Cyclosporin A protects striatal neurons in vitro and in vivo from 3‐nitropropionic acid toxicityLeventhal, Liza; Sortwell, Caryl E.; Hanbury, Rose; Collier, Timothy J.; Kordower, Jeffrey H.; Palfi, Stéphane
doi: 10.1002/1096-9861(20001002)425:4<471::AID-CNE1>3.0.CO;2-Upmid: 10975874
The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3‐nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20–30% reduction of striatal glutamic acid decarboxylase‐immunoreactive (GAD‐ir) neurons. A single treatment with CsA protected GAD‐ir neurons from 3NP toxicity at lower (0.2 or 1.0 μM), but not at higher (5.0 μM) doses. Similar findings were seen when the cultures were treated twice with cyclosporin. In vivo experiments used the Lewis rat model of Huntington's disease (HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injections to disrupt the blood‐brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP‐lesioned rats displayed significantly more dopamine‐and adenosine‐3`,5`‐monophosphate‐regulated phosphoprotein (DARPP32‐ir) neurons ipsilateral to BBB disruption compared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second experiment, stereological counts of DARPP32‐ir neurons revealed that CsA protected striatal neurons in a dose‐dependent manner following bilateral disruption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) but not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32‐ir striatal neurons relative to vehicle‐treated 3NP‐lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant protection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by protecting vulnerable neurons from the primary pathological event observed in HD. J. Comp. Neurol. 425:471–478, 2000. © 2000 Wiley‐Liss, Inc.
Vascular niche for adult hippocampal neurogenesisPalmer, Theo D.; Willhoite, Andrew R.; Gage, Fred H.
doi: 10.1002/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3pmid: 10975875
The thin lamina between the hippocampal hilus and granule cell layer, or subgranule zone (SGZ), is an area of active proliferation within the adult hippocampus known to generate new neurons throughout adult life. Although the neuronal fate of many dividing cells is well documented, little information is available about the phenotypes of cells in S‐phase or how the dividing cells might interact with neighboring cells in the process of neurogenesis. Here, we make the unexpected observation that dividing cells are found in dense clusters associated with the vasculature and roughly 37% of all dividing cells are immunoreactive for endothelial markers. Most of the newborn endothelial cells disappear over several weeks, suggesting that neurogenesis is intimately associated with a process of active vascular recruitment and subsequent remodeling. The present data provide the first evidence that adult neurogenesis occurs within an angiogenic niche. This environment may provide a novel interface where mesenchyme‐derived cells and circulating factors influence plasticity in the adult central nervous system. J. Comp. Neurol. 425:479–494, 2000. © 2000 Wiley‐Liss, Inc.
Comparative distribution of pituitary adenylate cyclase‐activating polypeptide (PACAP) binding sites and PACAP receptor mRNAs in the rat brain during developmentBasille, Magali; Vaudry, David; Coulouarn, Yolaine; Jegou, Sylvie; Lihrmann, Isabelle; Fournier, Alain; Vaudry, Hubert; Gonzalez, Bruno
doi: 10.1002/1096-9861(20001002)425:4<495::AID-CNE3>3.0.CO;2-Apmid: N/A
The distribution and density of pituitary adenylate cyclase‐activating polypeptide (PACAP) binding sites as well as PACAP‐specific receptor 1 (PAC1‐R), vasoactive intestinal polypeptide/PACAP receptor 1 (VPAC1‐R), and VPAC2‐R mRNAs have been investigated in the rat brain from embryonic day 14 (E14) to postnatal day 8 (P8). Significant numbers of binding sites for the radioiodinated, 27‐amino‐acid form of PACAP were detected as early as E14 in the neuroepithelia of the metencephalon and the myelencephalon. From E14 to E21, the density of binding sites in the germinative areas increased by 3‐ to 5‐fold. From birth to P12, the density of binding sites gradually declined in all neuroepithelia except in the external granule cell layer of the cerebellum, where the level of binding sites remained high during the first postnatal weeks. Only low to moderate densities of PACAP binding sites were found in regions other than the germinative areas, with the exception of the internal granule cell layer of the cerebellum, which contained a high density of sites. The localization of PACAP receptor mRNAs was investigated by in situ hybridization using [35S] uridine triphosphate‐specific riboprobes. The evolution of the distribution of PAC1‐R and VPAC1‐R mRNAs was very similar to that of PACAP binding sites, the concentration of VPAC1‐R mRNA being much lower than that of PAC1‐R mRNA. In contrast, intense expression of VPAC2‐R mRNA was observed in brain regions other than germinative areas, such as the suprachiasmatic, ventral thalamic, and dorsolateral geniculate nuclei. The discrete localization of PACAP binding sites as well as PAC1‐R and VPAC1‐R mRNAs in neuroepithelia during embryonic life and postnatal development strongly suggests that PACAP, acting through PAC1‐R and/or VPAC1‐R, may play a crucial role in the regulation of neurogenesis in the rat brain. J. Comp. Neurol. 425:495–509, 2000. © 2000 Wiley‐Liss, Inc.
Inferior parietal lobule projections to the presubiculum and neighboring ventromedial temporal cortical areasDing, Song‐Lin; Van Hoesen, Gary; Rockland, Kathleen S.
doi: 10.1002/1096-9861(20001002)425:4<510::AID-CNE4>3.0.CO;2-Rpmid: 10975877
The entorhinal and perirhinal cortices have long been accorded a special role in the communications between neocortical areas and the hippocampal formation. Less attention has been paid to the presubiculum, which, however, is also a component of the parahippocampal gyrus, receives dense inputs from several cortical areas, and itself is a major source of connections to the entorhinal cortex (EC). In part of a closer investigation of corticohippocampal systems, the authors applied single‐axon analysis to the connections from the inferior parietal lobule (IPL) to the presubiculum. One major result from this approach was the finding that many of these axons (at least 10 of 14) branch beyond the presubiculum. For 4 axons, branches were followed to area TF and to the border between the perirhinal and entorhinal cortices, raising the suggestion that these areas, which sometimes are viewed as serial stages, are tightly interconnected. In addition, the current data identify several features of presubicular organization that may be relevant to its functional role in visuospatial or memory processes: 1) Terminations from the IPL, as previously reported for prefrontal connections (Goldman‐Rakic et al. [1984] Neuroscience 12:719–743), form two to four patches in the superficial layers. These align in stripes, but only for short distances (≈1.5 mm). This pattern suggests a strong compartmentalization in layers I and II that is also indicated by cytochrome oxidase and other markers. 2) Connections tend to be bistratified, terminating in layers I–II and deeper in layer III. 3) Single axons terminate in layer I alone or in different combinations of layers. This may imply some heterogeneity of subtypes. 4) Individual axons, both ipsilateral projecting (n = 14 axons) and contralateral projecting (n = 6 axons), tend to have large arbors (0.3–0.8 mm across). Finally, the authors observe that projections from the IPL, except for its anteriormost portion, converge at the perirhinal‐entorhinal border around the posterior tip of the rhinal sulcus. These projections partially overlap with projections from ventromedial areas TE and TF, and this convergence may contribute to the severe deficits in visual recognition memory resulting from ablations of rhinal cortex. J. Comp. Neurol. 425:510–530, 2000. © 2000 Wiley‐Liss, Inc.
Investigation of cortical reorganization in area 17 and nine extrastriate visual areas through the detection of changes in immediate early gene expression as induced by retinal lesionsArckens, Lutgarde; Van Der Gucht, Estel; Eysel, Ulf T.; Orban, Guy A.; Vandesande, Frans
doi: 10.1002/1096-9861(20001002)425:4<531::AID-CNE5>3.0.CO;2-Jpmid: 10975878
The effect of binocular central retinal lesions on the expression of the immediate early genes c‐fos and zif268 in the dorsal lateral geniculate nucleus (dLGN) and the visual cortex of adult cats was investigated by in situ hybridization and immunocytochemistry. In the deafferented region of the dLGN, the c‐fos mRNA level was decreased within 3 days. The dimensions of the geniculate region showing decreased amounts of c‐fos mRNA matched the predictions based on the lesion size and the retinotopic maps of Sanderson ([1971] J. Comp. Neurol. 143:101–118). We did not detect zif268 mRNA in the dLGN. At the cortical level, both c‐fos and zif268 mRNA expression decreased in the sensory‐deprived region of area 17. In addition, the portions of areas 18, 19, 21a, 21b, and 7, as well as the posterior medial lateral suprasylvian area, the posterior lateral lateral suprasylvian area, the ventral lateral suprasylvian area, and the dorsal lateral suprasylvian area corresponding to the retinal lesions also displayed decreased c‐fos and zif268 mRNA levels. Immunocytochemistry revealed similar changes for Zif268 and Fos protein. Three days post lesion, the dimensions of the lesion‐affected cortical loci exceeded the predictions in relation to the size of the retinal lesions and the available retinotopic maps. Longer postlesion survival times clearly resulted in a time‐dependent restoration of immediate early gene expression from the border to the center of the lesion‐affected cortical portions. Our findings represent a new approach for investigating the capacity of adult sensory systems to undergo plastic changes following sensory deprivation and for defining the topographic nature of sensory subcortical and cortical structures. J. Comp. Neurol. 425:531–544, 2000. © 2000 Wiley‐Liss, Inc.
Spatial and temporal expression of short, long/medium, or both opsins in human fetal conesXiao, Ming; Hendrickson, Anita
doi: 10.1002/1096-9861(20001002)425:4<545::AID-CNE6>3.0.CO;2-3pmid: N/A
Human cone photoreceptors are characterized by long (L), medium (M), or short (S) wavelength‐specific opsin. No reports have described the developmental pattern of human cone opsin expression, nor has the existence of human cones containing more than one opsin been tested. Single‐and double‐label immunocytochemistry and in situ hybridization have been used to determine the developmental pattern of opsin appearance and to investigate the presence of double‐labeled cones in sections and wholemounts of human fetal, neonatal, infant, and adult retina. S opsin protein appears in and around the fovea at fetal week (Fwk) 10.9, whereas L/M opsin first appears in the fovea at Fwk 14–15. S opsin mRNA and protein are consistently detected much farther into peripheral retina than L/M opsin, indicating that S appears before L/M opsin. S cones cover 90% of the retina by Fwk 19. L/M cones appear outside the central retina by Fwk 21.5 and reach the retinal edge by Fwk 34–37. The spatial pattern of mRNA expression closely matches that for protein, but mRNA appears slightly earlier than protein at a given retinal point, indicating that only short delays occur between mRNA expression and translation into protein. Cones containing both S and L/M opsin (S+L/M) appear around the fovea shortly after L/M opsin is expressed, are found in more peripheral retina at older ages, and decrease in number after birth. Some S+L/M cones are still detected in adult retina. Both S opsin protein and mRNA appear significantly earlier than L/M mRNA or protein across the human retina, suggesting that the two cone types differentiate under independent controlling factors. However, the presence of single cones containing both S and L/M opsin during development suggests that human cones can respond to the factors controlling expression of each opsin. J. Comp. Neurol. 425:545–559, 2000. © 2000 Wiley‐Liss, Inc.
Fundamental GABAergic amacrine cell circuitries in the retina: Nested feedback, concatenated inhibition, and axosomatic synapsesMarc, Robert E.; Liu, W.‐L.S.
doi: 10.1002/1096-9861(20001002)425:4<560::AID-CNE7>3.0.CO;2-Dpmid: 10975880
Presynaptic γ‐aminobutyrate‐immunoreactive (GABA+) profiles were mapped in the cyprinid retina with overlay microscopy: a fusion of electron and optical imaging affording high‐contrast ultrastructural and immunocytochemical visualization. GABA+ synapses, deriving primarily from amacrine cells (ACs), compose 92% of conventional synapses and 98% of the input to bipolar cells (BCs) in the inner plexiform layer. GABA+ AC synapses, the sign‐inverting elements of signal processing, are deployed in micronetworks and distinctive synaptic source/target topologies. Nested feedback micronetworks are formed by three types of links (BC → AC, reciprocal BC ← AC, and AC → AC synapses) arranged as nested BC↔ [AC → AC] loops. Circuits using nested feedback can possess better temporal performance than those using simple reciprocal feedback loops. Concatenated GABA+ micronetworks of AC → AC and AC → AC → AC chains are common and must be key elements for lateral spatial, temporal, and spectral signal processing. Concatenated inhibitions may represent exceptionally stable, low‐gain, sign‐conserving devices for receptive field construction. Some chain elements are GABA immunonegative (GABA−) and are, thus, likely glycinergic synapses. GABA+ synaptic baskets target the somas of certain GABA+ and GABA− cells, resembling cortical axosomatic synapses. Finally, all myelinated intraretinal profiles are GABA+, suggesting that some efferent systems are sources of GABAergic inhibition in the cyprinid retina and may comprise all axosomatic synapses. These micronetworks are likely the fundamental elements for receptive field shaping in the inner plexiform layer, although few receptive field models incorporate them as functional components. Conversely, simple feedback and feedforward synapses may often be chimeras: the result of an incomplete view of synaptic topology. J. Comp. Neurol. 425:560–582, 2000. © 2000 Wiley‐Liss, Inc.
Human cocaine‐ and amphetamine‐regulated transcript (CART) mRNA is highly expressed in limbic‐ and sensory‐related brain regionsHurd, Yasmin L.; Fagergren, Pernilla
doi: 10.1002/1096-9861(20001002)425:4<583::AID-CNE8>3.0.CO;2-#pmid: 10975881
Cocaine‐ and amphetamine‐regulated transcript (CART) is a novel putative peptide neurotransmitter. We studied the expression of CART mRNA throughout the human postmortem brain by using in situ hybridization histochemistry. The cortical expression was distinct with high mRNA expression levels in the piriform cortex, dorsolateral prefrontal cortex, lateral orbital prefrontal cortex, medial orbitofrontal cortex, and middle temporal cortex, but extremely low levels in immediately adjacent cortical areas, e.g., the medial prefrontal cortex, subcallosal gyrus, and superior temporal cortex. Within the striatum, CART mRNA was only detected in the nucleus accumbens, primarily in the most medial area. No positive CART mRNA‐expressing neurons were found in the dorsal caudate nucleus and putamen. High mRNA expression levels were evident within the bed nucleus of the stria terminalis as well as the amygdala (central, cortical, and medial nuclei). In the hippocampus, intense expression was found within the uncal gyrus and moderate to high levels in the CA3 and polymorphic layer of the dentate gyrus. CART mRNA expression was also detected in the locus coeruleus and dorsal raphe, but no positive labeling was apparent in the substantia nigra. Overall, the most abundant CART mRNA expression levels in the human brain were detected within in the hypothalamus (posterior, paraventricular nucleus, premammillary, tuberomamillary, dorsomedial, arcuate) and the thalamus (mediodorsal, pulvinar, anterior, zona incerta, geniculate). Rat brain specimens were also studied and many similarities to the human CART mRNA expression were evident. However, the most marked species difference was the virtual absence of the CART mRNA in the rat thalamus. J. Comp. Neurol. 425:583–598, 2000. © 2000 Wiley‐Liss, Inc.
Parallel analyses of nociceptive neurones in rat superior colliculus by using c‐fos immunohistochemistry and electrophysiology under different conditions of anaesthesiaWang, Shaomei; Wang, Hongying; Niemi‐Junkola, Uura; Westby, G.W. Max; Mchaffie, John G.; Stein, Barry E.; Redgrave, Peter
doi: 10.1002/1096-9861(20001002)425:4<599::AID-CNE9>3.0.CO;2-Epmid: 10975882
Multiple sensory inputs to the superior colliculus (SC) play an important role in guiding head and eye movements toward or away from biologically significant stimuli. Much is now known about the visual, auditory, and somatosensory response properties of SC neurones that mediate these behavioural reactions. Rather less is known about the responses of SC neurones to noxious stimuli, and thus far, most of this information has been obtained in anaesthetised animals. Therefore, the purpose of the present study was to use the c‐fos immunohistochemical technique and standard extracellular electrophysiology as parallel measures of nociceptive activity in the SC under different conditions of anaesthesia. In unanaesthetised animals, experimental and control treatments induced a qualitatively similar pattern of Fos‐like immunoreactivity (FLI) in the SC, which was quantitatively related to the severity or biologic salience of the treatment; thus, baseline control < control injections of saline < a nonpainful stressor (immobilisation) < noxious injections of formalin. Compared with baseline levels, urethane and avertin anaesthesia induced FLI expression in the SC intermediate layers, although the FLI response to both noxious stimulation and control conditions was differentially suppressed in different layers of the SC by anaesthesia. Parallel electrophysiologic recordings found that anaesthesia was associated with high levels of spontaneous activity in the SC intermediate layers, often in neurones which were also nociceptive. High rates of background spike activity were also induced in the SC intermediate layers by noxious stimulation in chronically recorded awake animals. Although these results point to some differences between the nociceptive responses of SC neurones in anaesthetised and unanaesthetised animals, both data sets support the view that there are different populations of nociceptive neurones in the rodent SC that may be related to different adaptive functions of pain. J. Comp. Neurol. 425:599–615, 2000. © 2000 Wiley‐Liss, Inc.