Repeated finasteride administration promotes synaptic plasticity and produces antidepressant- and anxiolytic-like effects in female rats.

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.

Enriched Environment Rescues Impaired Sleep-Wake Architecture and Abnormal Neural Dynamics in Chronic Epileptic Rats.

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.

Differential effects of levetiracetam on hippocampal CA1 synaptic plasticity and molecular changes in the dentate gyrus in epileptic rats.

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.

Enriched environment ameliorates chronic temporal lobe epilepsy-induced behavioral hyperexcitability and restores synaptic plasticity in CA3-CA1 synapses in male Wistar rats.

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.

Short photoperiod restores ventral subicular lesion-induced deficits in affective and socio-cognitive behavior in male Wistar rats.

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.

Enriched environment attenuates behavioral seizures and depression in chronic temporal lobe epilepsy.

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.

Short-term exposure to enriched environment rescues chronic stress-induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits.

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.