Neuronal Reorganization Research Articles

Role of peripheral nerve fibres in acute and chronic inflammation in arthritis

The peripheral nervous system takes an active part in inflammatory processes by regulating effector cell function and reallocation of energy to the immune system. During acute inflammation, rapid neuronal reorganization and change of activity takes place. The hallmarks of this process are an increase in systemic sympathetic activity, a decrease in systemic parasympathetic activity and loss of sympathetic nerve fibres from sites of inflammation concomitant with increased innervation with sensory nerve fibres and increased sensory nerve fibre activity. On a systemic level, the increase in sympathetic activity (and decrease in parasympathetic activity) is necessary to provide enough energy to nourish the activated immune system. In locally inflamed tissue, the decrease in sympathetic nerve fibre density results in reduced anti-inflammatory signalling and, together with neuropeptides released from sensory nerve fibres, promotes local inflammation. In acute inflammation, this 'inflammatory configuration' of the peripheral nervous system favours the rapid clearance of antigenic threats. However, in chronic autoimmune inflammation, these changes of the peripheral nervous system lead to an unfavourable situation with ongoing energy reallocation and continuous local destruction. As an example of a chronic inflammatory condition, we discuss evidence for neuroimmune regulation in autoimmune arthritis with a focus on the sympathetic nervous system.

Resection of the epileptogenic lesion abolishes seizures and reduces inflammatory cytokines of patients with temporal lobe epilepsy

Persistent neuroinflammation is implicated in the pathogenesis of seizures and neuronal degeneration of temporal lobe epilepsy (TLE). Circulating level of inflammatory cytokines was determined during inter-ictal period of 25 non-operated and 10 patients (OP) submitted to anterior temporal lobectomy. OP patients showed marked reduction of IL-1β, TNFα, MIP-1α, but not IL-6 and TGF-β1. Paired analysis done before and after lobectomy showed reduction of inflammatory cytokines but increased TGF-β1 levels, and lack of seizures for more than 6months. Maintenance of high TGF-β1 and IL-6 cytokines in both groups suggests a role in down-regulation of neuroinflammation and promotion of brain tissue remodeling for neuronal reorganization.

Sensory Neuropathy May Cause Central Neuronal Reorganization but Does Not Respecify Perceptual Quality or Localization of Sensation

Functional reorganization in the somatosensory network after peripheral nerve lesions has been suspected to modify the clinical expression of symptoms. However, no conclusive evidence exists to support this notion. We addressed this question by investigating the topographic distribution of the subjective sensory report in various chronic human mononeuropathies. We report the clinical results of 86 patients who were diagnosed with meralgia paresthetica, 86 patients with ulnar neuropathy at the elbow, and 203 patients with carpal tunnel syndrome. In the carpal tunnel syndrome group, 10% of the patients exhibited a spread of sensory symptoms beyond the innervation territory of the median nerve. As previously reported, this spread was contingent upon an indirect compressive lesion of the ulnar nerve at the wrist. In all of the patients who were affected with meralgia paresthetica or ulnar neuropathy at the elbow, the peripheral referral of sensation was always within the anatomic distribution of the affected nerve. In human neuropathies, the projected sensory symptoms are restricted to the innervation territories of the affected nerves, with no extraterritorial spread. Thus, the somatosensory localization function remains accurate, despite the central reorganization that presumably occurs after nerve injury. We conclude that reorganization of the sensory connections within the central nervous system after peripheral nerve injury in humans is a clinically silent adaptive phenomenon.

Neuroimaging predictors of stroke outcome: Implications for neurorehabilitation

Advances in neuroimaging have greatly improved our understanding of stroke not only in the acute, but also in the subacute and chronic stages of recovery. More recently developed magnetic resonance techniques such as diffusion and perfusion weighted imaging, as well as more traditional magnetic resonance and computed tomography studies allow clinicians to more accurately diagnosis stroke subtypes, optimize treatment, and predict prognosis. Although not widely utilized for clinical use, functional neuroimaging techniques have also been shown to be useful in terms of predicting prognosis and advancing our understanding of reorganization and recovery following stroke. Thus, neuroimaging in stroke may also be utilized to monitor response to both medical treatment as well as physical rehabilitation. The following is a review of current research relevant to the field of neuroimaging of stroke. We begin with a discussion of structural imaging techniques with the goal of familiarizing the reader with recent developments in this area. Next, the discussion moves to functional imaging, its role in advancing our understanding of neuronal reorganization and functional recovery following stroke, and its usefulness at predicting recovery. Finally, a brief discussion regarding the future of neuroimaging and its implications for stroke and stroke recovery is presented.

Detection of Trace Processes in the Networks of Neurons Cultured on Microelectrode Arrays

We compared the effects of electrical stimulation of primary dissociated neuronal cultures cultured on microelectrode arrays in terms on the expression of c-fos transcriptional factor that is involved in plastic reorganization in neurons. Dissociated hippocampal neurons cultured on multielectrode arrays were exposed to two stimulation protocols: high-frequency and low-frequency stimulations. Expression of c-fos was evaluated using immunofluorescence. Both high-frequency and low-frequency stimulations significantly increased c-fos expression in comparison with non-stimulated control. These findings indicate that c-fos expression can be induced in neuronal cell culture by different types of electrical stimulations and can be used for studying plasticity processes in microphysiological in vitro systems.

Pain and persistent occlusal awareness: What should dentists do?

Pain and persistent occlusal awareness: What should dentists do?

Persistent decrease in multiple components of the perineuronal net following status epilepticus

In the rodent model of temporal lobe epilepsy, there is extensive synaptic reorganization within the hippocampus following a single prolonged seizure event, after which animals eventually develop epilepsy. The perineuronal net (PN), a component of the neural extracellular matrix (ECM), primarily surrounds inhibitory interneurons and, under normal conditions, restricts synaptic reorganization. The objective of the current study was to explore the effects of status epilepticus (SE) on PNs in the adult hippocampus. The aggrecan component of the PN was studied, acutely (48 h post-SE), sub-acutely (1 week post-SE) and during the chronic period (2 months post-SE). Aggrecan expressing PNs decreased by 1 week, likely contributing to a permissive environment for neuronal reorganization, and remained attenuated at 2 months. The SE-exposed hippocampus showed many PNs with poor structural integrity, a condition rarely seen in controls. Additionally, the decrease in the aggrecan component of the PN was preceded by a decrease in hyaluronan and proteoglycan link protein 1 (HAPLN1) and hyaluronan synthase 3 (HAS3), which are components of the PN known to stabilize the connection between aggrecan and hyaluronan, a major constituent of the ECM. These results were replicated in vitro with the addition of excess KCl to hippocampal cultures. Enhanced neuronal activity caused a decrease in aggrecan, HAPLN1 and HAS3 around hippocampal cells in vivo and in vitro, leaving inhibitory interneurons susceptible to increased synaptic reorganization. These studies are the foundation for future experiments to explore how loss of the PN following SE contributes to the development of epilepsy.

Blindsight in children with congenital and acquired cerebral lesions

It has been shown that unconscious visual function can survive lesions to optical radiations and/or primary visual cortex (V1), a phenomenon termed “blindsight”. Studies on animal models (cat and monkey) show that the age when the lesion occurs determines the extent of residual visual capacities. Much less is known about the functional and underlying neuronal repercussions of early cortical damage in humans. We measured sensitivity to several visual tasks in four children with congenital unilateral brain lesions that severely affected optic radiations, and in another group of three children with similar lesions, acquired in childhood. In two of the congenital patients, we measured blood oxygenation level dependent (BOLD) activity in response to stimulation of each visual field quadrants. Results show clear evidence of residual unconscious processing of position, orientation and motion of visual stimuli displayed in the scotoma of congenitally lesioned children, but not in the children with acquired lesions. The calcarine cortical BOLD responses were abnormally elicited by stimulation of the ipsilateral visual field and in the scotoma region, demonstrating a profound neuronal reorganization. In conclusion, our data suggest that congenital lesions can trigger massive reorganization of the visual system to alleviate functional effects of early brain insults.

Pre‐synaptic dopamine D3 receptor mediates cocaine‐induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways

Exposure to psychostimulants results in neuroadaptive changes of the mesencephalic dopaminergic system including morphological reorganization of dopaminergic neurons. Increased dendrite arborization and soma area were previously observed in primary cultures of mesencephalic dopaminergic neurons after 3-day exposure to dopamine agonists via activation of D(3) autoreceptors (D(3) R). In this work, we showed that cocaine significantly increased dendritic arborization and soma area of dopaminergic neurons from E12.5 mouse embryos by activating phosphorylation of extracellular signal-regulated kinase (ERK) and thymoma viral proto-oncogene (Akt). These effects were dependent on functional D(3) R expression because cocaine did not produce morphological changes or ERK/Akt phosphorylation neither in primary cultures of D(3) R mutant mice nor following pharmacologic blockade with D(3) R antagonists SB-277011-A and S-33084. Cocaine effects on morphology and ERK/Akt phosphorylation were inhibited by pre-incubation with the phosphatidylinositol 3-kinase inhibitor LY294002. These observations were corroborated in vivo by morphometrical assessment of mesencephalic dopaminergic neurons of P1 newborns exposed to cocaine from E12.5 to E16.5. Cocaine increased the soma area of wild-type but not of D(3) R mutant mice, supporting the translational value of primary culture. These findings indicate a direct involvement of D3R and ERK/Akt pathways as critical mediators of cocaine-induced structural plasticity, suggesting their involvement in psychostimulant addiction.

Spinal neuronal dysfunction after stroke

Central nervous system lesions, such as stroke or spinal cord injury (SCI), are followed by both cortical and spinal neuronal reorganization. In a severe chronic SCI a spinal neuronal dysfunction develops which is reflected in an exhaustion of leg muscle electromyographic (EMG) activity during assisted locomotion and a change in the dominance from an early to a late polysynaptic spinal reflex (SR) component. The aim of this study was to investigate the course of spinal neuronal function after a severe stroke, i.e., a unilateral deprivation of supraspinal input. In 30 hemiparetic stroke subjects locomotor and SR behavior were assessed. SR responses in the tibialis anterior muscle were evoked by non-noxious tibial nerve stimulation on both, the affected and the unaffected leg. In nine stroke subjects EMG activity of the leg muscles was recorded during assisted locomotion. In a similar way to SCI subjects, in severely affected chronic (>12months post-incidence) stroke subjects a late SR component was prominent in the affected leg, while an early one dominated in the unaffected leg. The late SR component correlated with muscle paresis (rho=0.714) and walking ability (rho=0.493). In contrast to SCI subjects, no exhaustion of the EMG activity was observed in the affected leg muscles during prolonged assisted locomotion. It is concluded that spinal neuronal circuits undergo functional changes also after a stroke which have common as well as divergent features compared to SCI subjects. As a consequence, different rehabilitative strategies might be required.

Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat

Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain.

Impaired reelin processing and secretion by Cajal–Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy

Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln (orl/orl) ) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln (orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of ∼300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal reorganization in TLE.

Intermediate and long-term memory are different at the neuronal level in Lymnaea stagnalis (L.)

Both intermediate-term memory (ITM) and long-term memory (LTM) require novel protein synthesis; however, LTM also requires gene transcription. This suggests that the behavioural output of the two processes may be produced differently at the neuronal level. The fresh-water snail, Lymnaea stagnalis, can be operantly conditioned to decrease its rate of aerial respiration and, depending on the training procedure, the memory can last 3h (ITM) or >24h (LTM). RPeD1, one of the 3 interneurons that form the respiratory central pattern generator (CPG) that drives aerial respiration, is necessary for memory formation. By comparing RPeD1’s electrophysiological properties in naïve, ‘ITM-trained’, ‘LTM-trained’ and yoked control snails we discovered that while the behavioural phenotype of memory at 3 and 24h is identical, the situation at the neuronal level is different. When examined 3h after either the ‘ITM’ or ‘LTM’ training procedure RPeD1 activity is significantly depressed. That is, the firing rate, input resistance, excitability and the number of action potential bursts are all significantly decreased. In snails receiving the ITM-training, these changes return to normal 24h post-training. However, in snails receiving the ‘LTM-training’, measured RPeD1 properties (firing rate, excitability, membrane resistance, and the number of action potential bursts fired) are significantly different at 24h than they were at 3h. Additionally, 24h following LTM training RPeD1 appears to be functionally “uncoupled” from its control of the pneumostome as the link between RPeD1 excitation and pneumostome opening is weakened. These data suggest that the behavioural changes occurring during LTM are due to more widespread neuronal reorganization than similar behavioural changes occurring during ITM. Thus ITM and LTM are not just distinct in a chronological and transcriptional manner but are also distinct at the level of neuronal properties.

Image-Based Identification of Single Neurons for Noninvasive Imaging Purification

A single-cell-based screening assay requires strict identification and isolation of particular target cells from a mixture of various kinds of cells. We have developed a visual-image-based on-chip microfluidic cell sorting method for the collection of neurons. One of the advantages of our method of purifying neurons is the direct monitoring and reorganization of neurons with specific image indexes, such as the cell size, shape, internal complexity, and spatial distribution of a fluorescent dye of a specific antibody marker by phase-contrast/fluorescence microscopy and image processing, which has not been realized using conventional diffraction-based cell sorting systems. First, we compared the differences of microscopic images (shapes) of neurons and glia cells, and found that only neurons have neurites extending from the cell body. We also found that the smooth surface shape indicates neurons, and the rough surface shape indicates glia cells. After picking the neuron cells manually chosen by observing their shapes as described above, we confirmed that the purified neurons can be cultivated and can keep their electrophysiological functions on the chip even after the purification procedure. The results indicate the potential of a nonlabel, noninvasive on-chip cell sorting procedure for neurons using micrograph images for an on-chip ultrahigh-speed camera-based imaging cell sorter.

Image-Based Identification of Single Neurons for Noninvasive Imaging Purification

A single-cell-based screening assay requires strict identification and isolation of particular target cells from a mixture of various kinds of cells. We have developed a visual-image-based on-chip microfluidic cell sorting method for the collection of neurons. One of the advantages of our method of purifying neurons is the direct monitoring and reorganization of neurons with specific image indexes, such as the cell size, shape, internal complexity, and spatial distribution of a fluorescent dye of a specific antibody marker by phase-contrast/fluorescence microscopy and image processing, which has not been realized using conventional diffraction-based cell sorting systems. First, we compared the differences of microscopic images (shapes) of neurons and glia cells, and found that only neurons have neurites extending from the cell body. We also found that the smooth surface shape indicates neurons, and the rough surface shape indicates glia cells. After picking the neuron cells manually chosen by observing their shapes as described above, we confirmed that the purified neurons can be cultivated and can keep their electrophysiological functions on the chip even after the purification procedure. The results indicate the potential of a nonlabel, noninvasive on-chip cell sorting procedure for neurons using micrograph images for an on-chip ultrahigh-speed camera-based imaging cell sorter.

Granule cell dispersion in temporal lobe epilepsy is associated with changes in dendritic orientation and spine distribution

Granule cell dispersion is a characteristic feature of Ammon's horn sclerosis in temporal lobe epilepsy. It was recently shown that granule cell dispersion is associated with decreased expression of the extracellular matrix protein Reelin. Reelin controls neuronal lamination and the differentiation of dendrites and spines. Here, we studied dendritic orientation and the distribution of dendritic spines on granule cells in surgical specimens of patients suffering from temporal lobe epilepsy. In this material, we compared granule cells in dentate areas showing granule cell dispersion with granule cells in areas exhibiting a normal, densely packed granule cell layer. Granule cells (GC) were Golgi-stained and analyzed using a computer-based camera lucida system and were categorized as being located proximal or distal to the hilus (GCprox, GCdist). We found that GCprox in a densely packed granule cell layer exhibited a mainly vertically oriented dendritic arbor with a small bifurcation angle (17°) between branching dendrites. In contrast, GCdist in a densely packed granular layer showed a wider bifurcation angle (35°), suggesting a widening of the dendritic field during the migratory process to superficial positions. Granule cells in the dispersed granule cell layer showed an even wider bifurcation angle of their apical dendrites (GCprox: 40°; GCdist: 58°) and also exhibited recurrent basal dendrites. Spine density on dendrites of GCprox in dispersed areas was increased compared to GCprox in the normal, compact granule cell layer. In contrast, dendrites of GCdist extending into the molecular layer showed a reduced spine density in dispersed areas. The results are discussed in view of other findings on neuronal reorganization in the epileptic dentate gyrus.

White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: A diffusion‐tensor imaging and voxel‐based morphometry study

We applied diffusion-tensor imaging (DTI) including measurements of mean diffusivity (MD), a parameter of brain tissue integrity, fractional anisotropy (FA), a parameter of neuronal fiber integrity, as well as voxel-based morphometry (VBM), a measure of gray and white matter volume, to detect brain tissue changes in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Magnetic resonance imaging (MRI) was performed in 26 patients with iRBD (mean disease duration, 9.2 ± 6.4 years) and 14 age-matched healthy control subjects. Statistical parametric mapping (SPM) was applied to objectively identify focal changes of MRI parameters throughout the entire brain volume. SPM localized significant decreases of FA in the tegmentum of the midbrain and rostral pons and increases of MD within the pontine reticular formation overlapping with a cluster of decreased FA in the midbrain (p < 0.001). VBM revealed increases of gray matter densities in both hippocampi of iRBD patients (p < 0.001). The observed changes in the pontomesencephalic brainstem localized 2 areas harboring key neuronal circuits believed to be involved in the regulation of REM sleep and overlap with areas of structural brainstem damage causing symptomatic RBD in humans. Bilateral increases in gray matter density of the hippocampus suggest functional neuronal reorganization in this brain area in iRBD. This study indicates that DTI detects distinct structural brainstem tissue abnormalities in iRBD in the regions where REM is modulated. Further studies should explore the relationship between MRI pathology and the risk of patients with iRBD of developing alpha-synuclein-related neurodegenerative diseases like Parkinson disease.

Do subtle cortical structure changes indicate a developmental basis for temporal lobe epilepsy?

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of intractable epilepsy in adolescents and adults. It is also one of the most intensively studied. The pathologic hallmark of classic MTLE is hippocampal sclerosis (HS). This is characterized histologically by a specific pattern of neuronal loss and synaptic reorganization. On MRI, one often observes reduced hippocampal volume with increased T2 signal. One of the oldest debates in epilepsy is whether HS is a preexisting cause or effect of the seizures in MTLE. Cogent arguments have been made in both directions, but have been based on differing rationales and investigational methods. The coexistence of HS with cortical dysplasia and more subtle types of developmental anomalies at the histologic level suggest that, in some cases, HS and MTLE may represent later manifestations of a process that begins earlier in life.1,2 In this issue of Neurology ®, Voets et al.3 provide new insight into this question by demonstrating subtle changes in structure and spatial orientation of limbic cortex and hippocampus based on MRI in 43 patients with MTLE and HS. By documenting the presence of increased folding complexity of limbic cortex and malrotation of hippocampi in these …

Cholinergic systems of the rat brain and neuronal reorganization under conditions of acute hypoxia

We studied the role of cholinergic systems of the rat brain in the mechanisms of acute response of the neocortex and hippocampus to acute hypobaric hypoxia. The activity of choline acetyltransferase and Na/K-ATPase and the protein content were measured in subfractions of synaptic membranes and the synaptoplasm of “light” and “heavy” synaptosomes. The same biochemical indices were measured in fractions of light and heavy synaptosomes from the nucleus of the solitary tract of the medulla oblongata. In the neocortex, we analyzed the ultrastructure of the synaptic pool. We found active involvement of cholinergic systems in the response to acute hypoxia in all brain structures studied. The synapses of cholinergic projection neurons from the basal nuclei of the frontal cortex (light fractions of synaptosomes), neocortical interneurons (heavy fractions of synaptosomes), and, presumably, GABAergic interneurons of the hippocampus (heavy fraction) were the most sensitive to hypoxia. At the limit of resistance to hypoxia, increased metabolic activity predominated in the synapses of rats that had poorly resistance to hypoxia, while in highly resistant rats this activity was diminished. This difference is related to the different duration of their exposure to critical altitude. We found a reduction in the number of synapses and staging in the development of the functional response of synapses to acute hypoxia. We propose a mechanism for the structural and functional reorganization of synaptic links during acute hypoxia, which is general for both poorly and highly resistant rats. We also hypothesize that a reduction of synapses is one of early triggers that switches neurons to levels of interaction that are adequate for hypoxia.

Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors

Chronic stress induces dendritic retraction in the hippocampal CA3 subregion, but the mechanisms responsible for this retraction and its impact on neural circuitry are not well understood. To determine the role of NMDA (N-methyl- d-aspartic acid) receptor (NMDAR)-mediated signaling in this process, we compared the effects of chronic immobilization stress (CIS) on hippocampal dendritic morphology, hypothalamic-pituitary-adrenal (HPA) axis activation, and anxiety-related and hippocampus-dependent behaviors, in transgenic male mice in which the NMDAR had been selectively deleted in CA3 pyramidal cells and in non-mutant littermates. We found that CIS exposure for 10 consecutive days in non-mutant mice effectively induces HPA axis activation and dendritic retraction of CA3 short-shaft pyramidal neurons, but not CA3 long-shaft pyramidal neurons, suggesting a differential cellular stress response in this region. Dendritic reorganization of short-shaft neurons occurred throughout the longitudinal axis of the hippocampus and, in particular, in the ventral pole of this structure. We also observed a robust retraction of dendrites in dorsal CA1 pyramidal neurons in the non-mutant C57BL/6 mouse strain. Strikingly, chronic stress-induced dendritic retraction was not evident in any of the neurons in either CA3 or CA1 in the mutant mice that had a functional lack of NMDARs restricted to CA3 pyramidal neurons. Interestingly, the prevention of dendritic retraction in the mutant mice had a minimal effect on HPA axis activation and behavioral alterations that were induced by chronic stress. These data support a role for NMDAR-dependent glutamatergic signaling in CA3 in the cell-type specific induction of dendritic retraction in two hippocampal subregions following chronic stress.