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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="Fetal Tissue Allografts in the Central Visual System of Rodents" /><meta name="citation_publisher" content="University of Utah Health Sciences Center" /><meta name="citation_date" content="2007/06/25" /><meta name="citation_author" content="Frederic Gaillard" /><meta name="citation_author" content="Yves Sauve" /><meta name="citation_pmid" content="21413373" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK11505/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Fetal Tissue Allografts in the Central Visual System of Rodents" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Utah Health Sciences Center" /><meta name="DC.Contributor" content="Frederic Gaillard" /><meta name="DC.Contributor" content="Yves Sauve" /><meta name="DC.Date" content="2007/06/25" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK11505/" /><meta name="description" content="Injury to the brain areas concerned with vision can cause a variety of disorders ranging from visual field defects to much more complex deficits, such as visual agnosia. It all depends on the location and the extent of the damage. Injury to the occipital striate cortex results in corresponding homonymous visual field defects where typically all visual capacities are lost in the fields. Injury to occipito-temporal structures can affect discrimination, selection, and recognition of visual stimulus dimensions and, at higher stages of processing, of objects, faces, scenes, and letters (for review, see Zihl (1)) (Fig. 1)." /><meta name="og:title" content="Fetal Tissue Allografts in the Central Visual System of Rodents" /><meta name="og:type" content="book" /><meta name="og:description" content="Injury to the brain areas concerned with vision can cause a variety of disorders ranging from visual field defects to much more complex deficits, such as visual agnosia. It all depends on the location and the extent of the damage. Injury to the occipital striate cortex results in corresponding homonymous visual field defects where typically all visual capacities are lost in the fields. Injury to occipito-temporal structures can affect discrimination, selection, and recognition of visual stimulus dimensions and, at higher stages of processing, of objects, faces, scenes, and letters (for review, see Zihl (1)) (Fig. 1)." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK11505/" /><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/ch34regeneration2/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK11505/" /><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="#__NBK11505_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK11505_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&targetsite=external&targetcat=link&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/ch33regeneration1/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/webvision/electroretinography/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK11505_"><span class="title" itemprop="name">Fetal Tissue Allografts in the Central Visual System of Rodents</span></h1><p class="contrib-group"><span itemprop="author">Frederic Gaillard</span> and <span itemprop="author">Yves Sauve</span>.</p><p class="small">Created: <span itemprop="datePublished">May 1, 2005</span>; Last Update: <span itemprop="dateModified">June 25, 2007</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ch34regeneration2.Introduction"><h2 id="_ch34regeneration2_Introduction_">Introduction</h2><p>Injury to the brain areas concerned with vision can cause a variety of disorders ranging
|
||
from visual field defects to much more complex deficits, such as visual agnosia. It all
|
||
depends on the location and the extent of the damage. Injury to the occipital striate cortex
|
||
results in corresponding homonymous visual field defects where typically all visual
|
||
capacities are lost in the fields. Injury to occipito-temporal structures can affect
|
||
discrimination, selection, and recognition of visual stimulus dimensions and, at higher
|
||
stages of processing, of objects, faces, scenes, and letters (for review, see Zihl (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.1">1</a>)) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F1/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F1" rid-ob="figobch34regeneration2F1">Fig. 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F1" co-legend-rid="figlgndch34regeneration2F1"><a href="/books/NBK11505/figure/ch34regeneration2.F1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F1" rid-ob="figobch34regeneration2F1"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f1.gif" src-large="/books/NBK11505/bin/regeneration2f1.jpg" alt="Figure 1. Visual deficits in human and related injured brain regions." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F1"><h4 id="ch34regeneration2.F1"><a href="/books/NBK11505/figure/ch34regeneration2.F1/?report=objectonly" target="object" rid-ob="figobch34regeneration2F1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Visual deficits in human and related injured brain regions. A, visual
|
||
location (lateral occipital gyrus). B, motion blindness (middle temporal gyrus). C,
|
||
achromatopsia (occipito-temporal gyrus). D, visual agnosia (posterior and medial
|
||
temporo-occipital <a href="/books/NBK11505/figure/ch34regeneration2.F1/?report=objectonly" target="object" rid-ob="figobch34regeneration2F1">(more...)</a></p></div></div><p>Since the 1970s, numerous investigations have focused on trying to restore lost function by
|
||
replacement of injured brain structures with homologous, allogeneic, embryonic neural
|
||
tissue. Such approaches have even reached the clinical level as a therapy for the treatment
|
||
of some neurological disorders such as Parkinson's and Huntington's diseases. With the
|
||
exception of these specific cases, though, we are not yet ready to go to the clinic.
|
||
Intracerebral grafting presently remains an experimental model used to address fundamental
|
||
questions concerning brain development, neuronal plasticity, regeneration, and formation of
|
||
topographic connections. The latter is a minimal requirement for functional recovery in
|
||
point-to-point sensory systems such as the visual system (see previous chapter).</p><p>Putting fetal brain tissue grafts in the mature central nervous system (CNS) differs from
|
||
peripheral nerve (PN) grafting in at least the following two ways. First, although a PN
|
||
graft is used to bridge two brain areas, an intracerebral embryonic tissue graft is meant to
|
||
restore the function of the damaged area. The fetal grafted tissue must develop its own set
|
||
of connections with the right structures in the host brain, and these connections must be
|
||
orderly arranged. Second, although all elements in PN grafting are at the same age, the
|
||
intracerebral embryonic tissue graft is heterochronic with respect to the host tissue. For a
|
||
short period after implantation, grafted tissue behaves as an immature piece of brain.
|
||
Theoretically, this immature status should allow circuitry reconstruction. Donor embryonic
|
||
cells have a greater potential for axonal outgrowth and regeneration than mature host
|
||
neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.2">2</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.3">3</a>). Thus, they may be better at
|
||
establishing contacts with host target cells. Furthermore, the fetal graft may produce
|
||
trophic factors or signaling cues, which are present in the brain only at early
|
||
developmental stages, and should reactivate neurotropic processes in "dormant" host neuron
|
||
populations. For instance, embryonic cortical transplants will produce NT-3, which is absent
|
||
from the cortex past 2 weeks of age (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.4">4</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.5">5</a>). In vitro
|
||
assays (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.6">6</a>) have shown that
|
||
NT-3 has dual effects on layer 2-3 and layer 6 cortical neurons. Fifteen days after implant,
|
||
cortical grafts will also produce a glial cell line-derived neurotrophic factor (GDNF), a
|
||
potent survival factor for claustral neurons that project to the occipital cortex (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.7">7</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.8">8</a>).</p><p>Unfortunately, there is abundant literature suggesting that environmental constraints from
|
||
the mature host brain alter the restorative capacities of fetal grafts in various ways.
|
||
First, the mature environment affects both the number of surviving neurons within a graft
|
||
and the size of the graft itself (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.9">9-12</a>). Second, the mature CNS environment is non-permissive for axonal
|
||
regeneration of host neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.13">13-17</a>) (see section 2 from the previous chapter). Third, the mature CNS
|
||
environment is poorly permissive for receiving outgrowing axons from embryonic allogeneic
|
||
neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.18">18-23</a>).</p><p>These above-mentioned results suggest that intracerebral embryonic tissue grafts might only
|
||
be effective in "diffuse" projection systems, i.e., by exerting a paracrine effect (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.24">24-28</a>). In opposition to this,
|
||
a few investigations have demonstrated that such grafts can restore, at least partially,
|
||
complex motor behaviors (skilled forelimb reaching for food) that require a precise
|
||
interaction between neuronal circuits, much more than expected of paracrine effects (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.19">19</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.29">29</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.30">30</a>). However, even in such reports, the donor
|
||
neurons appear to establish a very limited number of connections with the host.</p><p>Pioneer work in the visual system model was done in the mid-1970s by Drs. Raymond Lund and
|
||
Alan Harvey and colleagues, who transplanted parts of the embryonic CNS to various brain
|
||
locations in neonatal rats (for a review, see Lund (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.31">31</a>)). Most of their studies were focused on CNS
|
||
development and, therefore, consisted of examining whether such grafts developed near-normal
|
||
architecture and established extensive connections with appropriate host structures. The
|
||
outcome of fetal grafts into adult hosts has been studied less extensively, but a limited
|
||
number of reports suggest that fetal tissues can integrate functionally within the adult
|
||
host CNS. We will review these investigations that, in contrast to the mainstream opinion,
|
||
show that tectal and cortical allografts can receive highly ordered inputs and can project
|
||
to distant visual targets in the adult brain.</p></div><div id="ch34regeneration2.The_Visual_System_of"><h2 id="_ch34regeneration2_The_Visual_System_of_">The Visual System of Rodents: A Brief Overview</h2><p>Unless reconstruction of neural circuitries comparable to normal in terms of amount,
|
||
extension, and topical organization are achieved, we cannot expect complete functional
|
||
recovery in point-to-point neural systems. The normal structural and functional organization
|
||
of the visual system of adult rodents has been investigated extensively and now forms a
|
||
basis for regeneration experiments (for reviews, see Sefton and Dreher (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.32">32</a>), Zilles and Wree (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.33">33</a>), and Sefton et al (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.34">34</a>)). A brief summary of the
|
||
major findings is given below for comparative purposes.</p><div id="ch34regeneration2.Retinal_Output"><h3>Retinal Output</h3><p>In the adult rat, virtually all (>95%) retinal ganglion cells (RGCs) project
|
||
contralaterally to the superior colliculus (SC) and to the dorsal division of the lateral
|
||
geniculate nucleus (DLG). In the SC, axons from the retina enter at the level of the
|
||
stratum opticum (SO) and arborize in the SO and the superficial gray layer (SGL). Dense
|
||
terminals are also found in lateral posterior nucleus, LP; ventral division of the lateral
|
||
geniculate nucleus, magnocellular part, VLG; intergeniculate leaflet, IGL; and pretectal
|
||
nuclei (nucleus of the optic tract, OT; olivary pretectal nucleus, OPT; posterior
|
||
pretectal nucleus, PPT). Some of these inputs (30-50%) are collateral branches of
|
||
retinocollicular axons. A small contingent (<5%) of the RGCs contacts the same
|
||
structures ipsilaterally. Thus, each retinorecipient center receives input from both eyes.
|
||
Sparse projections are found in the suprachiasmatic nucleus (SCN), the various nuclei of
|
||
the accessory optic system, the hypothalamus, and the inferior colliculus. A schematic
|
||
view of these connections is given in Fig. 6 of the previous chapter.</p></div><div id="ch34regeneration2.Subcortical_Network"><h3>Subcortical Network</h3><p>The DLG is much more than a relay center for RGC projections to the cortex. In fact, it
|
||
receives most of its input from structures other than the retina, namely the visual
|
||
thalamic reticular nucleus (Rt), layer 6 small pyramidal neurons in the occipital cortex
|
||
(areas 17, 18, 18a; also called, respectively, areas Oc1, Oc2M, Oc2L; or areas V1, V2M,
|
||
V2L), the SC (SGL layer), some pretectal nuclei (OT, OPT), and the contralateral
|
||
parabigeminal nucleus (PBg), a homolog of the isthmo-optic nucleus in lower vertebrates.
|
||
Projections arising from relay cells in the DLG are restricted to Rt (dorsal part) and
|
||
occipital cortex.</p><p>The retinorecipient layers of the SC have reciprocal connections with the VLG, the
|
||
pretectum, and the ipsilateral PBg nucleus (ventral and dorsal divisions). They receive
|
||
further afferents from the contralateral PBg and from layer 5 pyramidal neurons in the
|
||
visual cortex. Major efferents go to the DLG, the LP thalamic nucleus, and to the
|
||
intermediate (IGL) and deep (DpL) gray layers of the SC, where other sensory systems are
|
||
represented. The LP nucleus (equivalent of the LP-pulvinar in cats and of the pulvinar in
|
||
primates) has reciprocal connections with visual (mainly Oc2L, layers 5 and 6) and
|
||
temporal areas in the ipsilateral cortex. The LP receives additional inputs from the Rt,
|
||
zona incerta (ZI), and the pretectum (OT). Neurons in the IGL and DpL layers of the SC
|
||
project to various structures in the pons, brain stem, cervical spinal cord, and
|
||
hypothalamus.</p><p>The VLG has reciprocal connections with the pretectum (OT, OPT and APT, the anterior
|
||
pretectal nucleus), SC (SGL and SO layers), and its contralateral homolog. It receives
|
||
further projection from the occipital cortex (layer 5 neurons) and projects to the ZI,
|
||
central gray, pons, and the suprachiasmatic nucleus (SCN). Finally, in addition to retinal
|
||
and collicular inputs, the pretectum receives cortical afferents from the occipital cortex
|
||
and projects to the LP, to the adjacent lateraldorsal (LD) thalamic nucleus (which has
|
||
reciprocal connections with the occipital cortex), and to the pons (largely to the
|
||
reticulotegmental nucleus) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F2/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F2" rid-ob="figobch34regeneration2F2">Fig. 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F2" co-legend-rid="figlgndch34regeneration2F2"><a href="/books/NBK11505/figure/ch34regeneration2.F2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F2" rid-ob="figobch34regeneration2F2"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f2.gif" src-large="/books/NBK11505/bin/regeneration2f2.jpg" alt="Figure 2. Major ipsilateral connections (designed as arrows) of the visual cortex of rodents." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F2"><h4 id="ch34regeneration2.F2"><a href="/books/NBK11505/figure/ch34regeneration2.F2/?report=objectonly" target="object" rid-ob="figobch34regeneration2F2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Major ipsilateral connections (designed as arrows) of the visual cortex of
|
||
rodents. Green-coded connections are valid for all areas. Specific, additional
|
||
connections for Oc1 (area 17) are white coded; those for Oc2M (area 18) are red coded;
|
||
and those <a href="/books/NBK11505/figure/ch34regeneration2.F2/?report=objectonly" target="object" rid-ob="figobch34regeneration2F2">(more...)</a></p></div></div></div><div id="ch34regeneration2.Cortical_Network"><h3>Cortical Network</h3><p>Afferents to cortical area Oc1 originate predominantly from the three thalamic relay
|
||
nuclei: DLG, LP, and LD. Termination sites are localized in layers 4, lower 3, 6, and 1.
|
||
Other thalamic sources are the posterior complex (Po), ventromedian (VM), centromedian
|
||
(CM), and the ventrolateral (VL) nuclei. Projections from Po and VM terminate in layer 1;
|
||
those from CM and VL in layers 1 and 6. Further afferents are provided by frontal (Fr2),
|
||
temporal (Te1-2), retrosplenial (RSA/RSG), perirhinal (PRh), and adjacent visual areas in
|
||
the ipsilateral cortex. With respect to this scheme, area Oc2M receives no afferent from
|
||
Te2 and PRh but an additional input from orbital cortical areas (MO/VO/VLO), whereas area
|
||
Oc2L receives no afferent from Te1 and PRh but an additional input from the hindlimb
|
||
region (HL) in the sensorimotor cortex. Afferents from the claustrum (CL) are mostly
|
||
distributed in the infragranular layers of Oc1 and/or Oc2M areas (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.35">35</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.36">36</a>). Oc1-2 areas also receive some callosal
|
||
inputs from visual areas (layer 2-3 and 5-6 neurons) in the opposite cortex. Callosal
|
||
terminations extend throughout the cortical depth at the borders of area Oc1 and adjacent
|
||
extrastriate areas as well as in multiple patches through Oc2M-L areas. Prominent labeling
|
||
also occurs in the infragranular layers of the temporal cortex. Finally, the visual cortex
|
||
and subcortical retinorecipient nuclei both receive nonspecific cholinergic,
|
||
noradrenergic, and serotonergic innervations from various structures in the basal
|
||
forebrain, from locus coeruleus (LC) and from dorsal raphe nuclei (DR), respectively.</p><p>In addition to reciprocal connections, visual cortical areas have widespread ipsilateral
|
||
projections through the normal adult brain. At the cortical level, efferents from area Oc1
|
||
are found into the dorsomedial frontal area Fr2 (layers 1 and 6), the ventrolateral
|
||
orbital area (VLO), the retrosplenial areas (layers 1 and 6), the perirhinal area (layer
|
||
5-6, up to the caudalmost pole of the cortex), and the entorhinal cortex. Additional
|
||
efferents originating from area Oc2M are observed in the cingulate area Cg1, the parietal
|
||
areas S1-2 (caudal part; layers 1-3 and 6), the temporal areas Te1-3 (layer 1-3 and 6,
|
||
mainly), and the claustrum (full extent). Efferents from area Oc2L also target the dorsal
|
||
half of the prelimbic cortex (PrL area) as well as lateral, basal, and central amygdaloid
|
||
nuclei (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.37">37</a>). Projections
|
||
from Oc2 areas to Fr2 and Cg1 extend up to the rostralmost pole of the cortex. At the
|
||
subcortical level, Oc1 and Oc2 areas have dense terminals in hippocampal structures
|
||
(presubiculum, PrS; and parasubiculum, PaS), striatum (the dorsomedial portion) (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.38">38</a>), visual thalamic nuclei
|
||
(DLG, VLG, LP/LD, Po, Rt), ZI, various pretectal nuclei (P-TECT), SGL and IGL layers of
|
||
the SC, and pontine nuclei (dorsolateral division) (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.39">39</a>). Contralateral projections are confined to
|
||
Oc1-2 and Te1 areas as well as, but sparsely, to the dorsomedial sector of the striatum
|
||
and the dorsolateral subdivision of the amygdala.</p></div><div id="ch34regeneration2.Visual_Field_Topogra"><h3>Visual Field Topography</h3><p>Retinofugal axons arising in different retinal quadrants maintain their relative
|
||
positions in the optic nerve, lose this initial order as they progress toward the chiasm,
|
||
and reform a distinct dorsal-ventral arrangement in the optic tract before reaching
|
||
primary visual targets, where they terminate in a precise topographic manner (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.40">40-43</a>). Retinotopy in visual
|
||
centers was first seen by Lashley (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.44">44</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.45">45</a>) and then abundantly documented by both
|
||
electrophysiological and anatomical approaches (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.46">46-52</a>). Recently, optical imaging techniques
|
||
have confirmed all previous findings (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.53">53</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.54">54</a>). A schematic representation of the visual
|
||
field topography onto the DLG, SC, and visual cortex is given below (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3">Fig. 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F3" co-legend-rid="figlgndch34regeneration2F3"><a href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f3.gif" src-large="/books/NBK11505/bin/regeneration2f3.jpg" alt="Figure 3. Schematic representation of the right visual field topography onto the DLG, SC, and visual cortex of normal rats." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F3"><h4 id="ch34regeneration2.F3"><a href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-ob="figobch34regeneration2F3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Schematic representation of the right visual field topography onto the DLG,
|
||
SC, and visual cortex of normal rats. Color code: red, upper nasal field; pink, upper
|
||
temporal field; deep blue, lower nasal field; sky blue, lower temporal field.
|
||
Subdivisions <a href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-ob="figobch34regeneration2F3">(more...)</a></p></div></div><p>At the geniculate level (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3">Fig. 3</a>, A
|
||
and D), the nasal field (temporal retina) is represented caudally and dorsomedially; the
|
||
temporal field (nasal retina) occupies most of the rostral part of the nucleus; the lower
|
||
field (upper retina) is mostly represented in the caudal part of the nucleus,
|
||
lateroventrally; and the upper field (lower retina) projects mainly to the rostral part of
|
||
the nucleus, dorsally. The dorsomedial part of the DLG also receives input from the lower
|
||
temporal quadrant (red sector; <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3">Fig.
|
||
3</a>B) of the ipsilateral retina. On the contralateral SC (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3">Fig. 3</a>, A and C), the nasal visual field is mapped
|
||
rostrally; the temporal visual field, caudally; the upper field, medially; and the lower
|
||
field, laterally. In rats, the representation of the central visual field is not
|
||
substantially magnified. The ipsilateral retinal contingent projects anteromedially (red
|
||
sector; <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F3/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F3" rid-ob="figobch34regeneration2F3">Fig. 3</a>B).</p><p>At the cortical level (area Oc1/17), the naso-temporal axis of the visual field projects
|
||
from lateral to medial, the lower field (upper retina) projects rostrally, and the upper
|
||
field projects caudally. A restricted caudal region of area Oc1 receives input from the
|
||
ipsilateral retina. The vertical meridian (body axis) is set at the border between area 17
|
||
and area 18. Beyond this point, the naso-temporal direction is inverted. Borderline zones
|
||
in areas 17 and 18 contain binocular neurons. Multiple ordered representations of the
|
||
visual field are present in the adjacent extrastriate areas (for discussion, see Rosa and
|
||
Krubitzer (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.55">55</a>)).</p></div></div><div id="ch34regeneration2.Standard_Strategy_fo"><h2 id="_ch34regeneration2_Standard_Strategy_fo_">Standard Strategy for Intracerebral Transplantation: Graft Morphology</h2><p>Grafts usually consist of blocks or sheets of neural tissue excised from 15-16-day-old
|
||
(E15-16) embryos, which are put into previously surgically made cavities in the host. Older
|
||
grafts survive poorly and have reduced size (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.56">56</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.57">57</a>). Although not critical for axonal sprouting
|
||
(see below), delayed implantation has been assumed to enhance cell survival and outgrowth
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.58">58-60</a>), probably because
|
||
endogenous neurotrophic factors can accumulate at the lesion site (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.61">61</a>) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F4/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F4" rid-ob="figobch34regeneration2F4">Fig. 4</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F4" co-legend-rid="figlgndch34regeneration2F4"><a href="/books/NBK11505/figure/ch34regeneration2.F4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F4" rid-ob="figobch34regeneration2F4"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f4.gif" src-large="/books/NBK11505/bin/regeneration2f4.jpg" alt="Figure 4. Basic transplantation protocols." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F4"><h4 id="ch34regeneration2.F4"><a href="/books/NBK11505/figure/ch34regeneration2.F4/?report=objectonly" target="object" rid-ob="figobch34regeneration2F4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Basic transplantation protocols. A, for current anatomical studies. Blocks of
|
||
embryonic tissue were implanted in aspirated lesion cavities performed in the host brain
|
||
3 days earlier. B, used by Girman (71) for
|
||
electrophysiological recordings. Grafts are <a href="/books/NBK11505/figure/ch34regeneration2.F4/?report=objectonly" target="object" rid-ob="figobch34regeneration2F4">(more...)</a></p></div></div><p>As in newborns (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.62">62</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.63">63</a>), primary connections with
|
||
the host brain appear 3-4 days after transplantation (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.64">64</a>), whereas neovascularization and blood supply
|
||
require approximately another week to be completed, a delay that may seriously hamper graft
|
||
cell metabolism (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.65">65</a>).
|
||
Nonetheless, both graft implantation and development in adults can be as successful as in
|
||
neonate recipients (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.62">62</a>,
|
||
<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.67">67</a>). Investigations are usually performed 3-4
|
||
months after grafting.</p><p>In serial histological sections, all implants look like disorganized cellular masses that
|
||
are more or less clearly separated from the host tissue by a region of lower cell density or
|
||
host white matter. Glial scarring at the host-graft interface, although highly variable, is
|
||
usually minimal (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.60">60</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.68">68</a>). At this time point, graft
|
||
development is achieved. Most neurons in cortical grafts (60-80%) seem mature (expression of
|
||
Hu/Elav proteins) (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>) and
|
||
look "normal" at the ultrastructural level (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.69">69</a>). The remaining neurons have immature
|
||
characteristics, such as multiple nucleoli or binuclear somas (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.60">60</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.70">70</a>) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F5/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F5" rid-ob="figobch34regeneration2F5">Fig. 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F5" co-legend-rid="figlgndch34regeneration2F5"><a href="/books/NBK11505/figure/ch34regeneration2.F5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F5" rid-ob="figobch34regeneration2F5"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f5.gif" src-large="/books/NBK11505/bin/regeneration2f5.jpg" alt="Figure 5. A and B, typical cellular aspect of tectal (from Girman (71)) and occipital (from Domballe et al." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F5"><h4 id="ch34regeneration2.F5"><a href="/books/NBK11505/figure/ch34regeneration2.F5/?report=objectonly" target="object" rid-ob="figobch34regeneration2F5">Figure 5</a></h4><p class="float-caption no_bottom_margin">A and B, typical cellular aspect of tectal (from Girman (71)) and occipital
|
||
(from Domballe et al. (66)) grafts 3 months
|
||
after grafting. Nissl staining. C and D, graft vascularization as observed in wild-type
|
||
E15 mouse cortical tissue grafted in an adult <a href="/books/NBK11505/figure/ch34regeneration2.F5/?report=objectonly" target="object" rid-ob="figobch34regeneration2F5">(more...)</a></p></div></div><p>A typical feature of fetal tectal tissue transplants in adult hosts is the presence of
|
||
dorsally located, myelinated "fiber-free" areas (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F6" rid-ob="figobch34regeneration2F6">Fig. 6</a>). In addition,
|
||
there is a proponderance of cells with small perikarya and short dendrites (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.67">67</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.71">71</a>), a relatively high acetylcholinesterase
|
||
(AChE) activity, a high concentration of alpha-bungarotoxin binding sites, and a low number
|
||
of neuroglial elements (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.57">57</a>,
|
||
<a class="bk_pop" href="#ch34regeneration2.EXTYLES.72">72-74</a>). Similar
|
||
characteristics are found in the retinorecipient layers of the SC in normal rats. In neonate
|
||
hosts, the "fiber-free" layer over the "fiber-rich" core of the graft (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F6" rid-ob="figobch34regeneration2F6">Fig. 6</a>) is penetrated by regenerated retinal afferents
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.75">75</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.76">76</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F6" co-legend-rid="figlgndch34regeneration2F6"><a href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F6" rid-ob="figobch34regeneration2F6"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f6.gif" src-large="/books/NBK11505/bin/regeneration2f6.jpg" alt="Figure 6. Typical morphological features of embryonic tectal grafts (sheets of tissue) in neonate hosts." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F6"><h4 id="ch34regeneration2.F6"><a href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" rid-ob="figobch34regeneration2F6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Typical morphological features of embryonic tectal grafts (sheets of tissue)
|
||
in neonate hosts. A, Holmes neurofibrillar staining. Note the fiber-free (ff) area
|
||
covering the fiber-rich core of the graft (T). B, Nissl staining. C, widespread retinal
|
||
input <a href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" rid-ob="figobch34regeneration2F6">(more...)</a></p></div></div><p>Grafts of blocks of fetal cortex lack the typical layered organization when integrating
|
||
into the host CNS. Neurons are 60-80% of the normal density and gathered into clusters
|
||
separated by myelinated bundles (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F7/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F7" rid-ob="figobch34regeneration2F7">Fig. 7</a>, A-C). They also contain high number of
|
||
neuroglial and microglial cells (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.69">69</a>). Regardless of their
|
||
origin, cortical grafts typically receive diffuse cholinergic and aminergic input, mostly in
|
||
their lower part, near the corpus callosum (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.77">77-79</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F7" co-legend-rid="figlgndch34regeneration2F7"><a href="/books/NBK11505/figure/ch34regeneration2.F7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F7" rid-ob="figobch34regeneration2F7"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f7.gif" src-large="/books/NBK11505/bin/regeneration2f7.jpg" alt="Figure 7. Gross morphology of cortical grafts." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F7"><h4 id="ch34regeneration2.F7"><a href="/books/NBK11505/figure/ch34regeneration2.F7/?report=objectonly" target="object" rid-ob="figobch34regeneration2F7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Gross morphology of cortical grafts. A, absence of lamination. Cresyl violet
|
||
staining. B, typical cell cluster (inset in A). C, intragraft myelin sheets (arrows).
|
||
Luxol blue staining. D, distribution of the soma sizes in the normal rat cortex,
|
||
responsive <a href="/books/NBK11505/figure/ch34regeneration2.F7/?report=objectonly" target="object" rid-ob="figobch34regeneration2F7">(more...)</a></p></div></div><p>Although roughly similar at a first glance, different cortical grafts show differences in
|
||
their neuronal phenotypes. On the basis of Golgi-Cox stained material, Aleksandrova and
|
||
Girman (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.80">80</a>) proposed a three-group
|
||
classification:</p><ul><li id="A4242" class="half_rhythm"><div>Type I: grafts contain multiple neuron morphologies resembling those in the normal
|
||
cortex. The small layer 2-3 pyramids have small or medium perikarya (10-16 and 20-26
|
||
μm in diameter, respectively) and apical dendrites running for considerable
|
||
distances along the graft boundary with unpredictable orientations.</div></li><li id="A4243" class="half_rhythm"><div>Type II: grafts contain a single class of multipolar neuron with oval or pyriform soma,
|
||
a short apical dendrite, and several thick processes. Soma sizes are typically large or
|
||
hypertrophied, ranging between 16 and 50 μm in diameter (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F7/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F7" rid-ob="figobch34regeneration2F7">Fig. 7</a>D).</div></li><li id="A4244" class="half_rhythm"><div>Type III: grafts have intermediate characteristics. In addition to the neuronal
|
||
phenotypes found in the first group, one-third of the neurons have large somas (30-32
|
||
μm in diameter). Interestingly, whereas type I and III graft neurons respond
|
||
to visual stimuli (see below), type II graft neurons do not, displaying only highly
|
||
synchronized, burst-like spontaneous discharges (Fig. 10). It remains to be clarified
|
||
whether unresponsiveness is linked to abnormal neuron morphology or lack of input(s), or
|
||
both (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.81">81</a>).</div></li></ul></div><div id="ch34regeneration2.Neurons_within_the_T"><h2 id="_ch34regeneration2_Neurons_within_the_T_">Neurons within the Transplant Can Be Driven by Host Eye Visual Stimulation</h2><p>What we learned from the above-mentioned and other histological studies is that fetal
|
||
tissue blocks grafted in a mature brain will never develop the specific architecture of the
|
||
normal tissue that they replace. They lack continuity with the host tissue, intrinsic
|
||
laminar organization, and neuronal arrangement in columns. Structural disorganization,
|
||
however, does not prevent the formation of synapses able to excite grafted neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.69">69</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.82">82-86</a>).
|
||
Girman and Golovina (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.87">87</a>) provided indisputable
|
||
evidence that both transplanted tectal and cortical neurons can respond to visual stimuli
|
||
presented to the adult host eye.</p><div id="ch34regeneration2.Tectal_Graft_Respons"><h3>Tectal Graft Responsiveness</h3><p>Girman (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.71">71</a>) reported good visual
|
||
activity in about half of the tectal implants. Spontaneously active at rest, single-units
|
||
respond to flashing light spots as well as to stationary and manually moved targets (5-16
|
||
degrees in diameter) with circular receptive fields (RFs). Best responses are obtained
|
||
with small (3-5 degrees in diameter) black disks moved on a white background. Some units
|
||
(29%) are direction selective. Response latencies to flashing spots (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F8/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F8" rid-ob="figobch34regeneration2F8">Fig. 8</a>) are in the
|
||
normal range. Tactile and auditory stimuli are ineffectual. No visual response can be
|
||
recorded in cortical tissue grafts placed at the tectal level.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F8" co-legend-rid="figlgndch34regeneration2F8"><a href="/books/NBK11505/figure/ch34regeneration2.F8/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F8" rid-ob="figobch34regeneration2F8"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f8.gif" src-large="/books/NBK11505/bin/regeneration2f8.jpg" alt="Figure 8. Neuronal discharges in visually responsive (A) and unresponsive (B) tectal grafts in response to light flashes (s)." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F8"><h4 id="ch34regeneration2.F8"><a href="/books/NBK11505/figure/ch34regeneration2.F8/?report=objectonly" target="object" rid-ob="figobch34regeneration2F8">Figure 8</a></h4><p class="float-caption no_bottom_margin">Neuronal discharges in visually responsive (A) and unresponsive (B) tectal
|
||
grafts in response to light flashes (s). PSTH for 30 presentations. E, excitatory phase;
|
||
I, inhibitory phase. Time bin: 1 ms. Redrawn from Girman (71). C, stimulating
|
||
electrodes <a href="/books/NBK11505/figure/ch34regeneration2.F8/?report=objectonly" target="object" rid-ob="figobch34regeneration2F8">(more...)</a></p></div></div></div><div id="ch34regeneration2.Cortical_Graft_Respo"><h3>Cortical Graft Responsiveness</h3><p>Both field potential (FP) and single-unit recordings have been done in types I and III
|
||
cortical grafts. FPs in grafts always consist of a negative/positive component. Wave onset
|
||
and peak have normal latencies (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.87">87-89</a>).
|
||
However, it is interesting to note that none of the FPs undergo polarity reversal with
|
||
depth, as occus in the normal rat primary visual cortex (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.90">90</a>), and peak amplitudes
|
||
correlate with the density of afferents (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F9/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F9" rid-ob="figobch34regeneration2F9">Fig. 9</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F10/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F10" rid-ob="figobch34regeneration2F10">Fig. 10</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F9" co-legend-rid="figlgndch34regeneration2F9"><a href="/books/NBK11505/figure/ch34regeneration2.F9/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F9" rid-ob="figobch34regeneration2F9"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f9.gif" src-large="/books/NBK11505/bin/regeneration2f9.jpg" alt="Figure 9. A, field potential mapping in a large occipital tissue graft." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F9"><h4 id="ch34regeneration2.F9"><a href="/books/NBK11505/figure/ch34regeneration2.F9/?report=objectonly" target="object" rid-ob="figobch34regeneration2F9">Figure 9</a></h4><p class="float-caption no_bottom_margin">A, field potential mapping in a large occipital tissue graft. Low responses
|
||
are from the medial yellowish area devoid of thalamic afferents (see Fig. 10). Note the
|
||
wave reversal with depth (400 <i>versus</i> 100 μm) in the
|
||
adjacent host cortex (point <a href="/books/NBK11505/figure/ch34regeneration2.F9/?report=objectonly" target="object" rid-ob="figobch34regeneration2F9">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F10" co-legend-rid="figlgndch34regeneration2F10"><a href="/books/NBK11505/figure/ch34regeneration2.F10/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F10" rid-ob="figobch34regeneration2F10"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f10.gif" src-large="/books/NBK11505/bin/regeneration2f10.jpg" alt="Figure 10. Thalamic input to the preceeding graft (see Fig." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F10"><h4 id="ch34regeneration2.F10"><a href="/books/NBK11505/figure/ch34regeneration2.F10/?report=objectonly" target="object" rid-ob="figobch34regeneration2F10">Figure 10</a></h4><p class="float-caption no_bottom_margin">Thalamic input to the preceeding graft (see Fig. 9A) is restricted to the
|
||
most responsive area. A, biotinylated dextran amine (BDA) injection confined mostly to
|
||
the LP nucleus (dotted line, lower inset). Strong projections are present in the host
|
||
cortex <a href="/books/NBK11505/figure/ch34regeneration2.F10/?report=objectonly" target="object" rid-ob="figobch34regeneration2F10">(more...)</a></p></div></div><p>Although recording field potentials is useful for delineating the graft outer limits and
|
||
the most active zones within the graft for tracer injections, field potentials do not mean
|
||
that these neurons can actually partake in any visual operation. Girman and Golovina
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.87">87</a>), however, showed, at
|
||
the single-unit level, that many graft neurons did respond to visual stimuli.
|
||
Approximately 84% of the spontaneously active neurons in type I grafts have well-defined
|
||
RFs (5-20 degrees in diameter; <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F11/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F11" rid-ob="figobch34regeneration2F11">Fig. 11</a>) and exhibit clear responses for
|
||
either moving or stationary stimuli. Cells preferring the same stimulus seem to be in
|
||
clusters. Flashing light spots typically evoke a biphasic excitatory/inhibitory response
|
||
of 36-62 ms latency, followed by a second excitatory discharge. Movement-sensitive neurons
|
||
fire weakly, or not at all, to light spots. Most of them show clear direction selectivity
|
||
and orientation specificity. A few active neurons (16.5%) can be driven by stimulation of
|
||
either eye, the contralateral stimulation being dominant. Visually driven neurons are less
|
||
frequently encountered in type III grafts. These neurons have larger RFs (20-30 degrees)
|
||
and react only to light spots after a long delay (100-250 ms).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F11" co-legend-rid="figlgndch34regeneration2F11"><a href="/books/NBK11505/figure/ch34regeneration2.F11/?report=objectonly" target="object" title="Figure 11" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F11" rid-ob="figobch34regeneration2F11"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f11.gif" src-large="/books/NBK11505/bin/regeneration2f11.jpg" alt="Figure 11. Upper row: autocorrelograms of spontaneous neuronal activity." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F11"><h4 id="ch34regeneration2.F11"><a href="/books/NBK11505/figure/ch34regeneration2.F11/?report=objectonly" target="object" rid-ob="figobch34regeneration2F11">Figure 11</a></h4><p class="float-caption no_bottom_margin">Upper row: autocorrelograms of spontaneous neuronal activity. A, in visually
|
||
responsive grafts (desynchronized regular pattern). As in the intact visual cortex
|
||
(94), the spike rate
|
||
increases with the recording depth. B, in unresponsive grafts (periodic <a href="/books/NBK11505/figure/ch34regeneration2.F11/?report=objectonly" target="object" rid-ob="figobch34regeneration2F11">(more...)</a></p></div></div><p>Finally, graft neurons also fire in response to electrical stimulation (10-50
|
||
μA) of either the host ipsilateral DLG nucleus or the contralateral visual
|
||
cortex. An important finding, suggestive of some form of topographic organization between
|
||
the DLG and the cortical graft, is that small displacements (200 μm) of the
|
||
stimulating electrode from the optimal geniculate site lead to a decrease or a complete
|
||
loss of response.</p></div><div id="ch34regeneration2.Are_Responses_from_t"><h3>Are Responses from the Graft Retinotopically Ordered?</h3><p>To a degree, they are. The same studies by Girman and Golovina (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.87">87</a>) indicate that large (3 mm in diameter),
|
||
highly responsive cortical grafts contain an ordered representation of the contralateral
|
||
visual field, at least of its central part, which projects normally onto area 17. First,
|
||
neurons recorded simultaneously at a given electrode position have roughly the same RF
|
||
location. Second, there is no change in RF position with depth during a single
|
||
penetration. Third, ordered changes in the recording positions on the graft surface induce
|
||
concomitant changes in the RF locations. Fourth, the orientation of the visual field
|
||
projection onto the graft appears normal relative to the skull landmarks (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F12/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F12" rid-ob="figobch34regeneration2F12">Fig.
|
||
12</a>). A rough retinotopic order is also observed in large, type III grafts. The
|
||
larger the grafts, the better the visual field projection: small grafts contain only a
|
||
non-ordered representation of a restricted part (20-30 degrees wide) of the nasal visual
|
||
field. Visual map order and neuron properties remain unchanged up to at least 10 months
|
||
after grafting. This is a logical result in view of the fact that long-term survival (2
|
||
years <i>in situ</i>) does not significantly affect the basic morphological
|
||
features of cortical grafts (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.91">91</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F12" co-legend-rid="figlgndch34regeneration2F12"><a href="/books/NBK11505/figure/ch34regeneration2.F12/?report=objectonly" target="object" title="Figure 12" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F12" rid-ob="figobch34regeneration2F12"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f12.gif" src-large="/books/NBK11505/bin/regeneration2f12.jpg" alt="Figure 12. Near-normal visuotopic projections in type I graft placed in the right primary visual area (Oc1/V1) of an adult rat." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F12"><h4 id="ch34regeneration2.F12"><a href="/books/NBK11505/figure/ch34regeneration2.F12/?report=objectonly" target="object" rid-ob="figobch34regeneration2F12">Figure 12</a></h4><p class="float-caption no_bottom_margin">Near-normal visuotopic projections in type I graft placed in the right
|
||
primary visual area (Oc1/V1) of an adult rat. A, recording loci at graft level (grayish
|
||
inset). Dorsal view. Graft is centered approximately 8 mm caudal to bregma and 4 mm
|
||
lateral <a href="/books/NBK11505/figure/ch34regeneration2.F12/?report=objectonly" target="object" rid-ob="figobch34regeneration2F12">(more...)</a></p></div></div></div></div><div id="ch34regeneration2.Do_Grafts_Receive_Ex"><h2 id="_ch34regeneration2_Do_Grafts_Receive_Ex_">Do Grafts Receive Extensive Afferents?</h2><p>By this point, it seems evident that under some highly controlled and replicable
|
||
experimental conditions, allogeneic fetal tissue grafts implanted at homotopic positions in
|
||
the visual brain can respond to visual stimulation of the host eye. Some cells from the
|
||
graft perform rather complex operations of visual driven signals, just like the SC and area
|
||
17 in the normal rat (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.92">92-95</a>).
|
||
The graft can resume at least a partial, ordered map of the visual field, a prerequisite for
|
||
recovery of function. However, topographic visual field representation on a graft is likely
|
||
to involve many more regenerated host afferents than the few, randomly branching fibers
|
||
reportedly able to generate light flash responses in the PN graft paradigm (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.96">96-98</a>).
|
||
Direction selectivity, orientation specificity, and binocular activation imply sophisticated
|
||
synaptic input to graft neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.99">99</a>). The next question, then, is whether homologous fetal grafts in the adult
|
||
primary visual cortex receive extensive input from appropriate brain areas.</p><div id="ch34regeneration2.Tectal_Graft_Connect"><h3>Tectal Graft Connectivity</h3><p>The actual substrate of the visual responses recorded in tectal grafts is a puzzling,
|
||
still unsolved problem. Receptive field properties, latency values, and ordered
|
||
organization together suggest the presence of direct, widely distributed host retinal
|
||
input to the grafts. However, the early studies in neonate hosts showed that retinal
|
||
afferents never filled the transplants and were restricted to discrete, fiber-free
|
||
patches. Within these patches, the density of optic terminals was nearly equivalent to
|
||
that seen in the stratum griseum superficiale of normal rats. By electron microscopy,
|
||
these terminals made asymmetric (excitatory) contacts onto small, post-synaptic profiles,
|
||
many of which were dendritic spines (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.75">75</a>). However, in striking contrast with
|
||
Girman's findings, neither visually (light flash and moving disk) nor electrically (optic
|
||
nerve stimulation) evoked activity were obtained from these grafts (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.100">100</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.101">101</a>).
|
||
Only a minor fraction of the tested units could be excited orthodromically from the
|
||
ipsilateral visual cortex, the major source of graft input in these preparations (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F8/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F8" rid-ob="figobch34regeneration2F8">Fig. 8</a>). The failure to record retinal
|
||
activity in the latter experiments could be attributable to the low number of electrode
|
||
tracks.</p><p>Tectal tissue grafts implanted in juvenile (P15/P18) and adult hosts with the same
|
||
technical approach also display discrete "fiber-free" patches dispersed dorsally within
|
||
the fiber-rich core. However, no definitive projections from the host brain have been
|
||
identified (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.67">67</a>), and retinal
|
||
innervation to the patches remains a matter of debate (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.67">67</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.73">73</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.102">102</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.103">103</a>).
|
||
In short, there is yet very little anatomical evidence for the visual responsiveness
|
||
recorded in tectal grafts. As suggested earlier by Golden et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.100">100</a>), a possible reason
|
||
for this discrepancy may be the grafting technique. Although grafts done by Golden et al.
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.100">100</a>) consist of partly
|
||
dissociated cells injected onto the surface of the SC, the transplants done by Girman
|
||
consist of "solid sheets of embryonic tectal tissue laid in the appropriate dorsoventral
|
||
orientation over the SC surface devoid of superficial laminae". In neonates, a similar
|
||
paradigm as used by Girman leads to the formation of a single, densely innervated
|
||
retinorecipient lamina covering a large part of the graft surface (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F6/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F6" rid-ob="figobch34regeneration2F6">Fig. 6</a>) (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.75">75</a>). Up to now, neither the connectivity nor
|
||
the neurofibrillar structure of such tectal implants in adult hosts have been studied.</p></div><div id="ch34regeneration2.Host_Afferents_to_Co"><h3>Host Afferents to Cortical Grafts</h3><p>As the electrophysiological data suggest, there should be a strong relationship between
|
||
graft responsiveness and the presence of regenerating axons (or collateral sprouts) from
|
||
ipsilateral DLG neurons. Indeed, retrograde tracers injected in type I grafts label high
|
||
numbers of DLG neurons (one-third of which projected initially to the lesioned cortical
|
||
site), whereas similar injections in type II grafts produce no labeling at all (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.81">81</a>). Whether direct DLG
|
||
input alone can account for graft visual responsiveness is, however, very unlikely,
|
||
because some type I grafts receive only extra-geniculate, and no direct geniculate,
|
||
inputs.</p></div><div id="ch34regeneration2.Major_Graft_Input_Or"><h3>Major Graft Input Originates in Host Layer 5-6</h3><p>After retrograde tracer (CTB, cholera toxin, b subunit) injection into types I-III
|
||
grafts, Gaillard and colleagues (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.88">88</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.89">89</a>)
|
||
saw a diversity of afferents. These afferents (always in very low number; Fig. 17) appear
|
||
in visual-related brain structures ipsilateral to the graft. The densest labeling (55-90%)
|
||
is observed in the isocortex, mostly in the occipital areas surrounding the graft (see
|
||
also Galick et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.104">104</a>) and Schultz et al.
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.78">78</a>)). Together, neurons
|
||
in claustrum, periallocortical areas, and various non-visual subcortical nuclei account
|
||
for some 20% of the graft input. As expected, labeling in dorsal thalamus is highly
|
||
variable. Although practically absent in one-half of the subjects, it represents 10-30% of
|
||
all the graft afferents in the other one-half. DLG input never exceeds 10% of the total
|
||
graft input. Orbital (VO/VLO), motor (Fr2), and brainstem structures (such as the basal
|
||
nucleus of Meynert, locus coeruleus, and dorsal raphe), all projecting to the normal
|
||
visual cortex (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F12/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F12" rid-ob="figobch34regeneration2F12">Fig. 12</a>), are never
|
||
labeled (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.33">33</a>). Labeling in
|
||
the hemisphere opposite to the graft is always negligible.</p><p>Apart from the isocortical area, most labeled neurons (91%) are confined to the
|
||
infragranular layers (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F13/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F13" rid-ob="figobch34regeneration2F13">Fig. 13</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F14/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F14" rid-ob="figobch34regeneration2F14">Fig. 14</a>),
|
||
noticeably layer 6 and sublayer 6b, close to the white matter. Layer 6b neurons in normal
|
||
adult rodents exhibit diverse cell body morphologies (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F14/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F14" rid-ob="figobch34regeneration2F14">Fig. 14</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F15/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F15" rid-ob="figobch34regeneration2F15">Fig. 15</a>) and have
|
||
widespread terminal arborizations (>3-4 mm) in superficial cortical layers (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.105">105</a>). They appear to be
|
||
remnants of subplate neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.106">106-108</a>),
|
||
which have pivotal functions during early cortical development, for instance in guiding
|
||
thalamic fibers to their appropriate cortical target area (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.109">109-111</a>)
|
||
and in governing the functional maturation of connections between DLG axons and layer 4
|
||
neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.112">112</a>). They are also
|
||
involved in coordinating ocular dominance column formation (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.113">113</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.114">114</a>).
|
||
In the adult cat, subplate (white matter) and pyramidal cells of the normal and inverted
|
||
types in the infragranular cortical layers support long-range, tangential connections
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.115">115</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F13" co-legend-rid="figlgndch34regeneration2F13"><a href="/books/NBK11505/figure/ch34regeneration2.F13/?report=objectonly" target="object" title="Figure 13" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F13" rid-ob="figobch34regeneration2F13"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f13.gif" src-large="/books/NBK11505/bin/regeneration2f13.jpg" alt="Figure 13. Representative labeling of projection neurons (arrows) in the host cortex (Cx) after injection of a retrograde tracer (CTb; cholera toxin, b-subunit) in a visually responsive graft (Tr)." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F13"><h4 id="ch34regeneration2.F13"><a href="/books/NBK11505/figure/ch34regeneration2.F13/?report=objectonly" target="object" rid-ob="figobch34regeneration2F13">Figure 13</a></h4><p class="float-caption no_bottom_margin">Representative labeling of projection neurons (arrows) in the host cortex
|
||
(Cx) after injection of a retrograde tracer (CTb; cholera toxin, b-subunit) in a
|
||
visually responsive graft (Tr). Note their location in layer 6, close to the white
|
||
matter (w.m.). <a href="/books/NBK11505/figure/ch34regeneration2.F13/?report=objectonly" target="object" rid-ob="figobch34regeneration2F13">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F14" co-legend-rid="figlgndch34regeneration2F14"><a href="/books/NBK11505/figure/ch34regeneration2.F14/?report=objectonly" target="object" title="Figure 14" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F14" rid-ob="figobch34regeneration2F14"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f14.gif" src-large="/books/NBK11505/bin/regeneration2f14.jpg" alt="Figure 14. A-C, gallery of retrogradely labeled layer 5 pyramidal cells after CTb injection into three different responsive grafts." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F14"><h4 id="ch34regeneration2.F14"><a href="/books/NBK11505/figure/ch34regeneration2.F14/?report=objectonly" target="object" rid-ob="figobch34regeneration2F14">Figure 14</a></h4><p class="float-caption no_bottom_margin">A-C, gallery of retrogradely labeled layer 5 pyramidal cells after CTb
|
||
injection into three different responsive grafts. Arrowheads indicate axons. All cells
|
||
are located 400-500 μm from the graft boundary. Scale bars, 13
|
||
μm. D-G, gallery <a href="/books/NBK11505/figure/ch34regeneration2.F14/?report=objectonly" target="object" rid-ob="figobch34regeneration2F14">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F15" co-legend-rid="figlgndch34regeneration2F15"><a href="/books/NBK11505/figure/ch34regeneration2.F15/?report=objectonly" target="object" title="Figure 15" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F15" rid-ob="figobch34regeneration2F15"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f15.gif" src-large="/books/NBK11505/bin/regeneration2f15.jpg" alt="Figure 15. Left panel: camera lucida drawings of retrogradely labeled cells in layer 6b after CTb injection into another responsive graft." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F15"><h4 id="ch34regeneration2.F15"><a href="/books/NBK11505/figure/ch34regeneration2.F15/?report=objectonly" target="object" rid-ob="figobch34regeneration2F15">Figure 15</a></h4><p class="float-caption no_bottom_margin">Left panel: camera lucida drawings of retrogradely labeled cells in layer 6b
|
||
after CTb injection into another responsive graft. Dotted lines denote the upper limit
|
||
of the white matter (w.m.). Arrowheads indicate the location and the distance of the
|
||
graft. <a href="/books/NBK11505/figure/ch34regeneration2.F15/?report=objectonly" target="object" rid-ob="figobch34regeneration2F15">(more...)</a></p></div></div></div><div id="ch34regeneration2.This_Pattern_Is_Spec"><h3>This Pattern Is Specified by Eye Opening</h3><p>When performed in neonate hosts, the same experiments always lead to greater density and
|
||
diversity of graft inputs (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.89">89</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.116">116</a>). At the cortical
|
||
level, for instance, frontal (Fr2; the frontal eye field in primates) and orbital (LO/VLO)
|
||
areas are moderately but systematically labeled, and the somas of the isocortical
|
||
afferents distribute about equally between layers 2-3 and 5-6. At the thalamic level,
|
||
owing to the severe (75%) atrophy of the DLG (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.117">117</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.118">118</a>),
|
||
most inputs originate in the LP/LD complex and the central intralaminar nuclei, an
|
||
unlabeled cell group in adult hosts (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F16/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F16" rid-ob="figobch34regeneration2F16">Fig. 16</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F16" co-legend-rid="figlgndch34regeneration2F16"><a href="/books/NBK11505/figure/ch34regeneration2.F16/?report=objectonly" target="object" title="Figure 16" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F16" rid-ob="figobch34regeneration2F16"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f16.gif" src-large="/books/NBK11505/bin/regeneration2f16.jpg" alt="Figure 16. Upper row: quantitative differences (mean ± SD) in graft input between neonates (P0) and adult (P120) recipients." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F16"><h4 id="ch34regeneration2.F16"><a href="/books/NBK11505/figure/ch34regeneration2.F16/?report=objectonly" target="object" rid-ob="figobch34regeneration2F16">Figure 16</a></h4><p class="float-caption no_bottom_margin">Upper row: quantitative differences (mean ± SD) in graft input
|
||
between neonates (P0) and adult (P120) recipients. A, raw number of isocortical cells.
|
||
B, proportions of cells per isocortical layer. Counts performed on half the brain of
|
||
each subject. <a href="/books/NBK11505/figure/ch34regeneration2.F16/?report=objectonly" target="object" rid-ob="figobch34regeneration2F16">(more...)</a></p></div></div><p>We conclude that the age of the recipient appears to affect both the density and the
|
||
topology of the graft afferents (for similar data with parietal grafts, see Castro et al.
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.119">119</a>) and Schultz et al
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.78">78</a>).
|
||
). Additional studies show,
|
||
moreover, that the most dramatic changes in the afferent pattern occur in the second
|
||
postnatal week, before the onset of the critical period for rat visual cortex (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.120">120</a>). Nearly all
|
||
isocortical inputs to the graft in P15 hosts originate in the infragranular layers, mostly
|
||
from layer 6, a proportion not significantly different from that found in older recipients
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.66">66</a>). This age-related
|
||
laminar shaping is a two-step process that affects all layers, but the supragranular
|
||
layers are affected more specifically. It is completed in frontal and temporal areas about
|
||
1 week earlier than in the occipital areas surrounding the graft (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F17/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F17" rid-ob="figobch34regeneration2F17">Fig. 17</a>). The delay
|
||
is likely related to the cortical ontogenetic program that proceeds radially (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.121">121</a>) as well as
|
||
tangentially through rostrocaudal and lateromedial directions (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.122">122</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.123">123</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F17" co-legend-rid="figlgndch34regeneration2F17"><a href="/books/NBK11505/figure/ch34regeneration2.F17/?report=objectonly" target="object" title="Figure 17" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F17" rid-ob="figobch34regeneration2F17"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f17.gif" src-large="/books/NBK11505/bin/regeneration2f17.jpg" alt="Figure 17. Proportions of labeled cells (mean ± SD) in the temporal (Te1-3) and occipital (Oc1-2M) areas as a function of the age of the host." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F17"><h4 id="ch34regeneration2.F17"><a href="/books/NBK11505/figure/ch34regeneration2.F17/?report=objectonly" target="object" rid-ob="figobch34regeneration2F17">Figure 17</a></h4><p class="float-caption no_bottom_margin">Proportions of labeled cells (mean ± SD) in the temporal (Te1-3)
|
||
and occipital (Oc1-2M) areas as a function of the age of the host. Note the absence of
|
||
supragranular input from temporal areas in 2-week-old recipients. Redrawn from Domballe
|
||
et <a href="/books/NBK11505/figure/ch34regeneration2.F17/?report=objectonly" target="object" rid-ob="figobch34regeneration2F17">(more...)</a></p></div></div></div><div id="ch34regeneration2.The_Potential_of_Lay"><h3>The Potential of Layer 6 Neurons to Survive Injury and to Drive Grafts</h3><p>A major outcome of all the above-mentioned studies is that afferent innervation to a
|
||
cortical graft in adult host originates mostly from a small population of layer 6 neurons
|
||
located in the immediate graft surround. Cortical layer 6 is a target for thalamic fibers.
|
||
The layer 6 neurons display all known visual response types (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.94">94</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.95">95</a>),
|
||
regardless of their morphology. Of the four layer 6 cells injected with HRP by Parnavelas
|
||
et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.124">124</a>), one multipolar
|
||
cell was an "ON-OFF" cell, two pyramidal cells were "complex" cells, and the last fusiform
|
||
cell type was a "non-oriented" cell. In the absence of direct thalamic input, layer 6
|
||
neurons may thus be able to drive visual information to the graft.</p><p>Why layer 2-3 neurons do not contact the graft in adults is not understood. Among many
|
||
possibilities, one would be that these late-generated (E17-E20) corticocortical projection
|
||
neurons, which have low survival rates during development (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.125">125</a>), are very sensitive
|
||
to lesion-induced retrograde degeneration and/or deleterious changes in their environment
|
||
(but see Szele et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.126">126</a>)). Conversely,
|
||
these neurons may be able to regenerate axons, but these axons do not penetrate the graft
|
||
because of negative influences from reactive astroglial elements and/or graft neurons. For
|
||
instance, <i>in vitro</i> assays (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.6">6</a>) have shown that
|
||
endogenous levels of neurotrophin-3 (NT-3) reduce axonal branching and repel layer 2-3
|
||
neurons but have opposite effects on layer 6 neurons. For some days after implantation,
|
||
the graft (which is producing NT-3) may thus be repulsive to layer 2-3 axons but
|
||
attractive to layer 6/6b neurons, which express NT-3 receptors (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.127">127</a>). Regardless of how
|
||
fascinating these latter observations are, multiple survival and growth-promoting factors
|
||
produced by the graft and the injured cortex may also allow layer 6 neuron survival and
|
||
axonal elongation. For instance, neurotrophin-4 (NT-4) is as effective as NT-3 in
|
||
increasing the length of the dendritic processes of layer 6 pyramidal cells of juvenile
|
||
ferrets (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.128">128</a>). Furthermore, layer
|
||
6b neurons have receptors to basic fibroblast growth factor (FGF-2), a critical survival
|
||
substrate for subplate neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.129">129</a>). FGF-2 is
|
||
suspected to protect adult layer 6b neurons from death after lesions (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.130">130</a>) but has no survival
|
||
effect on 1-week-old, layer 2-3 callosal projection neurons (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.131">131</a>). Deciphering why
|
||
some layer 6 neurons in the adult brain have the potential for elongating their axons and
|
||
whether these neurons have excitatory phenotypes will be an interesting challenge,
|
||
especially in the context of these cells consistently labeling regardless of the grafting
|
||
strategy (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.78">78</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.132">132</a>).</p></div><div id="ch34regeneration2.Anatomical_Support_f"><h3>Anatomical Support for Topographic Order in Grafts Is Still Lacking</h3><p>Mapping studies suggest that host afferents are topically organized in large tectal and
|
||
cortical E15-17 embryonic tissue grafts. These results need anatomical confirmation,
|
||
however. Beside occasional statements (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.119">119</a>), this issue has only been specifically
|
||
addressed in a single study using neonate recipients. The triple labeling approach by
|
||
Worthington and Harvey (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.133">133</a>) shows that tectal
|
||
tissue grafts receive non-topographically organized, but nevertheless non-random,
|
||
rudimentarily ordered cortical inputs. To date, no such investigation has been carried out
|
||
with adult hosts, likely because one can hardly imagine how the discrete afferent
|
||
projections reviewed above may form a coherent visual map onto grafts (see section 2.7.3
|
||
from the previous chapter). This negative reasoning does not consider: first that map
|
||
formation may require a specific, highly controlled transplantation procedure (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.71">71</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.133">133</a>),
|
||
including possibly the correct orientation of the graft in the lesion cavity (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.134">134</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.135">135</a>); second, that
|
||
labeled graft afferents may reflect only a negligible proportion of the actual projecting
|
||
host neurons; and third, that single-unit recordings with carefully engineered
|
||
microelectrodes (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.136">136</a>) may be more
|
||
powerful than tracer injections to detect small point-to-point shifts in connectivity
|
||
between restricted brain areas. Meticulous surgical preparation, ingenious recording
|
||
conditions, and use of self-made, highly specific tungsten in glass electrodes of the
|
||
Levick's type may together account for Girman's successful recordings (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.94">94</a>). In our opinion,
|
||
unequivocal assessment of topographic host-graft projections requires further studies
|
||
combining an optimal surgical strategy, a highly sensitive fiber detection process (see
|
||
below), and a careful electrophysiological approach replicating Girman's approach.</p></div></div><div id="ch34regeneration2.Can_Grafts_Send_Affe"><h2 id="_ch34regeneration2_Can_Grafts_Send_Affe_">Can Grafts Send Afferents to Host Targets?</h2><p>In line with numerous results showing low numbers of afferents coming to the transplant, it
|
||
has been repeatedly assumed that allogeneic embryonic tissue grafts do not send long-range
|
||
projections to the adult host. Our own attempts using either biotinylated dextran amine
|
||
(BDA) or the carbocyanine dye DiI (1,1'-didodecyl-3,3,3',3'-tetramethyl-indocarbocyanine
|
||
perchlorate) as anterograde tracers confirm this assumption. This failure is commonly
|
||
attributed to growth inhibitory conditions present in the mature brain (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.14">14</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.137">137</a>).
|
||
Possible technical limitations are rarely addressed (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.138">138-141</a>).
|
||
Yet, there are some intriguing morpho-functional observations (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.84">84</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.85">85</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.142">142-148</a>),
|
||
suggesting that blocks of embryonic neurons grafted into the mature brain might not be able
|
||
to transport exogenously provided tracers beyond the graft-host transition zone. In
|
||
opposition to this, long axonal trajectories have been clearly detected in some experimental
|
||
conditions, either after pre-loading dissociated donor cells with dyes (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.149">149</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.150">150</a>) or by targeting
|
||
specific markers expressed by grafted cells (Thy-1.2 allelic system; microtubule-associated
|
||
protein MAP1x/1B) (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.151">151-155</a>).
|
||
This has been a routine procedure for xenogeneic tissue grafts (for examples, see Lund et
|
||
al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.156">156</a>),
|
||
Li and Raisman (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.157">157</a>), Davies et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.158">158</a>), Isacson and Deacon
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.159">159</a>), and Armstrong et al.
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.18">18</a>)). A plausible
|
||
hypothesis is, then, that all fetal graft neurons, regardless of their origins, are
|
||
intrinsically capable of elongating processes when placed in a mature brain, but that
|
||
detection of these processes outside the graft structure requires a non-invasive, anatomical
|
||
approach. This hypothesis has been verified recently in occipital cortex tissue grafts
|
||
(<a class="bk_pop" href="#ch34regeneration2.EXTYLES.160">160</a>) using transgenic E15
|
||
mouse fetuses expressing a GFP protein variant under the control of a chicken beta-actin
|
||
promoter (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.161">161</a>) as donors (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F18/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F18" rid-ob="figobch34regeneration2F18">Fig.
|
||
18</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F19" rid-ob="figobch34regeneration2F19">Fig. 19</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F18" co-legend-rid="figlgndch34regeneration2F18"><a href="/books/NBK11505/figure/ch34regeneration2.F18/?report=objectonly" target="object" title="Figure 18" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F18" rid-ob="figobch34regeneration2F18"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f18.gif" src-large="/books/NBK11505/bin/regeneration2f18.jpg" alt="Figure 18. Dr." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F18"><h4 id="ch34regeneration2.F18"><a href="/books/NBK11505/figure/ch34regeneration2.F18/?report=objectonly" target="object" rid-ob="figobch34regeneration2F18">Figure 18</a></h4><p class="float-caption no_bottom_margin">Dr. Okabe's eGFP-expressing neonate mice look "green" all over their body
|
||
when illuminated with an UV source. See: http://kumikae01.gen-info.osaka-u.ac.jp/tg/tg-ad.cfm. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F19" co-legend-rid="figlgndch34regeneration2F19"><a href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" title="Figure 19" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F19" rid-ob="figobch34regeneration2F19"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f19.gif" src-large="/books/NBK11505/bin/regeneration2f19.jpg" alt="Figure 19. A, location of the eGFP-positive grafts at the cortical surface with respect to bregma (B = 0) after reconstruction from serial brain sections." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F19"><h4 id="ch34regeneration2.F19"><a href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" rid-ob="figobch34regeneration2F19">Figure 19</a></h4><p class="float-caption no_bottom_margin">A, location of the eGFP-positive grafts at the cortical surface with respect
|
||
to bregma (B = 0) after reconstruction from serial brain sections. B, representative
|
||
implantation (B-3.5). Darkfield microscopy. Note white matter bundles around and within
|
||
the <a href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" rid-ob="figobch34regeneration2F19">(more...)</a></p></div></div><div id="ch34regeneration2.Embryonic_Cortical_T"><h3>Embryonic Cortical Tissue Allografts Have Massive Efferents</h3><p>A major finding of the above study is that despite immediate implantation, nearly all
|
||
grafts into mature (P60/P90), wild-type mice appear physically well integrated in the host
|
||
cortex (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F19" rid-ob="figobch34regeneration2F19">Fig. 19</a>). Moreover, they
|
||
show massive outgrowth all along their interface with the cortical parenchyma and send
|
||
extensive efferents throughout the host ipsilateral pallium, mainly to its cortical mantle
|
||
(<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F20/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F20" rid-ob="figobch34regeneration2F20">Fig.
|
||
20</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F20" co-legend-rid="figlgndch34regeneration2F20"><a href="/books/NBK11505/figure/ch34regeneration2.F20/?report=objectonly" target="object" title="Figure 20" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F20" rid-ob="figobch34regeneration2F20"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f20.gif" src-large="/books/NBK11505/bin/regeneration2f20.jpg" alt="Figure 20. Camera lucida drawings of graft projections into the ipsilateral cortex of the former case as seen at a low magnification power (×4)." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F20"><h4 id="ch34regeneration2.F20"><a href="/books/NBK11505/figure/ch34regeneration2.F20/?report=objectonly" target="object" rid-ob="figobch34regeneration2F20">Figure 20</a></h4><p class="float-caption no_bottom_margin">Camera lucida drawings of graft projections into the ipsilateral cortex of
|
||
the former case as seen at a low magnification power (×4). Brain sections
|
||
are arranged according to their bregma level. The grayish zone in each section
|
||
corresponds to <a href="/books/NBK11505/figure/ch34regeneration2.F20/?report=objectonly" target="object" rid-ob="figobch34regeneration2F20">(more...)</a></p></div></div><p>Rostrally, graft fibers innervate a large medial sector of the brain including frontal
|
||
association (FrA), secondary motor (M2), prelimbic (PrL), anterior cingulate (Cg1-2),
|
||
medial orbital (MO), and infralimbic (IL) areas. Discrete fibers terminate within the
|
||
orbital areas VO/LO and the claustrum (CL). At the bregma level, efferents distribute from
|
||
area Cg1 medially to the somatosensory cortex laterally. Labeling extends throughout
|
||
layers 2-3 and 5-6 in motor (Fr2) and sensorimotor (HL) areas but remains in lamina 6b at
|
||
the barrel field (BF) level (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F21/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F21" rid-ob="figobch34regeneration2F21">Fig. 21</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F22/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F22" rid-ob="figobch34regeneration2F22">Fig. 22</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F21" co-legend-rid="figlgndch34regeneration2F21"><a href="/books/NBK11505/figure/ch34regeneration2.F21/?report=objectonly" target="object" title="Figure 21" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F21" rid-ob="figobch34regeneration2F21"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f21.gif" src-large="/books/NBK11505/bin/regeneration2f21.jpg" alt="Figure 21. Composite images showing the cortical distribution of graft efferents in HL (left) and V2L (right) areas of two different animals." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F21"><h4 id="ch34regeneration2.F21"><a href="/books/NBK11505/figure/ch34regeneration2.F21/?report=objectonly" target="object" rid-ob="figobch34regeneration2F21">Figure 21</a></h4><p class="float-caption no_bottom_margin">Composite images showing the cortical distribution of graft efferents in HL
|
||
(left) and V2L (right) areas of two different animals. Note the high density of fibers
|
||
in layer 6. Inverted contrast from fluorescent material. Corpus callosum (CC) is
|
||
downward. <a href="/books/NBK11505/figure/ch34regeneration2.F21/?report=objectonly" target="object" rid-ob="figobch34regeneration2F21">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F22" co-legend-rid="figlgndch34regeneration2F22"><a href="/books/NBK11505/figure/ch34regeneration2.F22/?report=objectonly" target="object" title="Figure 22" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F22" rid-ob="figobch34regeneration2F22"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f22.gif" src-large="/books/NBK11505/bin/regeneration2f22.jpg" alt="Figure 22. Graft efferents in the caudal brain (4 mm beyond bregma)." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F22"><h4 id="ch34regeneration2.F22"><a href="/books/NBK11505/figure/ch34regeneration2.F22/?report=objectonly" target="object" rid-ob="figobch34regeneration2F22">Figure 22</a></h4><p class="float-caption no_bottom_margin">Graft efferents in the caudal brain (4 mm beyond bregma). A, schematic
|
||
drawing (adapted from Paxinos and Franklin (175)) showing the location of the
|
||
accompanying pictures (red dots). Gray levels are representative of the fiber density.
|
||
B, efferents in <a href="/books/NBK11505/figure/ch34regeneration2.F22/?report=objectonly" target="object" rid-ob="figobch34regeneration2F22">(more...)</a></p></div></div><p>At the transplant level and beyond, labeling from the GFP donor tissue fills the host
|
||
ipsilateral cortex from the retrosplenial granular area to the lateral entorhinal region.
|
||
Efferents in V2L and Te1-2 areas are especially dense in layers 1-3, 5a, and 6. Further
|
||
caudally, labeled fibers occupy predominantly the cortical layers 5-6 as well as the
|
||
PrS/PaS hippocampic regions.</p><p>Finally, afferents with terminal-like profiles are systematically present in the
|
||
dorsomedial sector (as well as along the lateral rim) of the striatum and into the
|
||
basolateral and central amygdaloid nuclei (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F23/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F23" rid-ob="figobch34regeneration2F23">Fig. 23</a>). All these
|
||
structures, including the cortical areas listed above, are normal targets of the rodent
|
||
visual cortex (see <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F2/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F2" rid-ob="figobch34regeneration2F2">Fig. 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F23" co-legend-rid="figlgndch34regeneration2F23"><a href="/books/NBK11505/figure/ch34regeneration2.F23/?report=objectonly" target="object" title="Figure 23" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F23" rid-ob="figobch34regeneration2F23"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f23.gif" src-large="/books/NBK11505/bin/regeneration2f23.jpg" alt="Figure 23. Graft efferents in the striatum and the amygdala." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F23"><h4 id="ch34regeneration2.F23"><a href="/books/NBK11505/figure/ch34regeneration2.F23/?report=objectonly" target="object" rid-ob="figobch34regeneration2F23">Figure 23</a></h4><p class="float-caption no_bottom_margin">Graft efferents in the striatum and the amygdala. Fluorescence microscopy.
|
||
A, labeling in the dorsomedial striatum, below area Fr1 (B+1.2). Scale bar, 100
|
||
μm. B and C, labeling in the amygdala, laterodorsal nucleus (B+1.0). Scale
|
||
bars, 150 and <a href="/books/NBK11505/figure/ch34regeneration2.F23/?report=objectonly" target="object" rid-ob="figobch34regeneration2F23">(more...)</a></p></div></div><p>Although always disrupted by surgery (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F19/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F19" rid-ob="figobch34regeneration2F19">Fig. 19</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F27/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F27" rid-ob="figobch34regeneration2F27">Fig. 27</a>), the white matter (external capsule
|
||
and corpus callosum) never appears to provide an attractive substrate for graft efferents.
|
||
Even at the exit point from the graft, outgrowing fibers always appear to prefer
|
||
elongating through the deep gray matter (layer 6) of the cortex, the major pathway for
|
||
long distance, intrahemispheric corticocortical axons in rodents (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.162">162</a>) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F24/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F24" rid-ob="figobch34regeneration2F24">Fig.
|
||
24</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F27" co-legend-rid="figlgndch34regeneration2F27"><a href="/books/NBK11505/figure/ch34regeneration2.F27/?report=objectonly" target="object" title="Figure 27" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F27" rid-ob="figobch34regeneration2F27"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f27.gif" src-large="/books/NBK11505/bin/regeneration2f27.jpg" alt="Figure 27. Destruction of the underlying white matter (arrows) allows graft efferents to invade the hippocampus (B-3." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F27"><h4 id="ch34regeneration2.F27"><a href="/books/NBK11505/figure/ch34regeneration2.F27/?report=objectonly" target="object" rid-ob="figobch34regeneration2F27">Figure 27</a></h4><p class="float-caption no_bottom_margin">Destruction of the underlying white matter (arrows) allows graft efferents
|
||
to invade the hippocampus (B-3.6). Darkfield microscopy. Cx, host cortex; DG, dentate
|
||
gyrus; Hip, hippocampus; Tr, transplant; Sub, subiculum; w.m., white matter. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F24" co-legend-rid="figlgndch34regeneration2F24"><a href="/books/NBK11505/figure/ch34regeneration2.F24/?report=objectonly" target="object" title="Figure 24" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F24" rid-ob="figobch34regeneration2F24"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f24.gif" src-large="/books/NBK11505/bin/regeneration2f24.jpg" alt="Figure 24. Fiber outgrowth from a small (0." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F24"><h4 id="ch34regeneration2.F24"><a href="/books/NBK11505/figure/ch34regeneration2.F24/?report=objectonly" target="object" rid-ob="figobch34regeneration2F24">Figure 24</a></h4><p class="float-caption no_bottom_margin">Fiber outgrowth from a small (0.5 mm<sup>2</sup>) transplant centered 2 mm
|
||
caudal to bregma within the lateral parietal association (LptA) area. Outgrowth occurs
|
||
throughout the graft-cortex junction (V2L area). More laterally (S1 area), fibers
|
||
display obvious preference <a href="/books/NBK11505/figure/ch34regeneration2.F24/?report=objectonly" target="object" rid-ob="figobch34regeneration2F24">(more...)</a></p></div></div><p>Very few fibers can, therefore, extend to subcortical visual targets and the opposite
|
||
hemisphere. Terminal-like arrangements can nevertheless be detected in the dorsal visual
|
||
thalamus (Rt, LP/LD, DLG, Po), the pretectum (APT), SC, and even in the lateral division
|
||
of the pontine nuclei (Pn; <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F22/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F22" rid-ob="figobch34regeneration2F22">Fig.
|
||
22</a>), the ultimate target of the rodent visual cortex (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.39">39</a>) (<a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F25/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F25" rid-ob="figobch34regeneration2F25">Fig.
|
||
25</a> and <a class="figpopup" href="/books/NBK11505/figure/ch34regeneration2.F26/?report=objectonly" target="object" rid-figpopup="figch34regeneration2F26" rid-ob="figobch34regeneration2F26">Fig. 26</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F25" co-legend-rid="figlgndch34regeneration2F25"><a href="/books/NBK11505/figure/ch34regeneration2.F25/?report=objectonly" target="object" title="Figure 25" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F25" rid-ob="figobch34regeneration2F25"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f25.gif" src-large="/books/NBK11505/bin/regeneration2f25.jpg" alt="Figure 25. Graft efferents into the corpus callosum (CC)." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F25"><h4 id="ch34regeneration2.F25"><a href="/books/NBK11505/figure/ch34regeneration2.F25/?report=objectonly" target="object" rid-ob="figobch34regeneration2F25">Figure 25</a></h4><p class="float-caption no_bottom_margin">Graft efferents into the corpus callosum (CC). All pictures are taken
|
||
between the cingulate bundle (cg) and the brain midline. Fluorescence microscopy from
|
||
Alexa-fluor-treated material. A, callosal fibers are rare at this brain level (B-1.7).
|
||
Note the <a href="/books/NBK11505/figure/ch34regeneration2.F25/?report=objectonly" target="object" rid-ob="figobch34regeneration2F25">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch34regeneration2F26" co-legend-rid="figlgndch34regeneration2F26"><a href="/books/NBK11505/figure/ch34regeneration2.F26/?report=objectonly" target="object" title="Figure 26" class="img_link icnblk_img figpopup" rid-figpopup="figch34regeneration2F26" rid-ob="figobch34regeneration2F26"><img class="small-thumb" src="/books/NBK11505/bin/regeneration2f26.gif" src-large="/books/NBK11505/bin/regeneration2f26.jpg" alt="Figure 26. Single graft fiber elongating in the internal capsule to zona incerta, a normal subthalamic target of the occipital cortex." /></a><div class="icnblk_cntnt" id="figlgndch34regeneration2F26"><h4 id="ch34regeneration2.F26"><a href="/books/NBK11505/figure/ch34regeneration2.F26/?report=objectonly" target="object" rid-ob="figobch34regeneration2F26">Figure 26</a></h4><p class="float-caption no_bottom_margin">Single graft fiber elongating in the internal capsule to zona incerta, a
|
||
normal subthalamic target of the occipital cortex. Terminal fields are never seen in
|
||
this region. Fluorescence microscopy. Scale bar, 150 μm. Upper inset,
|
||
enlargement of <a href="/books/NBK11505/figure/ch34regeneration2.F26/?report=objectonly" target="object" rid-ob="figobch34regeneration2F26">(more...)</a></p></div></div></div><div id="ch34regeneration2.Implications_for_Fut"><h3>Implications for Future Research</h3><p>Besides the unequivocal demonstration that developing and regenerating fetal allograft
|
||
neurons possess a strong capacity for extending axons over considerable distances in the
|
||
mature host brain parenchyma, the results deserve further comments. First, allowing a
|
||
delay between tissue sampling and implantation is clearly not necessary for outgrowth.
|
||
Using a similar surgical protocol, extensive outgrowth can be achieved with cortical
|
||
frontal and substantia nigra tissue grafts (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.64">64</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.163">163</a>). For instance, 11
|
||
days after grafting, frontal graft growth cone-like figures end up in the cerebral
|
||
peduncle. Second, the massive fiber outgrowth taking place along the graft-host parenchyma
|
||
interface argues against the current suggestion that lesion-induced glial scar formation
|
||
and local overexpression of repulsive molecules (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.137">137</a>) impede neurite
|
||
growth <i>in vivo</i>. Third, most outgrowing axons follow a normal route in the
|
||
brain parenchyma and terminate in normal target fields, indicating that cues for correct
|
||
axonal guidance are readily present in the mature brain (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.159">159</a>, <a class="bk_pop" href="#ch34regeneration2.EXTYLES.164">164</a>).
|
||
However, some outgrowing axons spread into inappropriate targets. Fibers and terminal
|
||
fields have been detected at considerable distances from the graft locus in the acumbens
|
||
area, olfactory peduncle, tenia tecta, and PBg nucleus, raising again the question of the
|
||
specificity of innervation (see section 2.4 from the previous chapter).
|
||
Non-target-directed elongation in the mature brain has already been reported for olfactory
|
||
bulb neurons transplanted ectopically into the frontal cortex (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.152">152</a>). Fourth and
|
||
finally, adult white matter appears to be an insurmountable obstacle for most developing
|
||
axons in view that graft fibers grow clearly less through white matter tracts than through
|
||
infragranular cortical gray layers. In addition, accidental removal of the white matter
|
||
during surgery allows graft efferents to invade the underlying hippocampic structures
|
||
(neuropil layers, dentate gyrus, and subiculum).</p><p>Neurite growth inhibition by myelin is currently (but not exclusively (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.165">165</a>)) explained by
|
||
interactions between myelin-related inhibitory factors (Nogo-A protein; myelin-associated
|
||
glycoprotein, MAG; and oligodendrocytes-myelin glycoprotein, OMgp) and a common neuronal
|
||
Nogo receptor (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.166">166-168</a>). Whether such
|
||
inhibitory interactions make for graft axon repulsion in graft situations is debatable, in
|
||
part because the neuronal Nogo receptor seems barely detectable in the normal brain, at
|
||
least until the end of the first postnatal week (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.169">169</a>). The implication is
|
||
that graft axons would be able to navigate for some 2 weeks in white matter tracts before
|
||
being stopped by inhibitory ligands. This is clearly not what we saw.</p></div></div><div id="ch34regeneration2.Restoration_of_Visua"><h2 id="_ch34regeneration2_Restoration_of_Visua_">Restoration of Visual Behavior</h2><p>Only a few behavioral studies have investigated whether fetal tectal or occipital grafts
|
||
can mediate recovery of impaired visual function in adult rats. Results are inconsistent.
|
||
Stein et al. (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.170">170</a>) transplanted frontal
|
||
and occipital E18-19 tissue blocks into bilateral aspirated occipital cortices and then
|
||
trained subjects (albino rats) on both a brightness (neutral-grey levels) and a pattern
|
||
(oblique stripes) discrimination task. Rats with frontal tissue grafts can learn the
|
||
brightness task more rapidly and more accurately than animals with lesions alone. Occipital
|
||
tissue grafts are inefficient. None of the grafted subjects can solve the pattern
|
||
discrimination problem. In no case can graft efferents be clearly identified following HRP
|
||
tracing methods. In a later work, Stein and Mufson (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.171">171</a>) obtained equally good
|
||
results in both types of transplants in solving both tasks after pretreatment of the
|
||
recipients (pigmented rats) with cyclosporin A. How these experimental modifications might
|
||
affect the performance of rats having occipital tissue grafts is not discussed in this
|
||
study. The puzzling effect of the frontal grafts is attributed to the release of specific
|
||
(but unknown) recovery-promoting factors able to spare some residual visual circuits in the
|
||
host brain. Some studies emphasize, however, that sparing of function is possible only with
|
||
homotopic grafts (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.172">172</a>), and that heterotopic
|
||
transplants cannot form viable synapses with the host tissue (<a class="bk_pop" href="#ch34regeneration2.EXTYLES.173">173</a>). Clearly, the
|
||
behavioral performance of adult subjects with occipital grafts needs closer examination.</p></div><div id="ch34regeneration2.AFN1"><h2 id="_ch34regeneration2_AFN1_">About the Authors</h2><p>
|
||
<div class="graphic"><img src="/books/NBK11505/bin/regeneration1fu2.jpg" alt="Image regeneration1fu2.jpg" /></div>
|
||
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><p>
|
||
<div class="graphic"><img src="/books/NBK11505/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></div><div id="ch34regeneration2.References"><h2 id="_ch34regeneration2_References_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ch34regeneration2.EXTYLES.1">Zihl J. Localised CNS lesions and their effect on visual function. 2000. </div></dd><dt>2.</dt><dd><div class="bk_ref" id="ch34regeneration2.EXTYLES.2">Chen DF, Jhaveri S, Schneider GE. Intrinsic changes in developing retinal neurons result in regenerative
|
||
failure of their axons. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>1995;<span class="ref-vol">92</span>:7287–7291.</span> [<a href="/pmc/articles/PMC41324/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC41324</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7638182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7638182</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ch34regeneration2.EXTYLES.3">Shewan D, Berry M, Cohen J. Extensive regeneration in vitro by early embryonic neurons on immature and
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host hippocampus. <span><span class="ref-journal">Brain Res. </span>1998;<span class="ref-vol">788</span>:202–206.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9555013" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9555013</span></a>]</div></dd><dt>174.</dt><dd><div class="bk_ref" id="ch34regeneration2.EXTYLES.174">Paxinos G, Watson C. <span class="ref-journal">The rat brain in stereotaxic coordinates.</span> Sydney: Academic
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Press; 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/6110810" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6110810</span></a>]</div></dd><dt>175.</dt><dd><div class="bk_ref" id="ch34regeneration2.EXTYLES.175">Paxinos G, Franklin KBJ. <span class="ref-journal">The mouse brain in stereotaxic coordinates.</span> 2nd ed. San Diego: Academic Press; 1997. </div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a>: © 2025 Webvision .<p class="small">All copyright for chapters belongs to the individual authors who created them. However, for non-commercial, academic purposes, images and content from the chapters portion of Webvision may be used with a non-exclusive rights under a Attribution, <a href="https://creativecommons.org/licenses/by-nc/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">Noncommercial 4.0 International (CC BY-NC) Creative Commons license</a>. Cite Webvision, http://webvision.med.utah.edu/ as the source. Commercial applications need to obtain license permission from the administrator of Webvision and are generally declined unless the copyright owner can/wants to donate or license material. Use online should be accompanied by a link back to the original source of the material. All imagery or content associated with blog posts belong to the authors of said posts, except where otherwise noted.</p></div><div class="small"><span class="label">Bookshelf ID: NBK11505</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/21413373" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">21413373</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/webvision/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/webvision/ch33regeneration1/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/webvision/electroretinography/" title="Next page in this title">Next ></a></div></div></div></div>
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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/NBK11505/?report=reader">PubReader</a></li><li><a href="/books/NBK11505/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK11505" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK11505" style="display:none" title="Cite this Page"><div class="bk_tt">Gaillard F, Sauve Y. Fetal Tissue Allografts in the Central Visual System of Rodents. 2005 May 1 [Updated 2007 Jun 25]. 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/NBK11505/pdf/Bookshelf_NBK11505.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="#ch34regeneration2.Introduction" ref="log$=inpage&link_id=inpage">Introduction</a></li><li><a href="#ch34regeneration2.The_Visual_System_of" ref="log$=inpage&link_id=inpage">The Visual System of Rodents: A Brief Overview</a></li><li><a href="#ch34regeneration2.Standard_Strategy_fo" ref="log$=inpage&link_id=inpage">Standard Strategy for Intracerebral Transplantation: Graft Morphology</a></li><li><a href="#ch34regeneration2.Neurons_within_the_T" ref="log$=inpage&link_id=inpage">Neurons within the Transplant Can Be Driven by Host Eye Visual Stimulation</a></li><li><a href="#ch34regeneration2.Do_Grafts_Receive_Ex" ref="log$=inpage&link_id=inpage">Do Grafts Receive Extensive Afferents?</a></li><li><a href="#ch34regeneration2.Can_Grafts_Send_Affe" ref="log$=inpage&link_id=inpage">Can Grafts Send Afferents to Host Targets?</a></li><li><a href="#ch34regeneration2.Restoration_of_Visua" ref="log$=inpage&link_id=inpage">Restoration of Visual Behavior</a></li><li><a href="#ch34regeneration2.AFN1" ref="log$=inpage&link_id=inpage">About the Authors</a></li><li><a href="#ch34regeneration2.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div 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