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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 GABA A 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.

The ventral subiculum regulates emotion, stress responses, and spatial and social cognition. In our previous studies, we have demonstrated anxiety- and depression-like symptoms, deficits in spatial and social cognition in ventral subicular lesioned (VSL) rats, and restoration of affective and cognitive behaviors following photoperiod manipulation (short photoperiod regime, SPR; 6:18 LD cycle). In the present study, we have studied the impact of VSL on sleep-wake behavioral patterns and the effect of SPR on sleep-wakefulness behavior. Adult male Wistar rats subjected to VSL demonstrated decreased wake duration and enhanced total sleep time due to increased non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). Power spectral analysis indicated increased delta activity during NREMS and decreased sigma band power during all vigilance states. Light is one of the strongest entrainers of the circadian rhythm, and its manipulation may have various physiological and functional consequences. We investigated the effect of 21-day exposure to SPR on sleep-wakefulness (S-W) behavior in VSL rats. We observed that SPR exposure restored S-W behavior in VSL rats, resulting in an increase in wake duration and a significant increase in theta power during wake and REMS. This study highlights the crucial role of the ventral subiculum in maintaining normal sleep-wakefulness patterns and highlights the effectiveness of photoperiod manipulation as a non-pharmacological treatment for reversing sleep disturbances reported in mood and neuropsychiatric disorders like Alzheimer's disease, bipolar disorder, and major depressive disorder, which also involve alterations in circadian rhythm., (© 2024 Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Finasteride is used in female-pattern hair loss, hirsutism, and polycystic ovarian syndrome. It inhibits 5α-reductase, which is an important enzyme in the biosynthesis of neurosteroids. The effects of finasteride treatment on mental health in female patients as well as the effects of repeated/chronic finasteride administration in female rodents are still unknown. Accordingly, in our study, we administered finasteride (10, 30, or 100 mg/Kg, s.c.) for 6 days in female rats and evaluated behavior, plasma steroid levels, and synaptic plasticity. Depression-like behavior was evaluated using forced swim test (FST) and splash test. Anxiety-like behavior was evaluated using novelty-suppressed feeding task (NSFT), elevated plus maze (EPM), open field test (OFT), and light-dark test (LDT). Plasma steroid levels were assessed using ELISA and synaptic plasticity by field potential recordings. We observed that finasteride decreased total immobility duration in FST, indicating antidepressant-like effect and decreased the latency to first bite in NSFT, showing anxiolytic-like effect. We also found a significant increase in plasma estradiol and a significant decrease in plasma corticosterone level. Furthermore, field potential recordings showed that finasteride increased hippocampal long-term potentiation. These results indicate that repeated finasteride administration in female rats may have antidepressant- and anxiolytic-like effect, which might be mediated by enhanced estradiol levels or decreased corticosterone levels. Further studies are required to validate the molecular mechanisms underlying the effects of finasteride in female rats. Understanding the mechanisms will help us in developing novel neurosteroid-based therapeutics in the treatment of neuropsychiatric disorders in women., (© 2024 Wiley Periodicals LLC.)

Environmental enrichment (EE) is a process of brain stimulation by modifying the surroundings, for example, by changing the sensory, social, or physical conditions. Rodents have been used in such experimental strategies through exposure to diverse physical, social, and exploration conditions. The present study conducted an extensive analysis of the existing literature surrounding the impact of EE on dementia rodent models. The review emphasised the two principal aspects that are very closely related to dementia: cognitive function (learning and memory) as well as psychological factors (anxiety-related behaviours such as phobias and unrealistic worries). Also highlighted were the mechanisms involved in the rodent models of dementia showing EE effects. Two search engines, PubMed and Science Direct, were used for data collection using the following keywords: environmental enrichment, dementia, rodent model, cognitive performance, and anxiety-related behaviour. Fifty-five articles were chosen depending on the criteria for inclusion and exclusion. The rodent models with dementia demonstrated improved learning and memory in the form of hampered inflammatory responses, enhanced neuronal plasticity, and sustained neuronal activity. EE housing also prevented memory impairment through the prevention of amyloid beta (Aβ) seeding formation, an early stage of Aβ plaque formation. The rodents subjected to EE were observed to present increased exploratory activity and exert less anxiety-related behaviour, compared to those in standard housing. However, some studies have proposed that EE intervention through exercise would be too mild to counteract the anxiety-related behaviour and risk assessment behaviour deficits in the Alzheimer's disease rodent model. Future studies should be conducted on old-aged rodents and the duration of EE exposure that would elicit the greatest benefits since the existing studies have been conducted on a range of ages and EE durations. In summary, EE had a considerable effect on dementia rodent models, with the most evident being improved cognitive function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacological treatment with anti-seizure drugs (ASDs) remains the mainstay in epilepsy management. Levetiracetam (LEV) is a second-generation ASD with a novel SV2A protein target and is indicated for treating focal epilepsies. While there is considerable literature in acute models, its effect in chronic epilepsy is less clear. Particularly, its effects on neuronal excitability, synaptic plasticity, adult hippocampal neurogenesis, and histological changes in chronic epilepsy have not been evaluated thus far, which formed the basis of the present study. Six weeks post-lithium-pilocarpine-induced status epilepticus (SE), epileptic rats were injected with levetiracetam (54 mg/kg b.w. i.p.) once daily for two weeks. Following LEV treatment, Schaffer collateral - CA1 (CA3-CA1) synaptic plasticity and structural changes in hippocampal subregions CA3 and CA1 were evaluated. The number of doublecortin (DCX + ) and reelin (RLN + ) positive neurons was estimated. Further, mossy fiber sprouting was evaluated in DG by Timm staining, and splash test was performed to assess the anxiety-like behavior. Chronic epilepsy resulted in decreased basal synaptic transmission and increased paired-pulse facilitation without affecting post-tetanic potentiation and long-term potentiation. Moreover, chronic epilepsy decreased hippocampal subfields volume, adult hippocampal neurogenesis, and increased reelin expression and mossy fiber sprouting with increased anxiety-like behavior. LEV treatment restored basal synaptic transmission and paired-pulse facilitation ratio in CA3-CA1 synapses. LEV also restored the CA1 subfield volume in chronic epilepsy. LEV did not affect epilepsy-induced abnormal adult hippocampal neurogenesis, ectopic migration of newborn granule cells, mossy fiber sprouting in DG, and anxiety-like behavior. Our results indicate that in addition to reducing seizures, LEV has favorable effects on synaptic transmission and structural plasticity in chronic epilepsy. These findings add new dimensions to the use of LEV in chronic epilepsy and paves way for further research into its effects on cognition and affective behavior., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sleep dysfunctions in epilepsy increase the burden of seizures and cognitive impairments. Seizures and certain anti-seizure drugs (ASDs) can affect sleep quality, leading to excessive daytime sleepiness and poor cognitive performance. Therefore, it is imperative to develop non-pharmacological strategies to curb epilepsy and related sleep dysfunction. Enriched environment (EE) has been demonstrated to ameliorate seizures and associated comorbidity in animal models of epilepsy. However, its effects on epilepsy-induced sleep dysfunctions and altered neural activity remain unexplored. To study the same, chronic epilepsy was induced in male Wistar rats and subjected to standard or enriched housing (6 h/day for 14 days), after which sleep/wake cycle, EEG spectral power and coherence during all vigilance states were analysed. Further, hippocampal parvalbumin-positive (PV + ) interneurons were quantified to correlate the functional implications with the electrophysiological changes. Epileptic rats showed decreased rapid eye movement (REM) sleep, prolonged REM latency, and extended wake after sleep onset (WASO). Power spectrum analysis indicated an increase in delta and theta activity with a concomitant decrease in gamma activity during wake, an increase in prefrontal cortex (PFC)- Cornu ammonis (CA1) coherence, and a significant loss of hippocampal PV + interneuron density. Exposure to EE restored REM sleep duration and latency without altering WASO in epileptic rats. EE also restored delta power during non-rapid eye movement (NREM) and theta, gamma power during wake, PFC-CA1 coherence, and PV + interneurons density. These results further strengthen the role of EE's positive effects on brain plasticity and aid in developing non-pharmacological strategies to mitigate epilepsy-associated comorbidities., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Aim: Gestational diabetes mellitus (GDM) might predispose the mothers to depression. Studies have reported the role of biomarkers either in GDM or depression, but very few have examined them in GDM with depression. The present study profiled the circulating levels of brain-derived neurotrophic factor (BDNF), Beta Endorphin (BE) and nesfatin-1 in women with GDM (with and without depression)., Methods: 160 pregnant women at 24-28 weeks of pregnancy (NGT/GDM with & without depression, n = 40 each) were randomly selected from the ongoing STRiDE (STratification of Risk of Diabetes in Early pregnancy) study. Depression score was derived using PHQ-9 questionnaire and ELISA was used to quantify the biomarkers., Results: Circulatory levels of BDNF, BE and nesfatin-1 were lower in GDM women with or without depression compared to NGT without depression, however, nesfatin-1 levels were higher in NGT with depression. Notably, GDM with depression had the lowest levels of BDNF and BE. Both BDNF and BE levels were negatively correlated with depression, 1 h and 2 h plasma glucose. Regression analysis confirmed that each standard deviation decreases in BDNF and BE were independently associated with higher odds of GDM with or without depression even after adjusting for potential confounders., Conclusion: Our study has identified altered levels of a panel of neurobiological biomarkers (BDNF/BE/nesfatin-1) in those with combined GDM and depression. BDNF/BE could be potential biomarkers to assess the higher risk of coexisting depression and GDM., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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 control free 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 VSL free 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., (Copyright © 2022. Published by Elsevier B.V.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacoresistance and comorbidities pose significant challenges to its treatment necessitating the development of non-pharmacological approaches. In an earlier study, exposure to enriched environment (EE) reduced seizure frequency and duration and ameliorated chronic epilepsy-induced depression in rats. However, the cellular basis of beneficial effects of EE remains unknown. Accordingly, in the current study, we evaluated the effects of EE in chronic epilepsy-induced changes in behavioral hyperexcitability, synaptic transmission, synaptophysin (SYN), and calbindin (CB) expression, hippocampal subfield volumes and cell density in male Wistar rats. Epilepsy was induced by lithium-pilocarpine-induced status epilepticus. Chronic epilepsy resulted in behavioral hyperexcitability, decreased basal synaptic transmission, increased paired-pulse facilitation ratio, decreased hippocampal subfields volumes. Moreover, epileptic rats showed decreased synaptophysin and CB expression in the hippocampus. Six weeks post-SE, epileptic rats were exposed to EE for 2 weeks, 6 hr/day. EE significantly reduced the behavioral hyperexcitability and restored basal synaptic transmission correlating with increased expression of SYN and CB. Our results reaffirm the beneficial effects of EE on behavior in chronic epilepsy and establishes some of the putative cellular mechanisms. Since drug resistance and comorbidities are a major concern in TLE, we propose EE as a potent non-pharmacological treatment modality to mitigate these changes in chronic epilepsy., (© 2021 Wiley Periodicals LLC.)

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 (HPβCD) 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Photoperiod (day-length) has enduring effects on an organism's physiological functions like metabolism and behavioral phenotypes including cognition and affect. Circadian rhythm manipulations are potentially effective non-pharmacological strategies in the management of central nervous system insults. In our previous study, we demonstrated the efficacy of short photoperiod regime (SPR; 06/18 hr light-dark cycle) in establishing functional recovery in ventral subicular lesion (VSL) rats. The present study further demonstrates the efficacy of SPR in mitigating anxiety and depression as well as facilitating socio-cognitive behavior in VSL rats. VSL elevated the basal plasma corticosterone levels, increased anxiety, anhedonia, and behavioral despair with decreased self-care. The VSL rats also exhibited a considerable degree of impaired social cognition, in terms of altered social preference and social novelty. Exposure to SPR for 21 days mitigated the anxiety- and depressive-like phenotypes as well as improved social cognition significantly. Thus, the study demonstrated the effectiveness of SPR strategy in reversing most of the behavioral deficits caused by VSL. SPR, perhaps, would have regulated the hypothalamo-pituitary-adrenal axis responsiveness as we observed a decrease in plasma corticosterone levels following SPR in VSL rats. The study implies the need for developing a task-dependent SPR strategy to achieve complete behavioral recovery as the functional demands of each behavior is distinct. In summary, the study highlights the efficacy of photoperiod manipulation as a novel, non-pharmacological approach in mitigating the affective and cognitive deficits associated with neuropsychiatric disorders such as bipolar disorder and Alzheimer's disease wherein circadian rhythm alterations are implicated., (© 2020 Wiley Periodicals, Inc.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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-β-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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior., Aims: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice., Methods and Results: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT 2a R expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity., Conclusion: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N -methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 ( 6 ) and its active parent molecule BMS-986169 ( 5 ), which demonstrated high binding affinity for the GluN2B allosteric site ( K i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC 50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5 , 6 , or the major circulating metabolites met-1 and met-2 . The prodrug BMS-986163 ( 6 ) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder., Competing Interests: The authors declare no competing financial interest.

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.

Key Points: CA3 pyramidal cells display input-specific differences in the subunit composition of synaptic NMDA receptors (NMDARs). Although at low density, GluN2B contributes significantly to NMDAR-mediated EPSCs at mossy fibre synapses. Long-term potentiation (LTP) of NMDARs triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. GluN2B subunits are essential for the expression of LTP of NMDARs at mossy fibre synapses., Abstract: Single neurons express NMDA receptors (NMDARs) with distinct subunit composition and biophysical properties that can be segregated in an input-specific manner. The dynamic control of the heterogeneous distribution of synaptic NMDARs is crucial to control input-dependent synaptic integration and plasticity. In hippocampal CA3 pyramidal cells from mice of both sexes, we found that mossy fibre (MF) synapses display a markedly lower proportion of GluN2B-containing NMDARs than associative/commissural synapses. The mechanism involved in such heterogeneous distribution of GluN2B subunits is not known. Here we show that long-term potentiation (LTP) of NMDARs, which is selectively expressed at MF-CA3 pyramidal cell synapses, triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. This activity-dependent recruitment of GluN2B at mature MF-CA3 pyramidal cell synapses contrasts with the removal of GluN2B subunits at other glutamatergic synapses during development and in response to activity. Furthermore, although expressed at low levels, GluN2B is necessary for the expression of LTP of NMDARs at MF-CA3 pyramidal cell synapses. Altogether, we reveal a previously unknown activity-dependent regulation and function of GluN2B subunits that may contribute to the heterogeneous plasticity induction rules in CA3 pyramidal cells., (© 2017 Centre Nationnal de la Recherche Scientifique. The Journal of Physiology © 2017 The Physiological Society.)

( R )-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3 S ,4 S )-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (K i = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N -methyl-d-aspartate receptor subtypes (IC 50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC 50 = 28.4 μ M) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[ a,d ]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Approximately 30-60% of patients treated with existing antidepressants fail to achieve remission of depressive symptoms leading to Treatment Resistant Depression (TRD). There is an urgent need to develop novel medications, which is highly limited by the non-availability of relevant animal models with good predictive validity. ACTH administration has been shown to result in the resistance to acute and chronic effects of imipramine. However, the pharmacology of the model and the mechanisms contributing to the resistance are not completely understood. Furthermore, it is not known whether the ACTH administered animals show signs of depression-like behavior. Accordingly, we characterized the behavioral profile and sensitivity to antidepressants in BALB/c mice treated with ACTH and to evaluate some of the mechanisms responsible for the behavioral effects. Daily treatment with ACTH for 14, 21 or 28days failed to produce a depression-like phenotype in the sucrose preference test, voluntary wheel running or FST. In contrast, the acute antidepressant response in the FST was no longer observed in ACTH mice treated with fluoxetine, imipramine, duloxetine or bupropion. Interestingly, the combination of fluoxetine and a low dose of olanzapine, or the combination of fluoxetine and bupropion was efficacious in ACTH treated mice. Further, the sensitivity to a GluN2B receptor antagonist, radiprodil was retained in the ACTH model. To understand the mechanism responsible for the diminished response in these mice, we evaluated p11 (S100A10) mRNA expression and 5-HT2A protein expression. p11 expression was decreased and 5-HT2A protein content increased in ACTH treated mice. In summary, this model may have utility for the identification of novel treatments for TRD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long-term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety-like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short-term EE for 10 days can overcome restraint stress-induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short-term EE on chronic stress-induced impaired LTP, working memory, and anxiety-like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1-LTP, increased anxiety-like symptoms in elevated plus maze, and impaired working memory in T-maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Temporal lobe epilepsy (TLE) is commonly associated with depression, anxiety, and cognitive impairment. Despite significant progress in our understanding of the pathophysiology of TLE, it remains the most common form of refractory epilepsy. Enriched environment (EE) has a beneficial effect in many neuropsychiatric disorders. However, the effect of EE on cognitive changes in chronic TLE has not been evaluated. Accordingly, the present study evaluated the effects of EE on chronic epilepsy-induced alterations in cognitive functions, electrophysiology, and cellular changes in the hippocampus., Methods: Status epilepticus (SE) was induced in 2-month-old male Wistar rats with lithium and pilocarpine. Six weeks' post SE, epileptic rats were either housed in their respective home cages or in an enrichment cage (6 h/day) for 14 days. Seizure behavior was video-monitored 2 weeks before and during exposure to EE. Depression-like behavior, anxiety-like behavior, and spatial learning and memory were assessed using the sucrose preference test (SPT), elevated plus maze (EPM), and Morris water maze (MWM), respectively. Delta and theta power in the CA1 region of hippocampus was assessed from recordings of local field potentials (LFPs). Cellular changes in hippocampus were assessed by histochemistry followed by unbiased stereologic analysis., Results: EE significantly reduced seizure episodes and seizure duration in epileptic rats. In addition, EE alleviated depression and hyperactivity, and restored delta and theta power of LFP in the hippocampal CA1 region. However, EE neither ameliorated epilepsy-induced spatial learning and memory deficits nor restored cell density in hippocampus., Significance: This is the first study that evaluates the role of EE in a chronic TLE model, where rats were exposed to EE after occurrence of spontaneous recurrent seizures (SRS). Given that 30% of TLE patients are refractory to drug treatment, therapeutic strategies that utilize components of EE could be designed to alleviate seizures and psychiatric comorbidities associated with TLE., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Neurodegeneration of hippocampal structures is implicated in Alzheimer's disease (AD). Patients with AD exhibit 'sundown syndrome' featuring mood swings and anxiety. Although there are studies demonstrating circadian rhythm disruption associated with sundown phenomenon, the mechanisms underlying the emotional disturbances remain elusive. In the present study, we examined the relationship between subiculum (a key hippocampal output structure) and anxiety. Our study demonstrates that bilateral ventral subicular lesion (VSL) leads to anxiogenic behavior. In the elevated plus maze test, VSL rats made less number of entries into the open arms and spent significantly more time in the closed arms. Similarly, in the light-dark exploration test, VSL rats spent significantly more time in the dark chamber and made fewer entries into the light chamber. VSL also produced significant neurodegeneration in the paraventricular, suprachiasmatic and dorsomedial nuclei of the hypothalamus. Exposing VSL rats to a short photoperiod regime (SPR; 06/18h light-dark cycle) for 21days ameliorated the anxiety-like behavior. VSL rats on SPR also exhibited increased food consumption and higher core body temperature. Our study supports the hypothesis that the ventral subiculum regulates anxiety-like behavior and that SPR helps in the alleviation of such behavior. Even though the mechanisms underlying anxiolytic effects of light-dark cycle manipulation are yet to be elucidated, such non-pharmacological strategies can help to mitigate anxiety-like behavior. A proper understanding of the effectiveness of photoperiod manipulation will help in developing strategies in the management of emotional disturbances associated with affective and neurodegenerative disorders including AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression-associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression-associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression-induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long-term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight-arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression-associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments., (© 2014 Wiley Periodicals, Inc.)

Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.

The mammalian prefrontal cortex (PFC) has been implicated in a variety of motivational and emotional processes underlying working memory, attention and decision making. The PFC receives dopaminergic projections from the ventral tegmental area (VTA) and contains high density of D1 and D2 receptors and these projections are important in higher integrative cortical functions. The neurons of the PFC have been shown to undergo atrophy in response to stress. In an earlier study, we demonstrated that the chronic stress-induced atrophy of hippocampal neurons and behavioral impairment in the T-maze task were reversed by the activation of dopaminergic pathway by intracranial self-stimulation (ICSS) of the VTA. The stress-induced decrease in hippocampal dopamine (DA) levels was also restored by ICSS. Whether the reversal of stress-induced behavioral deficits by ICSS involves changes in the morphology of PFC neurons is unknown and the current study addresses this issue. Male Wistar rats underwent 21 days of restraint stress followed by ICSS for 10 days. The dendritic morphology of the PFC neurons was studied in Golgi-impregnated sections. Stress produced atrophy of the layer II/III and V PFC pyramidal neurons and ICSS to naïve rats significantly increased the dendritic arborization of these neurons compared to control. Interestingly, ICSS of stressed rats resulted in the reversal of the dendritic atrophy. Further, these structural changes were associated with a restored tissue levels of DA, norepinephrine and serotonin in the PFC. These results indicate that the behavioral restoration in stressed rats could involve changes in the plasticity of the PFC neurons and these results further our understanding of the role of dopaminergic neurotransmitter system in the amelioration of stress-induced deficits., (© Springer-Verlag 2011)

Rationale: Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function., Objectives: In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals., Methods: Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator., Results: Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume., Conclusions: These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.

Rationale: The neural basis of depression-associated cognitive impairment remains poorly understood, and the effect of antidepressants on learning and synaptic plasticity in animal models of depression is unknown. In our previous study, learning was impaired in the neonatal clomipramine model of endogenous depression. However, it is not known whether the cognitive impairment in this model responds to antidepressant treatment, and the electrophysiological and neurochemical bases remain to be determined., Objectives: To address this, we assessed the effects of escitalopram treatment on spatial learning and memory in the partially baited radial arm maze (RAM) task and long-term potentiation (LTP) in the Schaffer collateral-CA1 synapses in neonatal clomipramine-exposed rats. Also, alterations in the levels of biogenic amines and acetylcholinesterase (AChE) activity were estimated., Results: Fourteen days of escitalopram treatment restored the mobility and preference to sucrose water in the forced swim and sucrose consumption tests, respectively. The learning impairment in the RAM was reversed by escitalopram treatment. Interestingly, CA1-LTP was decreased in the neonatal clomipramine-exposed rats, which was restored by escitalopram treatment. Monoamine levels and AChE activity were decreased in several brain regions, which were restored by chronic escitalopram treatment., Conclusions: Thus, we demonstrate that hippocampal LTP is decreased in this animal model of depression, possibly explaining the learning deficits. Further, the reversal of learning and electrophysiological impairments by escitalopram reveals the important therapeutic effects of escitalopram that could benefit patients suffering from depression.

Neurogenesis is well-established to occur during adulthood in two regions of the brain, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. Research for more than two decades has implicated a role for adult neurogenesis in several brain functions including learning and effects of antidepressants and antipsychotics. Clear understanding of the players involved in the regulation of adult neurogenesis is emerging. We review evidence for the role of stress, dopamine (DA) and acetylcholine (ACh) as regulators of neurogenesis in the SGZ. Largely, stress decreases neurogenesis, while the effects of ACh and DA depend on the type of receptors mediating their action. Increasingly, the new neurons formed in adulthood are potentially linked to crucial brain processes such as learning and memory. In brain disorders like Alzheimer and Parkinson disease, stress-induced cognitive dysfunction, depression and age-associated dementia, the necessity to restore brain functions is enormous. Activation of the resident stem cells in the adult brain to treat neuropsychiatric disorders has immense potential and understanding the mechanisms of regulation of adult neurogenesis by endogenous and exogenous factors holds the key to develop therapeutic strategies for the debilitating neurological and psychiatric disorders.

Several drugs of herbal origin are known to possess anxiolytic and antidepressant effects. In a recent study, we showed that extracts from Euphorbia hirta L. (Euphorbiaceae) (Eh) demonstrated anxiolytic effects in rats subjected to chronic immobilization stress (CIS) but not in rats that underwent forced swim stress (FSS). Acetylcholine and the cholinergic system are known to be involved in anxiety. However, whether the cholinergic system is involved in the anxiolytic actions of Eh are not known. In the current study, we evaluated the effects of Eh treatment of rats subjected to either CIS or FSS on acetylcholinesterase (AChE) activity in the frontal cortex, hippocampus, and septum. CIS increased the AChE activity in all three regions, while Eh treatment restored it to normal levels. FSS increased the AChE activity only in the septum, and Eh treatment marginally restored this to normal levels. Thus, these results indicate the involvement of the cholinergic system in the behavioral effects of Euphorbia hirta.

Activity-dependent, bidirectional control of synaptic efficacy is thought to contribute to many forms of experience-dependent plasticity, including learning and memory. Although most excitatory synapses contain both AMPA and N-methyl-d-aspartate receptors (AMPARs and NMDARs), most studies have focused on the plasticity of synaptic AMPARs, and on the pivotal role of NMDA receptors for its induction. Here we review evidence that synaptic NMDARs themselves are subject to long-term activity-dependent changes by mechanisms that may differ from that of synaptic AMPARs. The bidirectional modulation of NMDAR-mediated synaptic responses is likely to have important functional implications for NMDAR-dependent forms of synaptic plasticity.

Chronic stress decreases neurogenesis in the adult brain, while exposure to enriched environment (EE) increases it. Recent studies demonstrate the ability of EE to ameliorate stress-induced behavioral deficits. Whether a restored neurogenesis contributes to these effects of EE is unknown. Recently, we demonstrated that EE following restraint stress restores cell proliferation in the dentate gyrus (DG), hippocampal volume and learning. In the current study, we examine the effects of EE following stress on survival and differentiation of the progenitor cells in the DG and behavioral depression using the forced swim test (FST) and sucrose consumption test (SCT). Adult male Wistar rats were subjected to 21 days of restraint stress followed by housing in either standard or enriched conditions (10 days, 6h/day). Survival and differentiation of BrdU-labeled cells were evaluated 31 days post-BrdU administration. Stress decreased the survival and differentiation of progenitor cells, which was ameliorated by EE. Also the percentage of BrdU-ir cells that did not co-localize with NeuN or S100beta was significantly greater in the stressed rats and was restored by EE. Stress increased immobility in FST and decreased sucrose preference in the SCT, and these behaviors were ameliorated by EE. Adult neurogenesis is thought to be linked to learning and memory and in mediating antidepressant effect. Taken together with our earlier report that EE restores stress-induced impairment in learning and cytogenesis, the current results indicate that the reversal of adult neurogenesis could be one of the mechanisms involved in the amelioration of stress-induced deficits.

Adult neurogenesis, particularly in the subgranular zone, is thought to be linked with learning and memory. Chronic stress inhibits adult hippocampal neurogenesis and also impairs learning and memory. On the other hand, exposure to enriched environment (EE) is reported to enhance the survival of new neurons and improve cognition. Accordingly, in the present study, we examined whether short-term EE after stress could ameliorate the stress-induced decrease in hippocampal cell proliferation and impairment in radial arm maze learning. After restraint stress (6 hr/day, 21 days) adult rats were exposed to EE (6 hr/day, 10 days). We observed that chronic restraint stress severely affected formation of new cells and learning. Stressed rats showed a significant decrease (70%) in the number of BrdU (5-bromo-2'-deoxyuridine)-immunoreactive cells and impairment in the performance of the partially baited radial arm maze task. Interestingly, EE after stress completely restored the hippocampal cell proliferation. On par with the restoration of hippocampal cytogenesis, short-term EE after stress resulted in a significant increase in percentage correct choices and a decrease in the number of reference memory errors compared with the stressed animals. Also, EE per se significantly increased the cell proliferation compared with controls. Furthermore, stress significantly reduced the hippocampal volume that was reversed after EE. Our observations demonstrate that short-term EE completely ameliorates the stress-induced decrease in cell proliferation and learning deficit, thus demonstrating the efficiency of rehabilitation in reversal of stress-induced deficits and suggesting a probable role of newly formed cells in the effects of EE.

Chronic restraint stress causes spatial learning and memory deficits, dendritic atrophy of the hippocampal pyramidal neurons and alterations in the levels of neurotransmitters in the hippocampus. In contrast, intracranial self-stimulation (ICSS) rewarding behavioral experience is known to increase dendritic arborization, spine and synaptic density, and increase neurotransmitter levels in the hippocampus. In addition, ICSS facilitates operant and spatial learning, and ameliorates fornix-lesion induced behavioral deficits. Although the effects of stress and ICSS are documented, it is not known whether ICSS following stress would ameliorate the stress-induced deficits. Accordingly, the present study was aimed to evaluate the role of ICSS on stress-induced changes in hippocampal morphology, neurochemistry, and behavioral performance in the T-maze. Experiments were conducted on adult male Wistar rats, which were randomly divided into four groups; normal control, stress (ST), self-stimulation (SS), and stress + self-stimulation (ST + SS). Stress group of rats were subjected to restraint stress for 6 h daily over 21 days, SS group animals were subjected to SS from ventral tegmental area for 10 days and ST + SS rats were subjected to restraint stress for 21 days followed by 10 days of SS. Interestingly, our results show that stress-induced behavioral deficits, dendritic atrophy, and decreased levels of neurotransmitters were completely reversed following 10 days of SS experience. We propose that SS rewarding behavioral experience ameliorates the stress-induced cognitive deficits by inducing structural and biochemical changes in the hippocampus.

Clinical studies show cognitive impairment in depression. However, the neural substrates underlying these remain elusive. Hence, we have examined the effect of neonatal clomipramine treatment on cognition in adulthood. The neonatal clomipramine treated rats displayed a profound impairment in partially baited 8-arm radial maze task. This work provides a novel perspective into neural basis of depression associated cognitive changes and help in development of therapeutic strategies to treat depression related memory dysfunctions.

Chronic stress is known to result in impairment of learning and memory and precipitate several affective disorders including depression and anxiety. Drugs of natural origin are known to possess several effects on the central nervous system and are emerging as promising alternative therapies. In this context, the hydroalcoholic extract of Euphorbia hirta (Eh) was evaluated for anxiolytic property in chronically stressed rats subjected to elevated plus maze (EPM) and open field test (OFT). Eh treatment (200 mg/kg, p.o.; seven days) showed marked anti-anxiety activity in chronic immobilization stress. In contrast, the forced swim stress-induced anxiety was only partially decreased by Eh. Co-treatment of rats with flumazenil (0.5 mg/kg, i.p.), bicuculline (1 mg/kg, i.p.) or picrotoxin (1 mg/kg, i.p.) resulted in a significant reduction of anxiolytic effect of Eh indicating that its actions are mediated through GABA(A) receptor-benzodiazepine receptor-Cl(-) channel complex. Thus, our studies indicate that Eh is a potential anxiolytic drug, which might be beneficial in the treatment of stress-induced anxiety disorders.

Rationale: Severe, traumatic stress or repeated exposure to stress can result in long-term deleterious effects, including hippocampal cell atrophy and death, which, in turn, result in memory impairments and behavioural abnormalities. The dopaminergic D(2) receptor agonist, bromocriptine, has been shown to modulate learning, and chronic stress is associated with dopaminergic dysfunction., Objectives: In the present study, we evaluated the effects of bromocriptine in the presence or absence of restraint stress., Materials and Methods: Adult male Wistar rats were subjected to restraint stress for 21 days (6 h/day) followed by bromocriptine treatment, and learning was assessed in the partially baited radial arm maze task. In a separate group of animals, the effects of bromocriptine per se was evaluated. Dopamine levels were estimated by high-performance liquid chromatography with electrochemical detection., Results: Stressed rats showed impairment in both acquisition and retention of the radial arm maze task, and bromocriptine treatment after stress showed a reversal of stress-induced impairment. Interestingly, in the absence of stress, bromocriptine exhibited dose-dependent differential effects on learning. While rats treated with bromocriptine 5 mg/kg, i.p., demonstrated impairment in learning, the bromocriptine 10 mg/kg and vehicle-treated groups did not differ from normal controls. To understand the neurochemical basis for the effects of bromocriptine, dopamine levels were estimated. The stress-induced decrease in dopamine levels in the hippocampus and frontal cortex were restored by bromocriptine treatment. In contrast, bromocriptine alone (5 mg/kg, i.p.) decreased dopamine levels in the frontal cortex and striatum., Conclusions: Our study shows that amelioration of stress-induced learning impairment correlates with restoration of dopamine levels by bromocriptine treatment.

Simulated hypobaric hypoxia (HBH), resembling high altitude hypoxia severely affects the CNS and results in several physiological changes. The hippocampus is closely associated with learning and memory and an insult to this region affects cognition. Previous studies suggest that rapid or prolonged exposures to HBH are associated with psychomotor and cognitive impairments. The defense personnel, mountain climbers and rescue teams are exposed to such harsh environment and thus it demands a systematic study emphasizing the subtle effects of such extreme environments on cognitive function. Accordingly, this study evaluated the effect of hypobaric hypoxia on structural changes in the principal neurons of the hippocampus and learning in eight-arm radial maze. Adult male Wistar rats, subjected to simulated hypobaric hypoxia equivalent to an altitude of 6000 m for a period of 2 or 7 days, in a hypoxic chamber served as hypoxic group (HY). Rats housed in a similar chamber for the same period of time, without hypoxic exposure served as sham control (SC), while normal control (NC) group of rats were housed in standard laboratory conditions. The dendritic morphology of neurons in cornu ammonis region 1 (CA1) and cornu ammonis region 3 (CA3) was studied in Golgi-impregnated hippocampal sections. Exposure for 2 days to hypobaric hypoxia had minimal deleterious effects on the CA1 pyramidal neurons, while exposure for 7 days resulted in a significant decrease in the number of branching points, intersections and dendritic length. Unlike the CA1 pyramidal neurons, the CA3 neurons exhibited dendritic atrophy following both 2 and 7 days of hypoxic exposure. Further, hippocampal-dependent spatial learning was affected marginally following 2 day exposure, while 7 day exposure severely affected learning of the partially baited radial arm maze task. Our study suggests that dendritic atrophy in the hippocampus on exposure to HBH could be one of the bases for the cognitive deficits exhibited under such conditions.

Environmental enrichment promotes structural and behavioral plasticity in the adult brain. We have evaluated the efficacy of enriched environment on the dendritic morphology and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of ventral subicular-lesioned rats. Bilateral ventral subicular lesion has significantly reduced the dendritic architecture and spine density of hippocampal pyramidal neurons. The lesioned rats exposed to enriched housing for 10 days showed a significant degree of morphological plasticity in terms of enhanced dendritic branching and spine density. However, the BDNF expression in the hippocampus remained unchanged following subicular lesion and following environmental enrichment. We suggest the participation of other neurotrophic factors in mediating the synaptic plasticity events following exposure to environmental enrichment in ventral subicular-lesioned rats.

Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and the possible reversal are poorly understood, thus limiting the number of drugs available for their treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits. Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10 days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task. Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2 mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In the retention test, oxotremorine treated rats committed less RMEs compared with the stress group. Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.