-ob="figobch33regeneration1F18">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F19" co-legend-rid="figlgndch33regeneration1F19"><a href="/books/NBK11507/figure/ch33regeneration1.F19/?report=objectonly" target="object" title="Figure 19" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F19" rid-ob="figobch33regeneration1F19"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f19.gif" src-large="/books/NBK11507/bin/regeneration1f19.jpg" alt="Figure 19. Spike-like activity arising from FSPs in single sweeps in response to static illumination of a spot." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F19"><h4 id="ch33regeneration1.F19"><a href="/books/NBK11507/figure/ch33regeneration1.F19/?report=objectonly" target="object" rid-ob="figobch33regeneration1F19">Figure 19</a></h4><p class="float-caption no_bottom_margin">Spike-like activity arising from FSPs in single sweeps in response
to static illumination of a spot. Recordings from units from two different
animals. A, an OFF response. Depth, 200 &#x003bc;m. Note increase in
baseline noise after closely spaced impulses <a href="/books/NBK11507/figure/ch33regeneration1.F19/?report=objectonly" target="object" rid-ob="figobch33regeneration1F19">(more...)</a></p></div></div><p>The results from Sauve et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.9">9</a>) indicate that
terminal arborizations of individual regenerated RGC axons can synapse with multiple
neurons in the SC and that convergence of inputs from regenerated RGC axons is not
required for activation of SC neurons in response to light.</p><p>Finally, <i>in vitro</i> studies by Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>) indicate that the deafferentation
of the SC, caused by optic nerve cut, and a surgical approach to insert the PN graft
into the SC together, lead to ultrastructural changes reflected functionally at the
synaptic level in the target structure, even after potential RGC axonal
regeneration. Such changes are likely to compromise the ability of the target
structure to function normally during information processing. Therefore, although
axons regenerating along peripheral nerve grafts can make functional synaptic
connections, their efficacy in activating the target structure will probably be
compromised by the local changes in synaptic connectivity.</p></div><div id="ch33regeneration1.Restoration_of_Retin"><h2 id="_ch33regeneration1_Restoration_of_Retin_">Restoration of Retinotopy</h2><div id="ch33regeneration1.Is_Restoration_of_Re"><h3>Is Restoration of Retinotopy Needed for Recovery of Function?</h3><p>Yes it is, for the appropriate execution of visually guided behaviors. We owe the
proof to the 1981 Physiology Nobel Prize co-winner Dr. Roger W. Sperry (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F20/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F20" rid-ob="figobch33regeneration1F20">Fig. 20</a>), who ingeniously took
advantage of the spontaneous functional recovery of the retinotectal system in
frogs (for a review, see Gaze (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.99">99</a>)).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F20" co-legend-rid="figlgndch33regeneration1F20"><a href="/books/NBK11507/figure/ch33regeneration1.F20/?report=objectonly" target="object" title="Figure 20" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F20" rid-ob="figobch33regeneration1F20"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f20.gif" src-large="/books/NBK11507/bin/regeneration1f20.jpg" alt="Figure 20. Photograph of Nobelist Roger Sperry." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F20"><h4 id="ch33regeneration1.F20"><a href="/books/NBK11507/figure/ch33regeneration1.F20/?report=objectonly" target="object" rid-ob="figobch33regeneration1F20">Figure 20</a></h4><p class="float-caption no_bottom_margin">Photograph of Nobelist Roger Sperry. </p></div></div><p>Sperry's impressive demonstration involved sectioning a frog's optic nerve and
rotating the eye by 180&#x000b0; (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.100">100</a>). After spontaneous
regeneration of the retinotectal pathway, the frog's attempt to catch a prey
resulted in an attack directed to the diametrically opposed direction (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F21/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F21" rid-ob="figobch33regeneration1F21">Fig. 21</a>). The frog's behavior gave
clues as to how the regenerating RGC axons had reconnected in the tectum. Note:
the structure equivalent to SC is named "tectum" in lower vertebrates. Sperry
inferred that the regenerating axons had returned to their original position in
the tectum, regardless of the new position they occupied in the rotated eye.
This gave experimental support for his chemo-specificity theory (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.100">100</a>), which
stipulates that "The connections are governed by intrinsic specificity of the
advancing fibre tip plus that of the various cellular elements it encounters in
its outgrowth" (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.101">101</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F21" co-legend-rid="figlgndch33regeneration1F21"><a href="/books/NBK11507/figure/ch33regeneration1.F21/?report=objectonly" target="object" title="Figure 21" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F21" rid-ob="figobch33regeneration1F21"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f21.gif" src-large="/books/NBK11507/bin/regeneration1f21.jpg" alt="Figure 21. When the eye is rotated 180&#x000b0;, the frog's prey-catching behavior is inverted." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F21"><h4 id="ch33regeneration1.F21"><a href="/books/NBK11507/figure/ch33regeneration1.F21/?report=objectonly" target="object" rid-ob="figobch33regeneration1F21">Figure 21</a></h4><p class="float-caption no_bottom_margin">When the eye is rotated 180&#x000b0;, the frog's prey-catching
behavior is inverted. After Sperry, 1956. </p></div></div><p>We can learn about the extent to which retinotopic projections have to be
re-established to achieve behavioral recovery by comparing species that have
various levels of regeneration of their retinotectal system and examining the
level of visually guided behavior they can recover. The capacity for RGC axon
regeneration in the vertebrate visual pathway is summarized in the study of
Dunlop et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.102">102</a>). For
instance, there is variability between various species of lizards. Some achieve
a stable restoration of retinotectal organization (accompanied by restoration of
visually guided behaviors), whereas others (<i>Ctenophorus
ornatus</i>) fail to maintain a retinotopic ordering of the regenerated
projection and lose their capacity to perform visually guided tasks (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.103">103</a>). However,
training on a visual task has been shown to improve the outcome of optic nerve
regeneration in <i>Ctenophorus ornatus</i> lizards (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.104">104</a>).</p></div><div id="ch33regeneration1.Guidance_Cues_in_the"><h3>Guidance Cues in the Injured Retinotectal Pathway</h3><p>The retinotectal system is the model of choice for studying the mechanisms
governing the formation of ordered connections in the CNS. In intact mature
rodents, axons from RGCs located in the temporal retina project to the rostral
(anterior) part of the contralateral SC, whereas axons from RGCs located in the
nasal retina project to the caudal (posterior) contralateral SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.17">17-19</a>).
Ventral RGCs project axons medially and dorsal RGCs project axons laterally in
the contralateral SC (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F22/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F22" rid-ob="figobch33regeneration1F22">Fig. 22</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F22" co-legend-rid="figlgndch33regeneration1F22"><a href="/books/NBK11507/figure/ch33regeneration1.F22/?report=objectonly" target="object" title="Figure 22" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F22" rid-ob="figobch33regeneration1F22"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f22.gif" src-large="/books/NBK11507/bin/regeneration1f22.jpg" alt="Figure 22. Ventral view schematic of retinotectal projections." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F22"><h4 id="ch33regeneration1.F22"><a href="/books/NBK11507/figure/ch33regeneration1.F22/?report=objectonly" target="object" rid-ob="figobch33regeneration1F22">Figure 22</a></h4><p class="float-caption no_bottom_margin">Ventral view schematic of retinotectal projections. </p></div></div><p>To elucidate the mechanisms involved in axonal guidance, especially with regard
to specificity of polarities in the tectum, Dr. Friedrich Bonhoeffer and
colleagues developed an <i>in vitro</i> assay, known as the "stripe
assay" (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.105">105</a>,
<a class="bk_pop" href="#ch33regeneration1.EXTYLES.106">106</a>).
The basis of this assay involves growing retinal explants on stripes made up of
tissues alternating from rostral and caudal parts of the tectum. Results using
tissues from developing chicks or rodents show that temporal RGC axons avoid
stripes made up of caudal tectal tissue, whereas nasal RGC axons grow equally
well on either rostral or nasal tectal tissue stripes (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.105">105-108</a>)
or show a preference for nasal stripes providing specific pre-treatments (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.109">109</a>). This
preference appears to be developmentally regulated in a way that is lost in the
mature system. However, Dr. Mathias Bahr and colleagues (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.110">110-112</a>) showed that this
capacity can be partially restored following optic nerve cut in adult
rats.
Their results indicate that guidance cues might be re-expressed in the
deafferented retinotectal system of adult mammals, and that these cues might
retain some level of function.</p><p>Several axonal guidance molecules and their respective receptors have been
identified. Among them, the best studied compose these four classes: netrins,
semaphorins, slits, and ephrins (for a review, see Koeberle and Bahr (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.44">44</a>)). In the
goldfish, in which spontaneous regeneration occurs, Eph/ephrins are upregulated
as gradients at the time that topography is restored during optic nerve
regeneration (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.113">113</a>).
Furthermore, the Eph/ephrin system is required to restore topography because
blocking their interactions <i>in vivo</i> with fusion proteins
results in abnormal topography (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.114">114</a>). In
rodents, in which spontaneous regeneration does not occur, most of the known
guidance molecules have been shown to be modulated after deafferentation.
However, although some molecules are up-regulated to levels similar to those
achieved in development, some (such as the ephrin receptor EphA5 in the retina
and the ephrin-B) are actually down-regulated. Therefore, it remains improbable
that these various changes might actually recapitulate developmental events. How
experimental manipulations might achieve such recapitulation of developmental
events is, for now, a mind-boggling puzzle.</p><p>Can RGC axon regenerated through a PN graft resume topological specificity when
reinnervating the superior colliculus? See an example from the study of Sauve et
al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>).</p><p>The study of Sauve et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>) indicates
that regenerating mammalian RGC axon terminals do not form a precise retinotopic
map (compared with normal intact animals; <a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F23/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F23" rid-ob="figobch33regeneration1F23">Fig.
23</a>) when reinnervating the SC (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F24/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F24" rid-ob="figobch33regeneration1F24">Fig.
24</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F23" co-legend-rid="figlgndch33regeneration1F23"><a href="/books/NBK11507/figure/ch33regeneration1.F23/?report=objectonly" target="object" title="Figure 23" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F23" rid-ob="figobch33regeneration1F23"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f23.gif" src-large="/books/NBK11507/bin/regeneration1f23.jpg" alt="Figure 23. A, multiunit receptive fields were recorded from the left eye of a normal hamster, plotted on a tangent screen 20 cm from the eye, and viewed from the side of the screen opposite to the animal." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F23"><h4 id="ch33regeneration1.F23"><a href="/books/NBK11507/figure/ch33regeneration1.F23/?report=objectonly" target="object" rid-ob="figobch33regeneration1F23">Figure 23</a></h4><p class="float-caption no_bottom_margin">A, multiunit receptive fields were recorded from the left eye of a
normal hamster, plotted on a tangent screen 20 cm from the eye, and viewed
from the side of the screen opposite to the animal. The nasotemporal axis of
the eye, defined by the position <a href="/books/NBK11507/figure/ch33regeneration1.F23/?report=objectonly" target="object" rid-ob="figobch33regeneration1F23">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F24" co-legend-rid="figlgndch33regeneration1F24"><a href="/books/NBK11507/figure/ch33regeneration1.F24/?report=objectonly" target="object" title="Figure 24" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F24" rid-ob="figobch33regeneration1F24"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f24.gif" src-large="/books/NBK11507/bin/regeneration1f24.jpg" alt="Figure 24. Positions of RGCs in the left retina and the projection sites of their respective axon terminals in the contralateral right SC of a grafted animal." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F24"><h4 id="ch33regeneration1.F24"><a href="/books/NBK11507/figure/ch33regeneration1.F24/?report=objectonly" target="object" rid-ob="figobch33regeneration1F24">Figure 24</a></h4><p class="float-caption no_bottom_margin">Positions of RGCs in the left retina and the projection sites of
their respective axon terminals in the contralateral right SC of a grafted
animal. Numbers refer to the recording sites in the SC. Letters indicate
multiple receptive fields recorded at <a href="/books/NBK11507/figure/ch33regeneration1.F24/?report=objectonly" target="object" rid-ob="figobch33regeneration1F24">(more...)</a></p></div></div><p>However, superimposed on the apparent randomness of distribution of RGC
terminals, there appears to be a small but nonetheless statistically significant
tendency for these terminals to array themselves appropriately within the
rostrocaudal axis of the SC. Because the PN graft tip was placed at different
locations in different animals, the assessment of topography was of necessity a
comparison of the relative positions of reinnervating axon terminals for each
animal rather than an identification of the absolute position of each terminal.
It must also must be emphasized that the method used by Sauve et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>) assessed
terminal positions but not trajectories of regenerating RGC axons. Nonetheless,
these results suggest that factor(s) may be present in the reinnervated SC, as
in the newly innervated SC, that can influence the direction of axonal growth
and/or the area within which arborization and synapse formation occur.</p><p>Topographic ordering of projections during normal development of retinofugal
pathways is thought to reflect at least two processes: 1) an initial pathfinding
to the approximately correct area directed by spatially specific molecular cues
as first suggested by Sperry (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.115">115</a>); and 2) a subsequent phase
of refinement of the projection due to activity-dependent processes in which
near-simultaneous firing of neighboring RGCs (for a review, see Wong (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.116">116</a>)) serves
mutually to stabilize the connections of their shared target neurons in the LGN
or tectum (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.117">117-121</a>).
Initial pathfinding of RGC axons in the tectum may be very precise, as in frogs
and fish (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.122">122</a>,
<a class="bk_pop" href="#ch33regeneration1.EXTYLES.123">123</a>),
or more exuberant and diffuse, as in rodents (166,
167).
Computer simulations suggest that a combination of positional cues and
activity-dependent mechanisms gives rise to a very precise retinotectal topology
in a variety of experimental situations (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.124">124</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.125">125</a>),
for example even if a molecular gradient is only transiently expressed during
the initiation of innervation of the tectum (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.126">126</a>).</p><p>During regeneration of the retinotectal pathway in frogs and fish, the initial
topography is only roughly organized. Functional synapses are formed
indiscriminately by regenerating goldfish RGC axons as they enter the tectum.
These may be unstable if inappropriately located (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.127">127</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.128">128</a>).
Projections become refined into a more precise retinotopic map over a period of
several weeks by mechanisms that depend upon ongoing activity in neighboring RGC
axons (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.117">117</a>,
<a class="bk_pop" href="#ch33regeneration1.EXTYLES.129">129</a>).</p><p><i>In vitro</i> experiments have shown that molecules with topological
specificity with respect to the rostral and caudal tectum or SC are transiently
expressed in the neonatal mammalian SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.105">105</a>). These
topologically specific markers disappear after the retinocollicular pathway is
laid down but reappear about 2 weeks after denervation of the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.112">112</a>). Such
positionally specific markers may be more strongly expressed in deafferented SC
than in embryonic SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.130">130</a>). The
experimental results of Sauve et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.24">24</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.131">131</a>) are
consistent with the possibility that a gradient of such positionally specific
markers could serve as an influence on the exploration of the SC by regenerating
RGC axons (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.132">132-134</a>),
either by exerting a repulsive or tropic effect on their axonal growth cones
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.105">105</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.106">106</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.135">135-138</a>),
or by influencing their branching patterns (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.108">108</a>).
Positionally specific markers could also influence the deployment of
regenerating RGC axons within the nerve graft as they approach the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.139">139</a>).</p><p>The question arises as to why the effects of these factor(s), if present, are so
minimally expressed or so difficult to document in the reinnervated mammalian
SC. In the reinnervated SC, the extent of exploration by a regenerated RGC axon
is 1 mm or less (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.140">140</a>). More
extensive exploration of the SC is perhaps limited by the presence of factors
inhibitory to axonal growth (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.141">141-144</a>)
that are present in the adult animal as well as by the developmental
down-regulation of growth permissive molecules (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.145">145</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.146">146</a>)
and receptors (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.147">147</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.148">148</a>).
This is in contrast to the situation during normal development, where RGC axons
from all portions of the retina initially innervate the entire SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.149">149</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.150">150</a>).
In the PN graft regeneration paradigm, no more than 10% of the normal total
number of RGCs usually regenerate their axons across the PN graft, and only a
portion of these reinnervate the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.4">4</a>). Many axons
terminate growth immediately after penetrating the CNS (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.23">23</a>). One way
to increase sprouting of regenerating RGC axons in the SC could be to provide
BDNF and chondroitinase ABC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.151">151</a>). However,
even in these conditions, with surviving RGCs widely separated in the retina and
their axon terminals widely dispersed within the SC, the influence of
activity-dependent mechanisms in shaping the topological pattern of innervation
would be expected, <i>a priori</i>, to be much more limited than in
normal development. Furthermore, with little competition among axons for
synaptic sites, it is possible that inappropriately located synapses, once
formed, would be much more stable than in the reinnervated frog or goldfish
tectum. Such premature formation of synapses could in turn curtail the further
exploration of the SC by regenerated RGC axons.</p></div></div><div id="ch33regeneration1.Preservation_of_Loca"><h2 id="_ch33regeneration1_Preservation_of_Loca_">Preservation of Local and Downstream Circuitry</h2><p>In the study by Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>), the local synaptic connectivity
in the superficial gray layer of the SC was assessed after RGC axonal regeneration
through a PN graft into the rat SC, using <i>in vitro</i> brain slice
techniques. Repair was achieved between the ipsilateral eye and SC, after bilateral
lesion of optic nerves and ablation of ipsilateral occipital cortex.</p><div id="ch33regeneration1.Impact_of_Deafferent"><h3>Impact of Deafferentation</h3><p>The normal rat superficial gray layer (SGL) of the SC receives the majority (90%)
of its excitatory input from the retina (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.152">152</a>) (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F25/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F25" rid-ob="figobch33regeneration1F25">Fig. 25</a>) and the remainder (10%)
from the visual cortex (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.153">153</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F25" co-legend-rid="figlgndch33regeneration1F25"><a href="/books/NBK11507/figure/ch33regeneration1.F25/?report=objectonly" target="object" title="Figure 25" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F25" rid-ob="figobch33regeneration1F25"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f25.gif" src-large="/books/NBK11507/bin/regeneration1f25.jpg" alt="Figure 25. Details of a vesicle and contact morphology in the normal SC of the rat." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F25"><h4 id="ch33regeneration1.F25"><a href="/books/NBK11507/figure/ch33regeneration1.F25/?report=objectonly" target="object" rid-ob="figobch33regeneration1F25">Figure 25</a></h4><p class="float-caption no_bottom_margin">Details of a vesicle and contact morphology in the normal SC of
the rat. a, normal S terminal make asymmetric contact (S) and F terminal
make symmetric contact (F). b, an F terminal makes symmetric contact. c, an
S terminal makes two asymmetric contacts <a href="/books/NBK11507/figure/ch33regeneration1.F25/?report=objectonly" target="object" rid-ob="figobch33regeneration1F25">(more...)</a></p></div></div><p>Interconnectivity within the SGL appears to be mediated by local GABAergic
interneurons (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.154">154</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.155">155</a>).
Both the GABAergic processes of local circuit interneurons (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.152">152</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.156">156</a>)
and the axon terminals of other projections proliferate (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.157">157</a>, <a class="bk_pop" href="#ch33regeneration1.EXTYLES.158">158</a>)
after optic deafferentation. These new neural processes appear to form
additional synapses or to take up positions apposed to the postsynaptic
densities left vacant by the degenerating retinal afferents in the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.152">152</a>). As a
result, the synapse-to-neuron ratio stays the same in the SC (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.159">159</a>), although
it is not known whether these synaptic contacts are functional. Because the
subsequent repair of retinal afferents is also going to alter the balance
between excitatory and inhibitory inputs, the connectivity between restored
retinal afferents and target neurons is likely to be very different from that in
the normal SGL (<a class="figpopup" href="/books/NBK11507/figure/ch33regeneration1.F26/?report=objectonly" target="object" rid-figpopup="figch33regeneration1F26" rid-ob="figobch33regeneration1F26">Fig. 26</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch33regeneration1F26" co-legend-rid="figlgndch33regeneration1F26"><a href="/books/NBK11507/figure/ch33regeneration1.F26/?report=objectonly" target="object" title="Figure 26" class="img_link icnblk_img figpopup" rid-figpopup="figch33regeneration1F26" rid-ob="figobch33regeneration1F26"><img class="small-thumb" src="/books/NBK11507/bin/regeneration1f26.gif" src-large="/books/NBK11507/bin/regeneration1f26.jpg" alt="Figure 26. Partial occupation of postsynaptic contacts." /></a><div class="icnblk_cntnt" id="figlgndch33regeneration1F26"><h4 id="ch33regeneration1.F26"><a href="/books/NBK11507/figure/ch33regeneration1.F26/?report=objectonly" target="object" rid-ob="figobch33regeneration1F26">Figure 26</a></h4><p class="float-caption no_bottom_margin">Partial occupation of postsynaptic contacts. a, the contact
(arrow) has a degenerate terminal (D) and an F terminal (F) adjacent to it.
b, the contact (arrow) is shared by an F terminal (F) and an unidentified
profile (U). Magnification &#x000d7;50,000. <a href="/books/NBK11507/figure/ch33regeneration1.F26/?report=objectonly" target="object" rid-ob="figobch33regeneration1F26">(more...)</a></p></div></div><p>There is as yet no evidence for local excitatory connections in the SGL.
Electrophysiological studies are consistent with the anatomical organization, in
that retinal input to the SGL is monosynaptic and there is no evidence for local
network-related activity, even when inhibition is blocked (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.160">160</a>). In
addition, contralateral enucleation 14 days before recording is sufficient to
result in a complete loss of excitatory inputs to the SGL <i>in
vitro</i> after intracollicular stimulation (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.161">161</a>). However,
the study by Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>) suggests that this is not
always the case: optic tract stimulation 3&#x02013;9 months after optic
nerve transection leads to excitation in the SC, and this is likely attributable
to the recruitment of corticocollicular projections, which run close to the
optic tract (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.162">162</a>).
Indeed, anatomical studies have shown that 30&#x02013;45 days after
contralateral enucleation, there is a reactive synaptogenesis of
corticocollicular terminals (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.157">157</a>). The
nature of this responsiveness also suggests that this cortical input recruits
local recurrent excitatory connections that have been formed as part of the
reactive process to retinal deafferentation.</p></div><div id="ch33regeneration1.Evidence_of_New_Inpu"><h3>Evidence of New Inputs after PN Graft Repair</h3><p>After combined retinal and cortical deafferentation (as part of the surgery for
PN bridging the retinocollicular pathway), all normal excitatory inputs to the
SGL are abolished. However, there is evidence from the study by Turner et al.
(<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>) for the
presence of both spontaneous and evoked EPSP-like events in SC slices from the
PN graft repair preparation. This suggests that excitatory inputs can form new
synaptic contacts on neurons within the SGL. These connections are likely to be
attributable to reactive sprouting of excitatory neurons, either in the SGL
itself or the deeper layers of the SC, such as the intermediate gray layer
(IGL). Because both the SGL and IGL contain neurons that have dendrites that
extend across the SO, this could provide a substrate on which such reactive
synaptogenesis could form a recurrent excitatory network. Certainly, the delay
(20&#x02013;30 ms) in the onset of the network depolarizations after
electrical stimulation (reported by Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>)) suggests that sprouted
excitatory input is polysynaptic, resulting from the recruitment of a relatively
remote population of neurons, as may be located in the IGL. Indeed, the
structure of the IGL is conducive to bursting activity because IGL neurons form
a recurrent collateral network in normal animals and produce long-lasting
synaptic responses in the presence of bicuculline (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.160">160</a>). The
network reorganization in the PN graft preparation (recorded <i>in
vitro</i> (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>)) is not that surprising, in view of the impact of
deafferentation in other structures, e.g., cerebral cortex (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.163">163</a>) or the
dentate gyrus of the hippocampus (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.164">164</a>). In both
cases, this process leads to sprouting of excitatory axons to form new recurrent
excitatory connections. One consequence of the reactive events found in most SC
slices (from PN graft repair preparation) is that they are likely to obscure
efficacy of regenerated RGC axons that had established monosynaptic connections
of retinorecipient neurons.</p></div><div id="ch33regeneration1.Impact_of_PN_Graft_R"><h3>Impact of PN Graft Repair Surgery on the SGL Function: The Future for Repair
Strategies</h3><p>It is clear from the work of Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>) that intrinsic changes in
response patterns will impact the way the SGL will function during visual
stimulation. Keirstead et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.8">8</a>)
demonstrated that, in comparison with normal controls, restoration of functional
retinal inputs into the SC, using the PN-graft method, had delays in the onset
of post-synaptic action (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.165">165</a>). This
delay probably reflects the fact that the underlying synaptic responses involve
the recruitment of recurrent excitatory connections. It may also reflect the
profound impact that GABAergic inhibition has in controlling this network. The
impact of visual deafferentation needs to be assessed throughout the SC to
identify the locus/loci of the reactive changes that underlie(s) altered network
behavior. In addition, for improvements in the current strategies of pathway
repair, there is the need to limit or reverse these deafferentation-induced
changes because: 1) this would allow a better assessment of the efficacy of new
connections; and 2) it would probably improve system function.</p><p>In conclusion, axonal regeneration to a target alone clearly does not guarantee
functional recovery. The study by Turner et al. (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.98">98</a>) highlights the fact that the
functional state of the target area is of fundamental importance for whether
normal function can be restored, once axonal reinnervation has been
achieved.</p></div></div><div id="ch33regeneration1.Evidence_for_Some_Le"><h2 id="_ch33regeneration1_Evidence_for_Some_Le_">Evidence for Some Level of Recovery of Function in the PN-bridged Retinofugal
Pathways</h2><p>The question of whether visual functions can be mediated by regenerated axons has
been explored by looking at: 1) the pupillary light reflex, a conditioned response;
2) EEG desynchronization; and 3) behavioral arousal. It was found that the
regenerated pathway could mediate pupillary constriction to light (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.166">166</a>). Additional
studies (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.167">167</a>) showed that
at best, the response amplitude and latency could be within normal range, but one
noticeable difference was that although in normals, repetitive stimulation gave
repeated responses of similar amplitude, regenerated pathways showed substantially
reduced amplitudes with successive stimulation. The conditioned response studied,
i.e., escape from a shuttle box in response to a light flash as a predictor of an
electric shock, showed that this task could be performed in rats with regenerated
optic input (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.168">168</a>). Finally,
animals were tested to demonstrate whether the regenerated pathways could mediate
EEG desynchronization behavior to light (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.169">169</a>). This
depended on the fact that, under normal conditions, rats show a slow wave sleep
pattern. A sensory stimulus, such as a flash of light or auditory signal,
desynchronizes this high-amplitude slow wave activity, replacing it with
low-amplitude, high-frequency activity. When presented with a light flash, blinded
rats do not show this response, but animals with nerve grafts connected into the SC
do. Associated with this, the rats also show a range of behavioral arousals.</p></div><div id="ch33regeneration1.Visual_Function_Asse"><h2 id="_ch33regeneration1_Visual_Function_Asse_">Visual Function Assessment</h2><p>Visual function runs at many levels from unconscious responses to perception. These
various functions are generally mediated through specific primary visual centers.
Unconscious responses include driving circadian rhythms (relayed through the
suprachiasmatic nucleus), photophobic responses (not specifically localized to any
specific visual center), pupillary light reflex (mediated by the olivary pretectal
nucleus), orienting responses (involving the SC), and head tracking to moving
stripes (involving the SC also, but requiring cortical input for higher spatial
frequencies). Perception requires elaborate decoding and integration of a set of
visual signals to achieve a representational image at the level of the cortex.</p><p>For some visually driven functions, such as circadian rhythms and photophobia, all
that is needed is to recognize a gradient, either temporal or spatial, of light and
dark. For the pupillary light reflex, ability to encode the light intensity is also
important, because the amount of pupillary constriction depends on brightness. For
orienting responses and head tracking, some level of topographic encoding must be
present. For perception, a much more elaborate degree of encoding must be achieved.
In any attempt to reconstruct the damaged visual system, or indeed to limit its
deterioration, the ideal is to recreate or preserve exactly the normal substrates of
the various visually driven behaviors. This is rarely possible and indeed may not
always be necessary. The CNS can sometimes adapt to an imperfect sensory input and
demonstrate a level of adaptation sufficient to achieve a normal response (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.170">170-173</a>):
even in an intact animal, the system is able to operate over a wide range of
luminance and contrast sensitivity (<a class="bk_pop" href="#ch33regeneration1.EXTYLES.174">174</a>). It is also
apparent, especially in conditions involving re-establishment of connections, that
specific visual responses can be modulated by associated events and may be
interdependent.</p><p>To reconstruct a particular function, therefore, it is necessary for axons to
innervate the appropriate brain region, subserving that function. Beyond this, it
may also be necessary for a topological representation of the retina to be resumed
within the region. Despite the likely neural circuit remodeling in a retinorecipient
nucleus previously devoid of visual inputs, information processing within this
particular nucleus should be relatively normal, and this becomes particularly
important when cortical functions are involved. Finally, the information must have
"significance" to the animal so that it can elaborate a suitable response strategy
or develop a percept.</p></div><div id="ch33regeneration1.AFN1"><h2 id="_ch33regeneration1_AFN1_">About the Authors</h2><p>
<div class="graphic"><img src="/books/NBK11507/bin/regeneration1fu1.jpg" alt="Image regeneration1fu1.jpg" /></div>
Dr. Yves Sauve was born in Montreal, Canada. He attended the
University of Montreal where he received his B.Sc. in Biochemistry in 1983
and his M.Sc. in Neuroscience in 1988 with Dr. Thomas Reader, focusing on
the neurochemistry of catecholamines and their receptors in the CNS. He then
obtained his Ph.D. in Physiology under Dr. Michael Rasminsky at McGill
University in 1995, where his research focused on the electrophysiological
evaluation of reformed synapses between regenerating RGC axons and neurons
in the superior colliculus, using the preparation developed in Dr. Albert
Aguayo's group. Dr. Sauve subsequently undertook postdoctoral studies with
Dr. Raymond Lund at the Institute of Ophthalmology (University College
London), where he developed electrophysiological approaches to evaluate
visual responsiveness in rodent models of retinal degeneration. In 2001, he
became assistant professor of Ophthalmology and Visual Sciences at the Moran
Eye Center (University of Utah), where he is currently evaluating rod and
cone function following retinal degeneration, transplant therapies, and
regeneration in the adult mammalian visual pathways.</p><p>
<div class="graphic"><img src="/books/NBK11507/bin/regeneration1fu2.jpg" alt="Image regeneration1fu2.jpg" /></div>
Dr. Frederic Gaillard was born in Tours, France. He attended
the University of Poitiers, where he received his B.Sc. (1969) and his M.Sc.
(1971) in physiology. He then obtained a Ph.D. (1975) and a
Doctorates-Sciences (1984) in neurophysiology. Until recently, most of his
studies focused on aspects of binocular information processing in the
amphibian visual system, mainly on the functional properties of the crossed
isthmo-tectal pathway. He is now examining host-graft relationships in the
adult mammalian visual system. Since 1977, Dr. Gaillard has been a senior
investigator (Charge de recherches) of the Centre National de la Recherche
Scientifique (CNRS) at the Institut de Physiologie et Biologie Cellulaires
(UMR 6187), Poitiers, France.</p></div><div id="ch33regeneration1.References"><h2 id="_ch33regeneration1_References_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.1">&#x0003e;Cajal SR. (1913&#x02013;1914). Estudios Sobre la Degeneraci&#x02014;n y
Regeneraci&#x02014;n del Sistema Nervioso. Madrid: Moya. Translated into
English as Degeneration and Regeneration of the Nervous System (R. M. May,
tran. and Ed.). London: Oxford University Press, 1928. Reprinted and edited
with additional translations by J. DeFelipe and E. G. Jones (), Cajal's
Degeneration and Regeneration of the Nervous System. New York: Oxford
University Press;1991.</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.2">Aguayo AJ, Rasminsky M, Bray GM, Carbonetto S, McKerracher L, Villegas-Perez MP, Vidal-Sanz M, Carter DA. Degenerative and regenerative responses of injured neurons in the
central nervous system of adult mammals. <span><span class="ref-journal">Philos Trans R Soc Lond B Biol Sci. </span>1991;<span class="ref-vol">331</span>:337–343.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1677478" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 1677478</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.3">So KF, Aguayo AJ. Lengthy regrowth of cut axons from ganglion cells after
peripheral nerve transplantation into the retina of adult
rats. <span><span class="ref-journal">Brain Res. </span>1985;<span class="ref-vol">328</span>:349–354.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3986532" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 3986532</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.4">Vidal-Sanz M, Bray GM, Villegas-Perez MP, Thanos S, Aguayo AJ. Axonal regeneration and synapse formation in the superior
colliculus by retinal ganglion cells in the adult rat. <span><span class="ref-journal">J Neurosci. </span>1987;<span class="ref-vol">7</span>:2894–2909.</span> [<a href="/pmc/articles/PMC6569122/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6569122</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/3625278" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 3625278</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.5">Tello F. La regeneration dans les voies optiques. <span><span class="ref-journal">Trab Lab Invest Biol Univ Madr. </span>1907;<span class="ref-vol">5</span>:237–248.</span></div></dd><dt>6.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.6">David S, Aguayo AJ. Axonal elongation into peripheral nervous system "bridges" after
central nervous system injury in adult rats. <span><span class="ref-journal">Science. </span>1981;<span class="ref-vol">214</span>:931–933.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6171034" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6171034</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.7">Richardson PM, McGuinness UM, Aguayo AJ. Axons from CNS neurons regenerate into PNS grafts. <span><span class="ref-journal">Nature. </span>1980;<span class="ref-vol">284</span>:264–265.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7360259" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7360259</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.8">Keirstead SA, Rasminsky M, Fukuda Y, Carter DA, Aguayo AJ, Vidal-Sanz M. Electrophysiologic responses in hamster superior colliculus
evoked by regenerating retinal axons. <span><span class="ref-journal">Science. </span>1989;<span class="ref-vol">246</span>:255–257.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2799387" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 2799387</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ch33regeneration1.EXTYLES.9">Sauve Y, Sawai H, Rasminsky M. Functional synaptic connections made by regenerated retinal
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK11507/?report=reader">PubReader</a></li><li><a href="/books/NBK11507/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK11507" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK11507" style="display:none" title="Cite this Page"><div class="bk_tt">Sauve Y, Gaillard F. Regeneration in the Visual System of Adult Mammals. 2005 May 1 [Updated 2007 Jun 21]. In: Kolb H, Fernandez E, Jones B, et al., editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK11507/pdf/Bookshelf_NBK11507.pdf">PDF version of this page</a> (3.2M)</li><li><a href="/books/n/webvision/pdf/">PDF version of this title</a> (235M)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ch33regeneration1.Introduction" ref="log$=inpage&amp;link_id=inpage">Introduction</a></li><li><a href="#ch33regeneration1.Reconstruction_of_Pr" ref="log$=inpage&amp;link_id=inpage">Reconstruction of Primary Visual Pathways</a></li><li><a href="#ch33regeneration1.Requirements_for_Rec" ref="log$=inpage&amp;link_id=inpage">Requirements for Recovery of Function following Lesions of CNS Pathways</a></li><li><a href="#ch33regeneration1.Promoting_the_Surviv" ref="log$=inpage&amp;link_id=inpage">Promoting the Survival of Axotomized RGCs</a></li><li><a href="#ch33regeneration1.Promoting_the_Growth" ref="log$=inpage&amp;link_id=inpage">Promoting the Growth of Axotomized RGC Axons</a></li><li><a href="#ch33regeneration1.Guidance_of_Regenera" ref="log$=inpage&amp;link_id=inpage">Guidance of Regenerating RGC Axons Toward Their Appropriate Target</a></li><li><a href="#ch33regeneration1.Arborization_and_Syn" ref="log$=inpage&amp;link_id=inpage">Arborization and Synapse Formation by RGC Axons Regenerating into Their CNS
Targets</a></li><li><a href="#ch33regeneration1.Generation_of_Action" ref="log$=inpage&amp;link_id=inpage">Generation of Action Potentials in Target Neurons</a></li><li><a href="#ch33regeneration1.Restoration_of_Retin" ref="log$=inpage&amp;link_id=inpage">Restoration of Retinotopy</a></li><li><a href="#ch33regeneration1.Preservation_of_Loca" ref="log$=inpage&amp;link_id=inpage">Preservation of Local and Downstream Circuitry</a></li><li><a href="#ch33regeneration1.Evidence_for_Some_Le" ref="log$=inpage&amp;link_id=inpage">Evidence for Some Level of Recovery of Function in the PN-bridged Retinofugal
Pathways</a></li><li><a href="#ch33regeneration1.Visual_Function_Asse" ref="log$=inpage&amp;link_id=inpage">Visual Function Assessment</a></li><li><a href="#ch33regeneration1.AFN1" ref="log$=inpage&amp;link_id=inpage">About the Authors</a></li><li><a href="#ch33regeneration1.References" ref="log$=inpage&amp;link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related Items in Bookshelf</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://www.ncbi.nlm.nih.gov/books?term=%22reference%20works%22%5BResource%20Type%5D" ref="pagearea=source-links&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">All 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