Anxiety-, and depression-like behavior following short-term finasteride administration is associated with impaired synaptic plasticity and cognitive behavior in male rats.

Finasteride, a 5α-Reductase inhibitor, is used to treat male pattern baldness and benign prostatic hyperplasia. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts and cognitive impairment and these symptoms are persistent even after its withdrawal. Previous results from our lab showed that repeated administration of finasteride for six days induces depression-like behavior. However, whether short-term finasteride administration induces anxiety-like behavior and memory impairment and alters synaptic plasticity are not known, which formed the basis of this study. Finasteride was administered to 2-2.5 months old male Wistar rats for six days and subjected to behavioral evaluation, biochemical estimation and synaptic plasticity assessment. Anxiety-like behavior was evaluated in the elevated plus maze (EPM), open field test (OFT), light/dark test (LDT), and novelty suppressed feeding test (NSFT), and learning and memory using novel object recognition test (NORT) and novel object location test (NOLT) and depression-like behavior in the sucrose preference test (SPT). Synaptic plasticity in the hippocampal Schaffer collateral-CA1 was evaluated using slice field potential recordings. Plasma corticosterone levels were estimated using ELISA. Finasteride administration induced anxiety-like behavior in the EPM, OFT, LDT and NSFT, and depression-like behavior in the SPT. Further, finasteride induced hippocampal dependent spatial learning and memory impairment in the NOLT. In addition, finasteride decreased basal synaptic plasticity and long-term potentiation (LTP) in the hippocampus. A trend of increased plasma corticosterone levels was observed following repeated finasteride administration. These results indicate the potential role of corticosterone and synaptic plasticity in finasteride-induced effects and further studies will pave way for the development of novel neurosteroid-based therapeutics in neuropsychiatric diseases.

Risky decision-taking task: A novel paradigm to assess the risk-taking behaviour in rats predisposed to early-life stress.

One of the characteristic features of adolescence is risk-taking behavioural traits. Uncontrolled risk-taking without proper assessment may have harmful impact on mental health later in life. Therefore, it is essential to identify it early for the preventable health problems. In the present study, we have designed a novel paradigm, viz. Risky Decision-taking Task (RDTT), to evaluate the spontaneous risk-taking behavioural repertoire in adolescent rodents. The task was designed based on both risk and cognitive factors. To validate and compare the risk-taking tendency, we have used early maternal separation and isolation (MS) stress model, as it is known to increase anxiety and curiosity-like behaviour at adolescence. We have used Sprague-Dawley rats of both sexes. Rats were exposed to MS stress for 10 days daily for six hours during stress hyporesponsive period (SHRP) from postnatal day 4-13. These rats were subjected to RDTT during adolescence. This task is a reward-based task where the latency to collect reward in the presence or absence of a risk factor is assessed. It consists of habituation, training to find the location of small and large rewards, reward preference for small and large reward and testing period under risky situation. Rats were trained individually to retrieve the valuation-based rewards under the risky, but innate aversive environments. The results from RDTT showed that as compared to controls, MS rats from both sexes showed reduced latency to collect large reward in the presence of a risk element and a reduced risk-index which is indicative of a higher risk-taking tendency in these rats. In addition, MS rats showed a trend towards anxiety-like behaviour as compared to controls in the Light-Dark Test. These results together show decreased risk latency for the large reward and reduced risk assessment in MS rats which is suggestive of more risk-taking tendency in these rats. Thus, we propose that RDTT paradigm can be used to evaluate the spontaneous risk-taking behavioural repertoire based on innate, spontaneous aversion and cognitive factors in rats.

Mifepristone blocks the anxiolytic- and antidepressant-like effects of allopregnanolone in male rats.

BACKGROUND: Allopregnanolone (3α, 5α-tetrahydroprogesterone) is an inhibitory neurosteroid synthesized from progesterone via 5α-reductase activity in the brain and has anxiolytic, antidepressant, sedative, anticonvulsant, and analgesic activity. Altered levels of allopregnanolone cause anxiety, depression, premenstrual syndrome, and psychiatric disorders. Although allopregnanolone exerts most of its actions by modulating GABAA receptor, NMDA receptor, BDNF expression, and PXR activity, a recent study showed its effects are blocked by mifepristone on lordosis behavior which indicates the involvement of progestin or glucocorticoid receptors in the effects of allopregnanolone since mifepristone blocks both these receptors. However, whether these receptors are involved in acute anxiolytic or antidepressant-like effects is unknown. METHODS: Adult male Wistar rats were used to study whether the prior administration of mifepristone would alter the effects of allopregnanolone in the elevated plus maze (EPM) and forced swim test (FST) was evaluated. RESULTS: 10 mg/Kg dose of allopregnanolone increased percent open arm entries in the EPM, whereas 3 mg/Kg dose of allopregnanolone decreased percent immobility in the FST. Mifepristone administration resulted in a U-shaped response in the FST (with 1 mg/Kg, s.c., decreasing the immobility time) without significantly impacting the behavior in the EPM. In combination studies, mifepristone blocked the anxiolytic and antidepressant effects of allopregnanolone. CONCLUSION: The current study provides evidence for the first time that progestin or glucocorticoid receptors are involved in the acute anxiolytic and antidepressant effects of allopregnanolone. Understanding the mechanism of action of allopregnanolone will help us design better therapeutic strategies to treat neuropsychiatric diseases such as depression and anxiety.

Mifepristone's effects on depression- and anxiety-like behavior in rodents.

Mifepristone is a non-selective progesterone (PR), glucocorticoid (GR), and androgen receptor (AR) antagonist with antidepressant and anxiolytic effects. The dose and duration of mifepristone administration vary in rodent preclinical studies to evaluate depression-like and anxiety-like behavior. This review summarizes the findings so far and attempts to reconcile some of the differences in the results. While a few studies assessed basal depression- and anxiety-like behavior, several studies have used mifepristone in conjunction with stress, corticosterone/dexamethasone (after adrenalectomy), or progesterone administration. The effect of mifepristone on depression-like behavior appears to depend not only on the dose and duration of administration but also on the intensity or type of stress. In addition, the anxiolytic effects may depend on the species and strain of the experimental animals. More reports assess antidepressant-like or anxiolytic-like effects following acute than chronic administration. These effects are dependent on the paradigms and the nature of stressors. Most mifepristone studies implicate the role of GRs, yet only two reports have confirmed its role using a genetic approach, whereas none implicate the role of PRs/ARs. There are several novel selective GR antagonists whose effects on depression- and anxiety-like behavior are yet to be studied. Future studies could aim to confirm the role of GRs and evaluate the contribution of PRs/ARs to the effects of mifepristone. Such studies will contribute to a better understanding of depression, anxiety, and other mood disorders and develop novel strategies, particularly for treatment-resistant conditions.

Ventral subicular lesion impairs pro-social empathy-like behavior in adult Wistar rats.

The subiculum, an important structure of the hippocampal formation, regulates spatial information processing, social cognition, and affective behavior. Earlier we demonstrated deficits in sociability and social novelty as a measure of social cognition in ventral subicular lesioned (VSL) rats. The present study investigated empathy-like pro-social behavior and the associated affective states in VSL rats. The ability of free rats to release trapped cagemates was assessed using a modified door-opening empathy task.The rat pairs (free rat and the trapped cagemate) used were from the same group and tested for eight days to assess the pro-social behavior displayed by the free rats. The controlfree rats learned to open the door quickly to release the trapped cagemate and both the rats displayed social responses by emitting 'hedonic' calls (50-kHz ultrasonic vocalizations) while playing after the release. The VSLfree rats, however, were less exploratory, displayed apathy towards the trapped cagemate, demonstrated freezing behavior following door-opening and did not interact with the cagemate even after its release. These findings indicate deficits of social motivation and reinforcement learning associated with lesions in possibly both the rats. In addition, the VSL rat pairs elicited more 22-kHz 'alarm' calls and fewer 50-kHz 'hedonic' calls highlighting the lesion-induced alterations of contextual processing and threat perception abilities. In conclusion, VSL led to significant pro-social deficits implicating the role of ventral subiculum in social cognition and empathy. More studies are needed to substantiate whether the subiculum is implicated in social deficits associated with psychiatric conditions such as autism spectrum disorder.

Exposure to Short Photoperiod Regime Restores Spatial Cognition in Ventral Subicular Lesioned Rats: Potential Role of Hippocampal Plasticity, Glucocorticoid Receptors, and Neurogenesis.

Ambient light influences our mood, behavior, and cognition. Phototherapy has been considered as an effective non-pharmacological intervention strategy in the restoration of cognitive functions following central nervous system insults. However, the cellular and molecular underpinnings of phototherapy-mediated functional recovery are yet to be studied. The present study examines the effectiveness of short photoperiod regime (SPR; 6:18-h light:dark cycle) in restoring the cognitive functions in ventral subicular lesioned rats. Bilateral ventral subicular lesion (VSL) resulted in significant impairment of spatial navigational abilities when tested in the Morris water maze (MWM) task. Further, VSL resulted in reduced expression of glucocorticoid receptors (GRs) and activity-regulated cytoskeletal (Arc) protein and suppression of neurogenesis in the hippocampus. VSL also suppressed the magnitude of long-term potentiation (LTP) in the hippocampal Schaffer collateral-CA1 synapses. However, exposure to SPR for 21 days showed significant restoration of spatial performance in the MWM task as the ventral subicular lesioned rats could deploy higher cognitive allocentric navigational strategies to reach the hidden platform. Further, SPR resulted in enhanced expression of hippocampal GR and Arc protein and neurogenesis but not hippocampal LTP suggestive of appropriate need-based SPR intervention. In conclusion, the study demonstrates the effectiveness of SPR in establishing functional recovery as well as the possible molecular and cellular basis of cognitive recovery in a rat model of neurodegeneration. Such studies provide a framework in understanding the efficacy of non-pharmacological strategies in establishing functional recovery in neurodegenerative conditions.

The potential involvement of cholinergic system in finasteride induced cognitive dysfunction.

OBJECTIVE: Neurosteroids are known to exert diverse functions in the brain. 5α-reductase (5α-R), a rate-limiting enzyme involved in the biosynthesis of neurosteroids is inhibited by finasteride. Clinical studies suggest that administration of finasteride causes the emergence of affective symptoms and cognitive dysfunction. Modeling this in rats would provide an opportunity to understand the mechanisms. Accordingly, in the present study, we evaluated the effects of repeated finasteride administration on spatial learning and memory in the partially baited radial arm maze task (RAM) and social cognitive behavior in the social interaction test. Further, to initiate the quest to understand the mechanisms underlying the effects of finasteride, in a separate group of animals, acetylcholinesterase (AChE) activity in the frontal cortex, hippocampus, septum and striatum was estimated. METHODS: 2 months old male Wistar rats were trained to learn a partially baited radial arm maze task (four trials per day till they reach a choice accuracy of 80 %). Following this, rats were administered with either vehicle (HPßCD) or finasteride (30 or 100 mg/Kg, s.c.) for 7 days and then subjected to retention test on the eighth day. To evaluate the social cognition, finasteride was administered for 7 days, followed by social interaction test on the eighth day. All the sessions were video-recorded and analyzed using Noldus Ethovision XT™ software. Following finasteride administration, on the eighth day, rats were euthanized, and AChE activity was estimated by modified Ellman's method. RESULTS: Finasteride (100 mg/Kg, s.c.) administration decreased the percent correct choice during the retention trial of the RAM task. This was paralleled by an increase in the number of total number of errors and reference memory errors. In the social interaction test, finasteride (100 mg/Kg, s.c.) administration decreased the time spent with the rat compared to the object, implying decreased sociability and diminished social preference evidenced by similar time spent with the novel and familiar rat. Reduced AChE activity was observed in the frontal cortex, hippocampus and septum. CONCLUSION: Our study provides evidence that repeated administration of finasteride decreases social interaction and results in cognitive deficits, potentially through a cholinergic mechanism. Further studies are required to understand the exact link between the cognitive effects and the cholinergic system. A deeper probe of the current findings holds promise for the development of novel neurosteroid-based therapeutics to treat affective and cognitive disorders.

Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment.

RATIONALE: Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown. OBJECTIVES: Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex. RESULTS: We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX). CONCLUSIONS: We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.

Brain stimulation rewarding experience attenuates neonatal clomipramine-induced adulthood anxiety by reversal of pathological changes in the amygdala.

Major depressive disorder (MDD) is associated with enhanced anxiety and reduced reward processing leading to impaired cognitive flexibility. These pathological changes during depression are accompanied by dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its impaired regulation by the amygdala. Notably, the electrical stimulation of brain reward areas produces an antidepressant effect in both MDD patients and animal models of depression. However, the effects of chronic electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-associated anxiety and accompanying changes in plasma corticosterone levels, structural, and neurochemical alterations in the amygdala are unknown. Here, we used the neonatal clomipramine (CLI) model of depression. During adulthood, neonatal CLI and vehicle administered rats were subjected to bilateral electrode implantation at LH-MFB and trained to receive intracranial self-stimulation (ICSS) for 14 days. Rats were then tested for anhedonic and anxiety-like behaviors, followed by estimation of plasma corticosterone levels, assessment of amygdalar volumes and neuronal/glial numbers, levels of monoamines and their metabolites in the amygdala. We found that chronic ICSS of LH-MFB reverses CLI-induced anhedonia and anxiety. Interestingly, amelioration of CLI-induced enhanced anhedonia and anxiety in ICSS rats was associated with partial reversal of enhanced plasma corticosterone levels, hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. We suggest that beneficial effects of ICSS on CLI-induced anxiety at least in part mediated by the restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that brain stimulation rewarding experience might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.

N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes.

Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.

Repeated finasteride administration induces depression-like behavior in adult male rats.

The enzyme 5α-Reductase (5α-R) catalyzes the formation of dihydrotestosterone, which is involved in male pattern hair loss and benign prostatic hyperplasia. Finasteride inhibits 5α-R and is used to treat both these conditions. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts, and cognitive impairment. The neural mechanisms underlying these effects of finasteride are not known and it is imperative that an animal model that mimics the clinical neuropsychiatric effects of finasteride is developed. Accordingly, we evaluated the behavioral effects of acute and repeated finasteride administration. Two months old male Wistar rats were administered with either vehicle (hydroxypropyl-ß-cyclodextrin) or different doses of finasteride, subcutaneously, either acutely (30 min or 2 h) or for 1, 3, and 6 days (one dose per day). Behavioral despair and motivational behavior were evaluated in the forced swim test (FST) and splash test, respectively. FST and splash test were video-recorded and analyzed offline. Finasteride did not show any effects in the acute, one day or three days studies in the FST. However, repeated finasteride administration for 6 days significantly increased the immobility time. In the splash test, finasteride (100 mg/kg) administration increased the latency to groom and decreased the grooming duration implying lack of motivation in the three-day study. In the six-day study, latency to groom was significantly increased by the 100 mg/Kg dose. Further, a significant dose dependent decrease in the grooming duration was observed. In summary, our results indicate that repeated finasteride administration induces depression-like behavior in rats. This study provides the evidence that an animal model of finasteride-induced depression is feasible to investigate the cellular and molecular mechanisms, and the pharmacology underlying the neuropsychiatric effects of finasteride. Further, these results provide insights into the potential involvement of neurosteroids in depression and will lead to the development of novel therapeutics for its treatment.

Chronic brain stimulation rewarding experience ameliorates depression-induced cognitive deficits and restores aberrant plasticity in the prefrontal cortex.

BACKGROUND: Major depressive disorder (MDD) is a multifactorial disease which often coexists with cognitive deficits. Depression-induced cognitive deficits are known to be associated with aberrant reward processing, neurochemical and structural alterations. Recent studies have shown that chronic electrical stimulation of brain reward areas induces a robust antidepressant effect. However, the effects of repeated electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-induced cognitive deficits and associated neurochemical and structural alterations in the prefrontal cortex (PFC) are unknown. OBJECTIVES: We investigated the effect of chronic rewarding self-stimulation of LH-MFB in neonatal clomipramine (CLI) model of depression. During adulthood, neonatal CLI and saline administered rats were implanted with bilateral electrodes stereotaxically in the LH-MFB and trained to receive intracranial self-stimulation (ICSS) for 14 days. The rats were tested for depressive-like behaviors, learning and memory followed by estimation of PFC volumes, levels of monoamines and its metabolites in the PFC. RESULTS: We found that chronic ICSS of LH-MFB reverses CLI-induced behavioral despair and anhedonia. Interestingly, self-stimulation normalizes the impaired novel object and location recognition memory in CLI rats. The amelioration of learning impairments in CLI rats was associated with the reversal of volume loss and restoration of monoamine metabolism in the PFC. CONCLUSION: We demonstrated that repeated intracranial self-stimulation of LH-MFB ameliorates CLI-induced learning deficits, reverses altered monoamine metabolism and the atrophy of PFC. Our results support the hypothesis that chronic brain stimulation rewarding experience might be evolved as a potential treatment strategy for reversal of learning deficits in depression and associated disorders.

Inactivation of Basolateral Amygdala Prevents Stress-Induced Astroglial Loss in the Prefrontal Cortex.

Repeated stress causes cognitive decline and decreases the expression of glial fibrillary acidic protein (GFAP)+ astroglial cells in the prefrontal cortex (PFC). The stress-induced alterations in astroglial density and morphology might significantly contribute to cognitive impairments. Apart from PFC, a key region involved in modulation of repercussions of stress is basolateral amygdala (BLA), which undergoes hypertrophy following chronic immobilization stress (CIS) and has intense reciprocal connections to the PFC. Interestingly, inactivation of BLA precludes stress-induced learning deficits. However, the modulatory role of BLA on CIS-induced alterations in GFAP+ astroglial density and associated learning deficits are presently unknown. Accordingly, we present two sets of experiments evaluating the effects of BLA inactivation either permanently or temporarily on CIS-induced changes in learning and astroglial expression in the PFC. CIS causes impairment in novel object recognition memory and astroglial loss in the PFC. In experiment I, we permanently inactivated the BLA by ibotenate lesion prior to CIS and observed a significant improvement in learning. Surprisingly, BLA lesion also prevented the stress-induced astroglial loss in the PFC. Furthermore, in the experiment II, we analyzed whether the effects of permanent inactivation could be mirrored by the temporary blockage of BLA specifically during stress. Interestingly, temporary inactivation of BLA mimics the effects of lesion. There was a notable prevention of learning impairment and astroglial loss in the PFC following BLA inactivation during stress. The present study emphasizes that stress-induced astroglial loss might contribute to cognitive deficits and modulation of BLA activity might be a viable strategy for management of stress-related PFC dysfunctions.

Prevention of chronic immobilization stress-induced enhanced expression of glucocorticoid receptors in the prefrontal cortex by inactivation of basolateral amygdala.

Repeated exposure to stress precipitates anxiety, depression and cognitive deficits. Stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis is modulated by the prefrontal cortex (PFC) and basolateral amygdala (BLA). It is well established that BLA positively regulates the HPA axis and undergoes hypertrophy following chronic immobilization stress (CIS). However, it is not known whether inactivation of the BLA can modulate the stress-induced changes in the expression of glucocorticoid receptors (GRs) in the PFC. To address this, we stereologically estimated GR+ cell densities in the prelimbic (PrL) and anterior cingulate cortex (ACC). Following ibotenate lesioning of the BLA, rats were subjected to CIS and GR+ cell densities were assessed. CIS increases the GR+ cell densities in PrL and ACC. BLA lesion prior to CIS abolished the CIS-induced increase in GR+ cell densities in both regions. In the second part of experiments, we evaluated whether selective inactivation of BLA during CIS would mimic the effects of BLA lesion. Interestingly, the BLA inactivation specifically during CIS prevented the increase in GR+ cell densities in the PrL and ACC. The findings of our study suggest that BLA regulates the stress-induced increase in prefrontal GR expression, which might be crucial in the emergence of affective and cognitive symptoms following stress. We speculate that modulation of BLA during stress might prevent HPA axis dysfunctions and GR resistance in stress-related disorders, and could assist in the development of novel therapeutic strategies to treat stress and associated disorders like depression. Further, molecular studies are warranted for the understanding of stress-induced GR resistance and its prevention via BLA inactivation.

Basolateral amygdalar inactivation blocks chronic stress-induced lamina-specific reduction in prefrontal cortex volume and associated anxiety-like behavior.

Chronic exposure to stress causes cognitive deficits, anxiety and depression. Earlier studies have suggested that the prefrontal cortex (PFC) and basolateral amygdala (BLA) can differentially modulate the stress-induced alterations either by their action on HPA axis or via direct reciprocal connections between them. The PFC dysfunction and BLA hypertrophy following stress are known to cause anxiety and affective symptoms. Recent studies indicate that inactivation of BLA projections to PFC remarkably decreases anxiety. However, the effect of BLA inactivation on stress-induced anxiety and associated volume loss in prelimbic (PrL) and anterior cingulate (ACC) subregions of PFC is not known. Accordingly, we evaluated the effect of BLA lesion or inactivation during chronic immobilization stress (CIS) on an approach-avoidance task and associated volume loss in the PFC. The stressed rats showed a significant volumetric reduction in layer I and II of the PrL and ACC. Interestingly, BLA lesion prior to stress prevented the volume loss in PrL and ACC. Further, BLA lesion blocked the anxiety-like behavior in stressed rats. However, in the absence of stress, BLA lesion increased the number of shocks as compared to controls. As BLA lesion produced an anticonflict effect, we performed temporary inactivation of BLA specifically during stress. Similar to BLA lesion, lidocaine-induced inactivation prevented the stress-induced volume loss and anxiety-like behavior. We demonstrate that inactivation of BLA during stress prevents CIS-induced anxiety and associated structural correlates in the PFC. The present study extends the hypothesis of amygdalar silencing as a possible management strategy for stress and associated disorders.

Temporal lobe epilepsy-induced neurodegeneration and cognitive deficits: Implications for aging.

Epilepsy is a neurological condition associated with seizures, neurodegeneration, circuit reorganization, and other structural and functional abnormalities. These elements ultimately lead to behavioural alterations such as anxiety, depression, and importantly cognitive impairment like learning disability and memory impairment. These factors can attribute to acceleration of aging and cognitive impairment in middle-aged people, which is otherwise evident in dementia and Alzheimer's disease among elderly people. In addition to epilepsy per se, several studies have shown that conventional anti-epileptic drugs used to treat epilepsy also contributes to aging and cognitive deficits through their adverse effects. The current review focuses on prevention of accelerated aging and cognitive impairment through an unconventional approach of combining non-pharmacological (enriched environment) and pharmacological therapy, which reduces the factors responsible for accentuated aging and memory impairment in chronic epileptic condition.

Contrasting effects of pre-training on acquisition of operant and radial arm maze tasks in rats.

Performing multiple tasks either simultaneously, in rapid alternation or in succession, is routine in daily life. Further, testing rodents in a battery of tests is common both in drug discovery and behavioral phenotyping research. However, learning of new tasks can be influenced by prior experience(s). There has been some research on 'switching cost' involved in the transition from one behavior to another. However, there has been no specific assessment of the effect of learning an operant paradigm on performance in a spatial memory task and vice versa. Accordingly, we evaluated task switching between two forms of learning paradigms, operant conditioning and radial arm maze (RAM) tasks. In experiment 1, rats were trained for operant conditioning with food reward followed by a partially baited RAM task. In experiment 2, rats were trained first on a RAM task followed by operant learning. Pre-training on the operant task, impaired the acquisition of the RAM. On the contrary, pre-training on the RAM enhanced operant performance. Our study reveals significant effects of the test order on task-switching in rats. This knowledge can be useful when framing test sequences in test batteries for drug discovery research and screening genetically modified mice.

Antioxidant action of grape seed polyphenols and aerobic exercise in improving neuronal number in the hippocampus is associated with decrease in lipid peroxidation and hydrogen peroxide in adult and middle-aged rats.

The present study explored the effects of swimming training and grape seed proanthocyanidin extract (GSPE) on neuronal survival in the hippocampus (HC) of middle-aged rats along with oxidative stress (OS) parameters. Further, the bioavailability of the GSPE, catechin, epicatechin and gallic acid were measured in the HC and plasma. Male Wistar rats were grouped into: sedentary control, SE-C; swimming trained, SW-T; SE-C, supplemented sedentary, SE-C(PA) and swimming trainees, SW-T(PA). The supplement was a daily dose of 400mg GSPE/kg body weight. Swimming training lasted for 2h/day and for 14weeks. Glutathione level was increased in response to single and combined interventions in the middle-aged rats. Adult trainees showed increased glutathione peroxidase activity unlike middle-aged wherein increase was seen in SE-C(PA) alone. Lowered catalase activity with age in the HC increased in response to the combined interventions although single interventions were also effective. HC from both ages showed decrease in lipid peroxidation and hydrogen peroxide levels in response to the interventions. GSPE constituents were seen in the HC of swimming trained middle-aged and adult rats. The study suggests that combined intervention is effective in decreasing LPO and H2O2 generation in the HC. Further, the neuronal numbers and planimetric volumes of CA1 pyramidal layer was significantly reduced in middle-aged rats compared to adults. Interestingly, both interventions enhanced the numbers and volumes in adult and middle-aged rats. Thus, age-associated decrease in CA1 neurons could be restored by both the interventions. The results of the present study will help in developing effective therapies for age-associated degenerative changes and cognitive deficits.

Inactivation of basolateral amygdala prevents chronic immobilization stress-induced memory impairment and associated changes in corticosterone levels.

Chronic stress causes detrimental effects on various forms of learning and memory. The basolateral amygdala (BLA) not only plays a crucial role in mediating certain forms of memory, but also in the modulation of the effects of stress. Chronic immobilization stress (CIS) results in hypertrophy of the BLA, which is believed to be one of the underlying causes for stress' effects on learning. Thus, it is plausible that preventing the effects of CIS on amygdala would preclude its deleterious cognitive effects. Accordingly, in the first part, we evaluated the effect of excitotoxic lesion of the BLA on chronic stress-induced hippocampal-dependent spatial learning using a partially baited radial arm maze task. The BLA was ablated bilaterally using ibotenic acid prior to CIS. Chronically stressed rats showed impairment in spatial learning with decreased percentage correct choice and increased reference memory errors. Excitotoxic lesion of the BLA prevented the impairment in spatial learning and reference memory. In the retention test, lesion of the BLA was able to rescue the chronic stress-induced impairment. Interestingly, stress-induced enhanced plasma corticosterone levels were partially prevented by the lesion of BLA. These results motivated us to evaluate if the same effects can be observed with temporary inactivation of BLA, only during stress. We found that chronic stress-induced spatial learning deficits were also prevented by temporary inactivation of the BLA. Additionally, temporary inactivation of BLA partially precluded the stress-induced increase in plasma corticosterone levels. Thus, inactivation of BLA precludes stress-induced spatial learning deficits, and enhanced plasma corticosterone levels. It is speculated that BLA inactivation-induced reduction in corticosterone levels during stress, might be crucial in restoring spatial learning impairments. Our study provides evidence that amygdalar modulation during stress might be beneficial for strategic management of stress-related cognitive deficits.

Environmental enrichment ameliorates chronic immobilisation stress-induced spatial learning deficits and restores the expression of BDNF, VEGF, GFAP and glucocorticoid receptors.

Severe and prolonged stress is the main environmental factor that precipitates depression, anxiety and cognitive dysfunctions. On the other hand, exposure to environmental enrichment (EE) has been shown to induce progressive plasticity in the brain and improve learning and memory in various neurological and psychiatric disorders. It is not known whether exposure to enriched environment could ameliorate chronic immobilisation stress-induced cognitive deficits and altered molecular markers. Hence, in the present study we aimed to evaluate the effect of enriched environment on chronic immobilisation stress (CIS) associated changes in spatial learning and memory, behavioural measures of anxiety, depression and molecular markers as well as structural alterations. Male Wistar rats were subjected to chronic immobilisation stress for 2h/day/10days followed by 2weeks of exposure to EE. CIS resulted in weight loss, anhedonia, increased immobility, spatial learning and memory impairment, enhanced anxiety, and reduced expression of BDNF, VEGF, GFAP and glucocorticoid receptors (GR) in discrete brain regions. Interestingly, stressed rats exposed to enrichment ameliorated behavioural depression, spatial learning and memory impairment and reduced anxiety behaviour. In addition, EE restored BDNF, VEGF, GFAP and GR expression and normalized hypotrophy of dentate gyrus and hippocampus in CIS rats. In contrast, EE did not restore hypertrophy of the amygdalar complex. Thus, EE ameliorates stress-induced cognitive deficits by modulating the neurotrophic factors, astrocytes and glucocorticoid receptors in the hippocampus, frontal cortex and amygdala.