B.N. Srikumar

Activity-dependent synaptic plasticity of NMDA receptors

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.

Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats

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.

Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats.

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.

HYPOBARIC HYPOXIA-INDUCED DENDRITIC ATROPHY OF HIPPOCAMPAL NEURONS IS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN ADULT RATS

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.

Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions

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 escitalopram treatment restores spatial learning, monoamine levels, and hippocampal long-term potentiation in an animal model of depression

RationaleThe 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.ObjectivesTo 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.ResultsFourteen 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.ConclusionsThus, 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.

Euphorbia hirta reverses chronic stress-induced anxiety and mediates its action through the GABAA receptor benzodiazepine receptor-Cl− channel complex

Summary.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 GABAA 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.

Neonatal clomipramine induced endogenous depression in rats is associated with learning impairment in adulthood.

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.

Regulation of adult neurogenesis in the hippocampus by stress, acetylcholine and dopamine

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.

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats

RationaleChronic 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.ObjectivesIn 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.MethodsChronic 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.ResultsHippocampal 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.ConclusionsThese 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.