A comparison of behavioral paradigms assessing spatial memory in tree shrews.

Impairments in spatial navigation in humans can be preclinical signs of Alzheimer's disease. Therefore, cognitive tests that monitor deficits in spatial memory play a crucial role in evaluating animal models with early stage Alzheimer's disease. While Chinese tree shrews (Tupaia belangeri) possess many features suitable for Alzheimer's disease modeling, behavioral tests for assessing spatial cognition in this species are lacking. Here, we established reward-based paradigms using the radial-arm maze and cheeseboard maze for tree shrews, and tested spatial memory in a group of 12 adult males in both tasks, along with a control water maze test, before and after bilateral lesions to the hippocampus, the brain region essential for spatial navigation. Tree shrews memorized target positions during training, and task performance improved gradually until reaching a plateau in all 3 mazes. However, spatial learning was compromised post-lesion in the 2 newly developed tasks, whereas memory retrieval was impaired in the water maze task. These results indicate that the cheeseboard task effectively detects impairments in spatial memory and holds potential for monitoring progressive cognitive decline in aged or genetically modified tree shrews that develop Alzheimer's disease-like symptoms. This study may facilitate the utilization of tree shrew models in Alzheimer's disease research.

Deconstructing the flight paths of hippocampal-lesioned homing pigeons as they navigate near home offers insight into spatial perception and memory without a hippocampus.

The aim of this study was to exploit detailed analyses of GPS-recorded tracks to better characterise the impact of hippocampal (HF) lesion on spatial memory and perception in the context of homing pigeon navigation when reliant on familiar landscape features near the home loft following repeated releases from the same three locations. As reported previously, following HF lesion, a low spatio-temporal resolution analysis revealed that homing pigeons fly less direct paths home once near the loft. We now further show that 1) HF-lesioned pigeons are less likely to display fidelity to a particular flight path home when released from the same locations multiple times, 2) intact pigeons are more likely to exploit leading-line landscape features, e.g., a road or the border of a woodlot, in developing flight-path fidelity and 3) even when flying a straight path HF-lesioned homing pigeons are more likely to display relatively rapid, oscillatory heading changes as if casting about for sensory, presumably visual information. The flight behaviour differences between the intact and HF-lesioned pigeons persisted across the four releases from the three locations, although the differences became smaller with increasing experience. Taken together, the GPS-track data offer a detailed characterisation of the effects of HF lesion on landscape-based, homing pigeon navigation, offering new insight into the role of the hippocampal formation in supporting memory-related, e.g., fidelity to a familiar route home, and perhaps perceptual-related, e.g., oscillating headings, navigational processes.

Advantages and Limitations of Animal Schizophrenia Models.

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

Transient global amnesia: 7 Tesla MRI reveals more hippocampal lesions with diffusion restriction compared to 1.5 and 3 Tesla MRI.

PURPOSE: To assess the ability of 7 T MRI to detect hippocampal DWI lesions in the acute phase of TGA compared to 1.5 T/3 T MRI. METHODS: Patients with a clinical diagnosis consistent with TGA and a 1.5/3 T MRI underwent an additional 7 T MRI when the 7 T system was available for clinical use, thus serving as their own controls. RESULTS: Thirteen TGA patients with a median age of 68.5 years (range 46-77 years) were included and imaged at 1.5/3 T (median 17 h after onset of symptoms, range 3-23 h) and 7 T (median 23 h after onset, range 15-46 h). The 7 T MRIs were performed a median of 15 h after the 1.5/3 T MRIs (range 1-28 h). At 1.5/3 T, six patients (46%) were found to have at least one hippocampal DWI-lesions supporting the TGA diagnosis, which increased to 11 patients (85%) when examined at 7 T (p = 0.03). At 1.5/3 T, nine hippocampal DWI lesions were detected, which increased to 19 at 7 T, giving an increased detection rate of 111% (p = 0.002). Both neuroradiologists found the hippocampal DWI lesions at 7 T to have higher conspicuity and be easier to categorize as true findings compared to 1.5/3 T. CONCLUSION: Seven-Tesla MRI showed both a statistically significant increase in the total number of detected hippocampal DWI lesions and the proportion of patients with at least one hippocampal DWI lesion supporting the TGA diagnosis compared to 1.5/3 T. Clinical use of 7 T will increase the number of patients having their TGA diagnosis supported by MRI, which can be especially useful in patients with negative 1.5/3 T MRI and low clinical certainty.

Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging.

Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

Longitudinal magnetic resonance evaluation of the schizophrenia model of neonatal lesion in the ventral hippocampus.

OBJECTIVE: To evaluate the progression by means of nuclear magnetic resonance of the lesion in the schizophrenia model of lesion of the ventral hippocampal nucleus (LVNH). METHOD: Magnetic resonance imaging (MRI) were performed in male Wistar rats, from 8 days postnatal to 139 days, in animals with LNHV and without lesion (sham). The MRI were carried out on a Variant 7 T equipment. The data were analyzed with the Amira software, for a voxel-based morphometric analysis. RESULTS: We observed the presence of hypersignals with a significant enhancement in the structures analyzed in the group with LVNH, and greater volume in the lateral ventricles, presenting a larger size of the lesion on day PD96 and significantly reducing on day PD139. CONCLUSIONS: We found a cell rearrangement during the progression of the lesion, which could be the effect of the activation of immune cells.

OBJETIVO: Evaluar mediante resonancia magnética (RM) la progresión de la lesión en el modelo de esquizofrenia de lesión del núcleo del hipocampo ventral (LNHV). MÉTODO: Se realizaron RM en ratas Wistar macho, desde los 8 días posnatales hasta los 139 días, en animales con LNHV y sin lesión (sham). Las RM se realizaron con un equipo Variant de 7 T. Los datos se analizaron con el software Amira para un análisis de morfometría basada en vóxels. RESULTADOS: Observamos hiperseñales con un realce significativo en las estructuras analizadas en el grupo con LNHV, y mayor volumen en los ventrículos laterales, presentando un mayor tamaño de la lesión el día PD96 y significativamente reducido en el día PD139. CONCLUSIONES: Encontramos un reacomodo celular durante la progresión de la lesión, lo cual podría ser efecto de la activación de las células inmunitarias.

GPS-profiling of retrograde navigational impairments associated with hippocampal lesion in homing pigeons.

The avian hippocampal formation (HF) is homologous to the mammalian hippocampus and plays a central role in the control of spatial cognition. In homing pigeons, HF supports navigation by familiar landmarks and landscape features. However, what has remained relatively unexplored is the importance of HF for the retention of previously acquired spatial information. For example, to date, no systematic GPS-tracking studies on the retention of HF-dependent navigational memory in homing pigeons have been performed. Therefore, the current study was designed to compare the pre- and post-surgical navigational performance of sham-lesioned control and HF-lesioned pigeons tracked from three different sites located in different directions with respect to home. The pre- and post-surgical comparison of the pigeons' flight paths near the release sites and before reaching the area surrounding the home loft (4 km radius from the loft) revealed that the control and HF-lesioned pigeons displayed similarly successful retention. By contrast, the HF-lesioned pigeons displayed dramatically and consistently impaired retention in navigating to their home loft during the terminal phase of the homing flight near home, i.e., where navigation is supported by memory for landmark and landscape features. The data demonstrate that HF lesions lead to a dramatic loss of pre-surgically acquired landmark and landscape navigational information while sparing those mechanisms associated with navigation from locations distant from home.

New insights on nitric oxide: Focus on animal models of schizophrenia.

Schizophrenia is a devastating complex disorder characterised by a constellation of behavioral deficits with the underlying mechanisms not fully known. Nitric oxide (NO) has emerged as a key signaling molecule implicated in schizophrenia. Three nitric oxide sinthases (NOS), endothelial, neuronal, and inducible, release NO within the cell. Animal models of schizophrenia are grouped in four groups, neurovedelopmental, glutamatergic, dopaminergic and genetic. In this review, we aim to evaluate changes in NO levels in animal models of schizophrenia and the resulting long-lasting behavioral and neural consequences. In particular, NO levels are substantially modified, region-specific, in various neurodevelopmental models, e.g. bilateral excitotoxic lesion of the ventral hippocampus (nVHL), maternal immune activation and direct NO manipulations early in development, among others. In regards to glutamatergic models of schizophrenia, phencyclidine (PCP) administration increases NO levels in the prefrontal cortex (PFC) and ventral hippocampus. As far as genetic models are concerned, neuronal NOS knock-out mice display schizophrenia-related behaviors. Administration of NO donors can reverse schizophrenia-related behavioral deficits. While most modifications in NO are derived from neuronal NOS, recent evidence indicates that PCP treatment increases NO from the inducible NOS isoform. From a pharmacological perspective, treatment with various antipsychotics including clozapine, haloperidol and risperidone normalize NO levels in the PFC as well as improve behavioral deficits in nVHL rats. NO induced from the neuronal and inducible NOS is relevant to schizophrenia and warrants further research.

Hippocampal damage attenuates habituation to videos in monkeys.

Monkeys with selective damage to the hippocampus are often unimpaired in matching-to-sample tests but are reportedly impaired in visual paired comparison. While both tests assess recognition of previously seen images, delayed matching-to-sample may engage active memory maintenance whereas visual paired comparison may not. Passive memory tests that are not rewarded with food and that do not require extensive training may provide more sensitive measures of hippocampal function. To test this hypothesis, we assessed memory in monkeys with hippocampal damage and matched controls by providing them the opportunity to repeatedly view small sets of videos. Monkeys pressed a button to play each video. The same 10 videos were used for six consecutive days, after which 10 new videos were introduced in each of seven cycles of testing. Our measure of memory was the extent to which monkeys habituated with repeated presentations, watching fewer videos per session over time. Monkeys with hippocampal lesions habituated more slowly than did control monkeys, indicating poorer memory for previous viewings. Both groups dishabituated each time new videos were introduced. These results, like those from preferential viewing, suggest that the hippocampus may be especially important for memory of incidentally encoded events.

The impact of sleep characteristics and epilepsy variables on memory performance in patients with focal seizures.

Disturbed sleep can negatively affect overnight memory retention as well as new learning the subsequent day. In healthy participants, positive associations between memory performance and sleep characteristics (e.g., time spent in slow-wave sleep [SWS]) have been detected. In a previous study, we found that SWS was much reduced in patients with focal seizures, but when correlations between memory complaints and various sleep characteristics were considered, the only significant relationship was with the time to onset of rapid eye movement (REM) sleep (i.e., REM latency). In this study, we investigated the relationships between sleep, epilepsy, and objective memory performance variables. Twenty-five patients with focal seizures had their memory tested while undergoing a two-day ambulatory electroencephalography (EEG). The sleep variables of interest were the percentage of time spent in SWS (%SWS) and REM latency. Epilepsy variables included the presence of (1) seizures, (2) interictal epileptiform discharges, and/or (3) hippocampal lesions as well as site of seizure origin (temporal vs extratemporal). Overnight retention (of autobiographical events, a story, and a complex geometric figure) and the ability to learn a word list on day 2 were the measures of memory. A significant positive correlation was found between word-list learning and %SWS during the previous night. A significant negative correlation was observed between REM latency and overnight retention of autobiographical events. Overnight retention scores for the story and geometric figure were not related to sleep characteristics but were negatively affected by the presence of epileptiform activity. Story retention was also worse for temporal lobe epilepsy (TLE) than for patients with extratemporal epilepsy (ETE). Those with hippocampal lesions were more impaired than those without lesions on word-list learning, autobiographical events' retention, and story retention. When multiple contributing factors were entered into regression analyses, %SWS was found to be the best predictor of subsequent word-list learning, whereas the presence of a hippocampal lesion was the best predictor of overnight retention of autobiographical events and a story. These findings provide further evidence of the ways in which particular sleep characteristics are associated with memory and suggest that treatment of sleep disturbances in patients with epilepsy might be helpful for improving their performance.

Research Domain Criteria versus DSM V: How does this debate affect attempts to model corticostriatal dysfunction in animals?

For decades, the nosology of mental illness has been based largely upon the descriptions in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM). A recent challenge to the DSM approach to psychiatric nosology from the National Institute on Mental Health (USA) defines Research Domain Criteria (RDoC) as an alternative. For RDoC, psychiatric illnesses are not defined as discrete categories, but instead as specific behavioral dysfunctions irrespective of DSM diagnostic categories. This approach was driven by two primary weaknesses noted in the DSM: (1) the same symptoms occur in very different disease states; and (2) DSM criteria lack grounding in the underlying biological causes of mental illness. RDoC intends to ground psychiatric nosology in those underlying mechanisms. This review addresses the suitability of RDoC vs. DSM from the view of modeling mental illness in animals. A consideration of all types of psychiatric dysfunction is beyond the scope of this review, which will focus on models of conditions associated with frontostriatal dysfunction.

Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions.

Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/µL) were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

Disruption of learning and long-term retention of prose passages in patients with focal epilepsy.

Recent investigations of accelerated long-term forgetting, a condition in which newly acquired memory is normal initially but decays rapidly over days or weeks, indicate that multiple factors might influence whether this phenomenon is seen in patients with epilepsy. Test-based differences such as learning condition or type of memory measure (e.g., recall vs recognition) as well as epilepsy variables (e.g., side, site, or frequency of epileptiform activity) may be important. The present study sought to characterize factors affecting learning and memory for prose passages in patients with focal epilepsy. We enrolled 21 patients with temporal lobe epilepsy, with and without hippocampal lesions, 11 patients with extratemporal epilepsy (ETE), and 29 healthy controls. Two matched passages were used to compare effects of initial learning condition (one exposure versus learning-to-criterion) on subsequent patterns of retention. Recall and recognition were tested at different delays (i.e., immediately, 30min, 24h, and 4days). Regression analyses and one-way ANOVAs indicated that having a left-hemisphere epileptic focus had a negative impact on learning, whilst presence of a hippocampal lesion (irrespective of side) was associated with deterioration in recall for intervals up to 24h postencoding. Learning condition affected patterns of memory decay in that the ETE group showed significant decline in recall between 24h and 4days only when stories were learned to criterion. In contrast with recall, no changes over time were evident in recognition memory, as patients with hippocampal lesions were impaired from 30min onward. Epilepsy variables other than side and site of epilepsy/lesion did not influence performance. In conclusion, the left hemisphere is involved in learning of prose material, and the hippocampus is involved in the consolidation of this material mainly for the first 24h. After this, cortical regions outside the hippocampus become important for recall.

Hippocampus and two-way active avoidance conditioning: Contrasting effects of cytotoxic lesion and temporary inactivation.

Hippocampal lesions tend to facilitate two-way active avoidance (2WAA) conditioning, where rats learn to cross to the opposite side of a conditioning chamber to avoid a tone-signaled footshock. This classical finding has been suggested to reflect that hippocampus-dependent place/context memory inhibits 2WAA (a crossing response to the opposite side is inhibited by the memory that this is the place where a shock was received on the previous trial). However, more recent research suggests other aspects of hippocampal function that may support 2WAA learning. More specifically, the ventral hippocampus has been shown to contribute to behavioral responses to aversive stimuli and to positively modulate the meso-accumbens dopamine system, whose activation has been implicated in 2WAA learning. Permanent hippocampal lesions may not reveal these contributions because, following complete and permanent loss of hippocampal output, other brain regions may mediate these processes or because deficits could be masked by lesion-induced extra-hippocampal changes, including an upregulation of accumbal dopamine transmission. Here, we re-examined the hippocampal role in 2WAA learning in Wistar rats, using permanent NMDA-induced neurotoxic lesions and temporary functional inhibition by muscimol or tetrodotoxin (TTX) infusion. Complete hippocampal lesions tended to facilitate 2WAA learning, whereas ventral (VH) or dorsal hippocampal (DH) lesions had no effect. In contrast, VH or DH muscimol or TTX infusions impaired 2WAA learning. Ventral infusions caused an immediate impairment, whereas after dorsal infusions rats showed intact 2WAA learning for 40-50 min, before a marked deficit emerged. These data show that functional inhibition of ventral hippocampus disrupts 2WAA learning, while the delayed impairment following dorsal infusions may reflect the time required for drug diffusion to ventral hippocampus. Overall, using temporary functional inhibition, our study shows that the ventral hippocampus contributes to 2WAA learning. Permanent lesions may not reveal these contributions due to functional compensation and extra-hippocampal lesion effects.

The sigma agonist 1,3-di-o-tolyl-guanidine reduces the morphological and behavioral changes induced by neonatal ventral hippocampus lesion in rats.

Sigma (σ) receptors have generated a great deal of interest due to their possible role in psychosis, neuroprotection, and various other behaviors including addictive processes. Sigma receptors have been located in brain areas involved in motor functions, including the dopaminergic projections from the substantia nigra to the striatum. Evidence suggests that one of their major roles might be to regulate the activity of the glutamatergic system via the N-methyl-D-aspartate receptor. The sigma receptor agonist 1,3-di-o-tolyl-guanidine (DTG) was found to increase dopamine release in the striatum, nucleus accumbens, and prefrontal cortex, in a dose-dependent manner, after central as well as peripheral administration, suggesting a modulatory role of these receptors on the dopaminergic system. The present study examines whether chronic administration of the DTG sigma agonist induces neuromorphological and behavioral changes in neonatal ventral hippocampal lesioned (nVHL) rats as a neurodevelopmental model of schizophrenia. The results show that the DTG administration reduces the hyperlocomotor activity in nVHL rats and reverses the neuronal hypotrophy generated in nVHL rats in the prefrontal cortex, amygdala, and nucleus accumbens. Our results demonstrate that DTG, a sigma-1 receptor agonist, reverses some of the behavioral and neuromorphological effects of nVHL on the rat and supports the possibility that DTG may have beneficial effects in the management of symptoms of schizophrenia.

Hypoglycemic Encephalopathy with Reversible Unilateral Hippocampal Lesion on Brain MRI / 계명의대학술지

There have been few reports of hypoglycemic encephalopathy (HE) with unilateral brain lesion. A 66-year-old male with hypoglycemia, who had history of diabetes and recent poor oral intake, presented with amnesia and confusion. Diffusionweighted imaging (DWI) showed high signal intensity in left hippocampus, which was low on apparent diffusion coefficient (ADC) map. By intravenous glucose, the symptoms improved besides amnesia for hypoglycemic period. Follow-up DWI revealed no lesion and single photon emission computed tomography (SPECT) showed decreased perfusion in left temporo-parieto-frontal area. We experienced a case of HE with a reversible unilateral hippocampal lesion.

Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion.

Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits.

Chronic cerebrolysin administration attenuates neuronal abnormalities in the basolateral amygdala induced by neonatal ventral hippocampus lesion in the rat.

The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders.