Lesion-induced Reorganization Research Articles

Synaptopodin Regulates Denervation-Induced Plasticity at Hippocampal Mossy Fiber Synapses.

Neurological diseases can lead to the denervation of brain regions caused by demyelination, traumatic injury or cell death. The molecular and structural mechanisms underlying lesion-induced reorganization of denervated brain regions, however, are a matter of ongoing investigation. In order to address this issue, we performed an entorhinal cortex lesion (ECL) in mouse organotypic entorhino-hippocampal tissue cultures of both sexes and studied denervation-induced plasticity of mossy fiber synapses, which connect dentate granule cells (dGCs) with CA3 pyramidal cells (CA3-PCs) and play important roles in learning and memory formation. Partial denervation caused a strengthening of excitatory neurotransmission in dGCs, CA3-PCs and their direct synaptic connections, as revealed by paired recordings (dGC-to-CA3-PC). These functional changes were accompanied by ultrastructural reorganization of mossy fiber synapses, which regularly contain the plasticity-regulating protein synaptopodin and the spine apparatus organelle. We demonstrate that the spine apparatus organelle and synaptopodin are related to ribosomes in close proximity to synaptic sites and reveal a synaptopodin-related transcriptome. Notably, synaptopodin-deficient tissue preparations that lack the spine apparatus organelle failed to express lesion-induced synaptic adjustments. Hence, synaptopodin and the spine apparatus organelle play a crucial role in regulating lesion-induced synaptic plasticity at hippocampal mossy fiber synapses.

Peripheral nerve injury induces glial activation in primary motor cortex

Peripheral nerve injury induces glial activation in primary motor cortex

Impaired Adrenergic-Mediated Plasticity of Prefrontal Cortical Glutamate Synapses in Rats with Developmental Disruption of the Ventral Hippocampus

Neonatal ventral hippocampus (nVH) lesion in rats is a useful model to study developmental origins of adult cognitive deficits and certain features of schizophrenia. nVH lesion-induced reorganization of excitatory and inhibitory neurotransmissions within prefrontal cortical (PFC) circuits is widely believed to be responsible for many of the behavioral abnormalities in these animals. Here we provide evidence that development of an aberrant medial PFC (mPFC) α-1 adrenergic receptor (α-1AR) function following neonatal lesion markedly affects glutamatergic synaptic plasticity within PFC microcircuits and contributes to PFC-related behavior abnormalities. Using whole-cell patch-clamp recording, we report that norepinephrine-induced α-1AR-dependent long-term depression (LTD) in a subset of cortico-cortical glutamatergic inputs is strikingly diminished in mPFC slices from nVH-lesioned rats. The LTD impairment occurs in conjunction with completely blunted α-1AR signaling through extracellular signal-regulated kinase 1/2. These α-1AR abnormalities have functional significance in a mPFC-related function, that is, extinction of conditioned fear memory. Post-pubertal animals with nVH lesion show significant resistance to extinction of fear by repeated presentations of the conditioned tone stimulus. mPFC infusion of an α-1AR antagonist (benoxathian) or LTD blocking peptide (Tat-GluR23Y) impaired fear extinction in sham controls, but had no significant effect in the lesioned animals. The data suggest that impaired α-1 adrenergic regulation of cortical glutamatergic synaptic plasticity may be an important mechanism in cognitive dysfunctions reported in neurodevelopmental psychiatric disorders.

Visually Evoked Responses in Extrastriate Area MT after Lesions of Striate Cortex in Early Life

Lesions of striate cortex [primary visual cortex (V1)] in adult primates result in blindness. In contrast, V1 lesions in neonates typically allow much greater preservation of vision, including, in many human patients, conscious perception. It is presently unknown how this marked functional difference is related to physiological changes in cortical areas that are spared by the lesions. Here we report a study of the middle temporal area (MT) of adult marmoset monkeys that received unilateral V1 lesions within 6 weeks of birth. In contrast with observations after similar lesions in adult monkeys, we found that virtually all neurons in the region of MT that was deprived of V1 inputs showed robust responses to visual stimulation. These responses were very similar to those recorded in neurons with receptive fields outside the lesion projection zones in terms of firing rate, signal-to-noise ratio, and latency. In addition, the normal retinotopic organization of MT was maintained. Nonetheless, we found evidence of a very specific functional deficit: direction selectivity, a key physiological characteristic of MT that is known to be preserved in many cells after adult V1 lesions, was absent. These results demonstrate that lesion-induced reorganization of afferent pathways is sufficient to develop robust visual function in primate extrastriate cortex, highlighting a likely mechanism for the sparing of vision after neonatal V1 lesions. However, they also suggest that interactions with V1 in early postnatal life are critical for establishing stimulus selectivity in MT.

What can we learn about the visual cortex from retinal lesions?

Event Abstract Back to Event What can we learn about the visual cortex from retinal lesions? Ulf T. Eysel1* and Dimitrios V. Giannikopoulos1 1 Ruhr University, Department of Neurophysiology, Germany Binocular central retinal lesions induce a lesion projection zone (LPZ) with complete loss of visual excitability followed by extensive reorganization in the cat primary visual cortex. In how far can functional single cell properties be restored during the lesion-induced reorganization process in adulthood? We studied the dynamics of reorganization in the LPZ by single cell recordings with special emphasis on receptive field size (RF), orientation (OS) and direction selectivity (DS) over a period of one year in adult cats. Inside the LPZ the percentage of reactivated cells increased with time, and after 1 year reactivation spanned a total distance of more than 3.5 mm from the border towards the center of the LPZ. New visually responsive single cells had exceptionally large RFs, reduced sharpness of OS and supernormal DS surprisingly biased to directions centrifugal from the center of the LPZ. The initially very large RFs recovered to sizes as normally present at the border of the central retinal lesion, while the fine grain resolution obtained in controls with normal input from the central retina was never reestablished. OS did not recover at all, it decreased in quality inside the LPZ with distance from the border (Giannikopoulos and Eysel, 2006). The centrifugal bias of DS remained up to 12 months, however, after 2 weeks the strength of DS returned to and stayed normal inside the LPZ close to the border (up to 0.5 mm). 2 mm further inside normal values were observed at 12 weeks, but subnormal DS strength prevailed within the LPZ after 1 year. In summary, the long-ranging reactivation of single cells inside the LPZ in cat visual cortex is accompanied by reductions of functional specificity that can only partially or not at all be compensated by the adult plasticity of lateral connections and intracortical computations. Subcortical input appears most crucial for OS. RF can be restored best and appears most robust after reorganization. Supported by the DFG (SFB 509). Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Oral Presentation Topic: Vision: from the evolution of retinas to the evolution of ideas Citation: Eysel UT and Giannikopoulos DV (2010). What can we learn about the visual cortex from retinal lesions?. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00250 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 May 2010; Published Online: 05 May 2010. * Correspondence: Ulf T Eysel, Ruhr University, Department of Neurophysiology, Bochum, Germany, eysel@rub.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Ulf T Eysel Dimitrios V Giannikopoulos Google Ulf T Eysel Dimitrios V Giannikopoulos Google Scholar Ulf T Eysel Dimitrios V Giannikopoulos PubMed Ulf T Eysel Dimitrios V Giannikopoulos Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Basal Forebrain Cholinergic Input Is Not Essential for Lesion-Induced Plasticity in Mature Auditory Cortex

The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.

Vascular endothelial growth factor and its receptor Flk-1 are expressed in the hippocampus following entorhinal deafferentation

Vascular endothelial growth factor (VEGF) has been thought of as a mitogen that promotes proliferation of endothelial cells and as a neurotrophic factor that stimulates neurogenesis and axonal growth in both peripheral and central nervous systems. To investigate the potential involvement of VEGF in the lesion-induced reorganization in the brain, the expression changes of VEGF and its receptor Flk-1 were analyzed in the mouse hippocampus after transections of the entorhinal afferents. In situ hybridization and immunohistochemistry showed the time-dependent expression upregulation of VEGF mRNA and protein in the entorhinally denervated hippocampal stratum lacunosum-moleculare and dentate outer molecular layer, which initiated by 3 days postlesion, reached its maximum at 7–15 days postlesion, still persisted by 30 days postlesion for protein, and recovered to the normal levels at 30 days postlesion for mRNA and at 60 days postlesion for protein. Double labeling of VEGF and glial fibrillary acidic protein revealed that VEGF-expressing cells in the denervated areas were reactive astrocytes. Semi-quantitative RT-PCR analysis showed that VEGF receptor Flk-1 mRNA was also time-dependently upregulated in the deafferented hippocampus with its maximal elevation at 7–15 days postlesion while the Flt-1 mRNA levels remained unchanged at any time point we examined. Immunohistochemistry analysis also displayed the upregulation of Flk-1 protein in the denervated stratum lacunosum-moleculare and outer molecular layer with a time course similar to that of VEGF mRNA upregulation. Flk-1 receptors were found to be expressed not only by reactive astrocytes but also by neurites, which most likely belong to sprouting axons by 7 days postlesion and regrowing dendrites by 15–30 days postlesion. From these data we suggest that the spatiotemporal upregulation of VEGF and Flk-1 in the hippocampus is induced by entorhinal deafferentation and that VEGF may be involved in the structural reorganization in the deafferented hippocampus via directly or indirectly promoting neurite growth.

Distribution of choline acetyltransferase immunoreactivity in the vestibular nuclei of normal and unilateral vestibular neurectomized cats.

Post-lesion recovery of vestibular functions is a suitable model for studying adult central nervous system plasticity. The vestibular nuclei complex (VN) plays a major role in the recovery process and neurochemical reorganizations have been described at this brainstem level. The cholinergic system should be involved because administration of cholinergic agonists and antagonists modify the recovery time course. This study was aimed at analysing the postlesion changes in choline acetyltransferase immunoreactivity (ChAT-Ir) in the VN of cats killed 1 week, 3 weeks or 1 year following unilateral vestibular neurectomy. ChAT-positive neurons and varicosities were immunohistochemically labelled and quantified (cell count and surface measurement, respectively) by means of an image analysing system. The spatial distribution of ChAT-Ir within the VN of control cats showed darkly stained neurons and varicosities mainly located in the caudal parts of the medial (MVN) and inferior (IVN) VN, the nucleus prepositus hypoglossi (PH) and, to a lesser extent, in the medial part of the superior vestibular nucleus (SVN). Lesion-induced changes consisted in a significant increase in both the number of ChAT-positive neurons (IVN, SVN) and the surface of ChAT-positive varicosities (IVN, SVN, PH). They were observed bilaterally in the acute (1 year and 3 weeks) and compensated (1 year) cats for the SVN and PH, while they persisted only in the IVN on the lesioned side in the compensated cats. These findings demonstrate vestibular lesion-induced reorganization of the cholinergic system in the IVN, SVN and PH which could contribute to postural and oculomotor function recovery.

Sensitive period for lesion-induced reorganization of intracortical projections within the vibrissae representation of rat's primary somatosensory cortex.

Previous experiments from this laboratory demonstrated that intracortical connections in lamina IV of the rat primary somatosensory cortex (SI) are most dense outside the patches of cytochrome oxidase (CO) staining that correspond to the mystacial vibrissae. This pattern of intracortical connections becomes apparent on postnatal day 4 (P-4), at least 2 days after the appearance of the vibrissae-related pattern of thalamocortical afferents. Transection of the infraorbital nerve (ION) on the day of birth (P-0) disrupts both the CO and intracortical projection patterns. This series of experiments was undertaken to determine whether the patterning of either thalamocortical afferents or intracortical projections defines the end of the period over which peripheral damage can alter intracortical projections in lamina IV of SI. The infraorbital nerve (ION) was transected in different cohorts of rats on P-1 through P-5, and animals were allowed to survive > or =45 days, at which time biotinylated dextran amine (BDA) injections were made into the SI. After 7 days, animals were killed, and alternate cortical sections were processed for the demonstration of BDA or CO. Transection of the ION on P-1 or P-2 altered the patterning of both CO and intracortical connections in the SI. In contrast, cutting the ION on P-3 left the pattern of CO densities in the SI intact, but significantly altered the patterning of intracortical connections. Transection of the nerve on P-5 resulted in qualitatively and quantitatively normal patterns of both CO densities and BDA-labelled intracortical projections. These results indicate that the establishment of a stable barrel pattern in layer IV of the SI is not sufficient for normal adult patterning of intracortical projections in this lamina. However, once the mature pattern of intracortical projections in layer IV is established, ION lesions can no longer alter it.

Plasticity of synaptic connections in sensory-motor pathways of the adult locust flight system.

We investigated possible roles of retrograde signals and competitive interactions in the lesion-induced reorganization of synaptic contacts in the locust CNS. Neuronal plasticity is elicited in the adult flight system by removal of afferents from the tegula, a mechanoreceptor organ at the base of the wing. We severed one hindwing organ and studied the resulting rearrangement of synaptic contacts between flight interneurons and afferent neurons from the remaining three tegulae (2 forewing, 1 hindwing). This was done by electric stimulation of afferents and intracellular recording from interneurons (and occasionally motoneurons). Two to three weeks after unilateral tegula lesion, connections between tegula afferents and flight interneurons were altered in the following way. 1) Axons from the forewing tegula on the operated side had established new synaptic contacts with metathoracic elevator interneurons. In addition, the amplitude of compound excitatory postsynaptic potentials elicited by electric stimulation was increased, indicating that a larger number of afferents connected to any given interneuron. 2) On the side contralateral to the lesion, connectivity between axons from the forewing tegula and elevator interneurons was decreased. 3) The efficacy of the (remaining) hindwing afferents appeared to be increased with regard to both synaptic transmission to interneurons and impact on flight motor pattern. 4) Flight motoneurons, which are normally restricted to the ipsilateral hemiganglion, sprouted across the ganglion midline after unilateral tegula removal and apparently established new synaptic contacts with tegula afferents on that side. The changes on the operated side are interpreted as occupation of synaptic space vacated on the interneurons by the severed hindwing afferents. On the contralateral side, the changes in synaptic contact must be elicited by retrograde signals from bilaterally arborizing flight interneurons, because tegula projections remain strictly ipsilateral. The pattern of changes suggests competitive interactions between forewing and hindwing afferents. The present investigation thus presents evidence that the CNS of the mature locust is capable of extensive synaptic rearrangement in response to injury and indicates for the first time the action of retrograde signals from interneurons.

Cerebral Metabolism following Neonatal or Adult Hemineodecortication in Cats: I. Effects on Glucose Metabolism Using [14C]2-Deoxy-D-Glucose Autoradiography

In the cat, cerebral hemispherectomy sustained neonatally results in a remarkable degree of recovery and/or sparing of function as compared with the effects of a similar lesion but sustained in adulthood. We have proposed that this effect is due to a combination of reduced neuronal loss within partially denervated structures and a lesion-induced reorganization of corticofugal projections arising from the remaining intact hemisphere in the neonatally lesioned animal. The current study was designed to assess the physiological consequences of these anatomical changes utilizing [14C]2-deoxy-D-glucose autoradiography. A total of 17 adult cats were studied. Seven animals served as intact controls, five received a left cerebral hemineodecortication as neonates (NH; mean age 11.4 days), and five sustained the same lesion in adulthood (AH). Histological analysis indicated that the lesion was very similar between the two age groups and essentially represented a unilateral hemineodecortication. Local CMRglc (LCMRglc; mumol 100 g-1 min-1) values were calculated for 50 structures bilaterally and indicated that in the remaining intact contralateral (right) cerebral cortex (including all areas measured), AH cats exhibited a significantly (p < 0.05) lower level of LCMRglc (ranging from 20 to 72 mumol 100 g-1 min-1) than NH (ranging from 49 to 81 mumol 100 g-1 min-1). In comparison, the rates of NH cats within the cerebral cortex were very similar to those seen in intact animals (ranging from 48 to 119 mumol 100 g-1 min-1). Ipsilateral to the lesion in AH cats, the structures spared by the resection, including the basal ganglia and thalamus, exhibited LCMRglc rates of between 23 and 69 mumol 100 g-1 min-1, which were significantly lower (p < 0.05) than in NH cats (range 47-72 mumol 100 g-1 min-1). Considering all structures, both age-at-lesion groups exhibited a lower level of metabolism compared with similar measurements for intact control animals (LCMRglc range 45-75 mumol 100 g-1 min-1). However, this depression of glucose metabolism was more pronounced in the AH cats (p < 0.05). These results indicate that following neonatal hemineodecortication, LCMRglc is maintained at a higher level in many regions of the brain than in animals that sustain the same resection in adulthood. This higher level of glucose metabolism in NH animals suggests that the lesion-induced anatomical reorganization of structures not directly injured by the lesion plays a functional role that is probably responsible for the greater degree of recovery and/or sparing of function in these early lesioned cats.

Lesion-induced reorganization in the brainstem is not completely expressed in somatosensory cortex.

Electrophysiological and neuroanatomical methods were used to determine the extent to which neonatal forelimb removal altered the organization of the cuneate nucleus and representations of the fore- and hindlimbs in the primary somatosensory cortex of adult rats. Neonatal forelimb removal resulted in invasion of the cuneate nucleus by sciatic nerve primary afferents and development of cuneothalamic projection neurons with split receptive fields that included both the hindlimb and forelimb stump. Mapping in the primary somatosensory cortex of the neonatally manipulated adult rats demonstrated abnormalities, but the major change observed in the cuneate nucleus was demonstrable at only a few (5%) cortical recording sites in the remaining stump representation and there were none at all in the hindlimb representation. These results suggest that lesion-induced brainstem reorganization may be functionally suppressed at either the thalamic or cortical level.

Effects of postnatal blockade of cortical activity with tetrodotoxin upon lesion-induced reorganization of vibrissae-related patterns in the somatosensory cortex of rat

Previous studies have shown that postnatal blockade of thalamocortical activity with either tetrodotoxin (TTX) or the NMDA, receptor antagonist dl-2-amino-5-phosphonovalerate (APV) does not prevent the formation of vibrissae-related patterns. In the present study, blockade of cortical activity with TTX was combined with ablation of a row of vibrissae follicles or transection of the infraorbital nerve (ION, the trigeminal nerve branch that supplies the vibrissae follicles) to determine whether the cortical reorganization that follows these lesions in otherwise untreated animals was dependent upon neuronal activity that could be blocked with TTX. The results demonstrated that cortical TTX implants had no quantitative or qualitative effects upon the cortical reorganization that followed either vibrissae follicle cauterization or ION transection.

The susceptibility of CA1 pyramidal cells to cerebral ischemia is maintained after neonatal, lesion-induced reorganization of the hippocampal circuitry.

Acute lesions of hippocampal pathways have been shown previously to ameliorate CA1 pyramidal cell loss after subsequent transient cerebral ischemia. In this study, we examined the effect of chronic neonatal lesion with reorganization of hippocampal circuitry on adult postischemic neuron loss in the hippocampus. Newborn rats were subjected to unilateral knife-cut lesions at various positions along the trisynaptic entorhino-dentato-hippocampal pathway. Seven months later, the rats were subjected to transient cerebral ischemia using the four-vessel occlusion technique. At the time of killing 4 days later, a Nissl stain was used to demonstrate neuronal degeneration, while connective reorganization resulting from the neonatal lesions was monitored by Timm staining. In one group of rats, neonatal lesions had caused severe depletion of entorhinal projections to the septodorsal fascia dentata and hippocampus (CA1 and CA3), without any direct damage to the dorsal hippocampus itself. Another group had extensive damage of the dorsal CA3, with removal of the Schaffer collaterals from these levels to CA1, and variable damage to the entorhinal afferents. In both groups, the extent and pattern of ischemia-induced degeneration of CA1 pyramidal cells were the same on the lesioned and nonlesioned sides of the brain, demonstrating that neonatal lesions and the subsequent connective reorganization did not have a sparing effect. Seen in relationship to previous observations in adult rats of the neuroprotective actions of acute, preischemic lesions of the trisynaptic hippocampal pathway, it is concluded that CA1 pyramidal cell loss requires the presence of intact excitatory afferents rather than an intact hippocampal circuitry.

Changes in the cat's visual system following retinal lesions. A functional reorganization in the mature central nervous system (author's transl)

Layers of the lateral geniculate nucleus (LGN) of mature cats were completely or partially deafferentated by precisely defined photocoagulation of the retina. Single neuron recordings were performed with microelectrodes from an experimentally modified layer and compared with neurons from a normally innervated layer in the same animal. The spontaneous activity of cells after monocular deafferentation was severely reduced in the beginning and increased subsequently without reaching normal values within ten weeks. At this time the pattern of excitation and inhibition after light stimulation of the nondominant unsevered eye had completely changed. Twenty-seven days and later after coagulation of a part of the nasal retina light-excitable cells with displaced receptive fields were found in the LGN in the border region of the partial visual deafferentation. This indicated a lesion-induced lateral expansion of excitation by up to 200 microns within the LGN. Small, round retinal lesions initially caused a complete visual deafferentation of a certain region in the LGN. After 30 days and later visual excitation from the normally innervated surrounding was observed in cells which were not light-excitable during the first days after coagulation. Thus, while the retinal lesion itself did not substantially change, its representation within the LGN was distinctly reduced. The results indicate lesion-induced reorganization in the subcortical visual system of the adult cat. This might enable the system to a certain degree of compensation after loss of visual inputs. The transferability of these results to human pathophysiology has to be critically considered.