[show abstract][hide abstract] ABSTRACT: Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition-including hyperactivity, repetitive behaviors, and seizures-as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor-which we call FRAX486-also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.
Proceedings of the National Academy of Sciences 03/2013; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neural Transmission 12/2011; 119(5):533-43. · 3.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: Severe stress is a major risk factor for the development of many psychiatric conditions including depression, anxiety and post traumatic stress disorder. After repeated exposure to uncontrollable stress, a cascade of degenerative changes is initiated and this eventually leads to profound, region specific brain dysfunctions. Chronic stress leads to dendritic atrophy of the hippocampus and medial prefrontal cortex and in contrast, hypertrophy of the basolateral complex of the amygdala (BLA). These morphological changes are associated with learning and memory deficits and enhanced anxiety respectively. Hypofunctioning of the medial prefrontal cortex and hippocampus and hyperactivity of the amygdala disrupts normal feedback regulation of the hypothalamo-pituitary adrenal axis. There are several lines of evidence which indicates that the BLA interacts with the hippocampus and prefrontal cortex in regulating stress effects. In the current study, we observed chronic immobilization stress-induced working memory impairment and enhanced anxiety-like behavior. At the cellular level, both CA1 long-term potentiation (LTP) and dentate gyrus/hippocampal volumes were decreased. Therefore to mitigate this uninhibited positive regulation of the HPA axis, we inactivated the BLA during stress using the sodium channel blocker, lidocaine. Upon inactivation, chronically stressed rats showed improved learning and working memory, decreased anxiety like behavior, restored hippocampal LTP and volumes. Our results show that inactivation of amygdala during stress could prevent dysfunctions at the synaptic, cellular and behavior levels. This novel approach of short term modulation of specific brain regions may help to develop new therapeutic strategies for treating neuropsychiatric disorders.
[show abstract][hide abstract] ABSTRACT: Multiple pathways including oxidative stress and mitochondrial damage are implicated in neurodegeneration during Parkinson's disease (PD). The current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Therefore, there is a demand for novel compound(s)/products that could target multiple pathways and protect the dying midbrain dopaminergic neurons, with potential utility as adjunctive therapy along with conventional drugs. Turmeric is a spice used in traditional Indian cuisine and medicine with antioxidant, anti-inflammatory and potential neuroprotective properties. To explore the neuroprotective property of turmeric in PD, mice were subjected to dietary supplementation with aqueous suspensions of turmeric for 3 months, mimicking its chronic consumption and challenged in vivo with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Brain samples from untreated and treated groups were characterised based on mitochondrial complex I (CI) activity, protein nitration and tyrosine hydroxylase immunoreactivity. Chronic turmeric supplementation induced the enzyme activity of γ-glutamyl cysteine ligase, which in turn increased glutathione levels and protected against peroxynitrite-mediated inhibition of brain CI. These mice were also protected against MPTP-mediated protein nitration, CI inhibition and degeneration of substantia nigra neurons in the brain. We conclude that chronic dietary consumption of turmeric protects the brain against neurotoxic insults, with potential application in neurodegeneration. Further characterisation of the active constituents of turmeric that potentially promote neuroprotection could improve the utility of dietary turmeric in brain function and disease.
The British journal of nutrition 07/2011; 106(1):63-72. · 3.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of natural science, biology, and medicine. 01/2011; 2(1):26-37.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neuroscience Research 12/2008; 87(4):831-43. · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Stress increases vulnerability to anxiety and depression. We have investigated the effect of acute immobilization stress in amygdalohippocampal circuits by measuring the electroencephalogram (EEG) in male Wistar rats during rapid eye movement (REM) sleep. Electrodes were implanted stereotaxically in the hippocampus (CA1 and CA3 subregions of the hippocampus) and the amygdala (lateral nucleus). Prior to the stress, two baseline recordings were taken. Twenty-four hours later rats were exposed once to acute immobilization stress (AIS) session for 2 h. After the release and on subsequent days, electrophysiological changes that occurred due to stress during REM sleep were analyzed by comparing them with baseline measurements. Our results suggest that acute immobilization stress induced significant increase in REM sleep in the first 24 h after the exposure. In addition to changes in the sleep patterns, we have observed increased theta oscillations in CA1 area of the hippocampus with decreased coherence at theta range (4-8 Hz) between hippocampus and amygdala. These results suggest that single exposure to aversive experience such as immobilization stress can lead to dynamic changes in neuronal activities with altered sleep morphology. The results obtained in the present study are comparable to those seen in human patients suffering from panic, and anxiety due to posttraumatic stress disorder (PTSD).
[show abstract][hide abstract] ABSTRACT: 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.
Behavioural Brain Research 03/2008; 187(1):190-4. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neural Transmission 02/2008; 115(1):35-42. · 3.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
[show abstract][hide abstract] ABSTRACT: 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.
Neurochemical Research 11/2007; 33(9):1651-62. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
In the present study, we evaluated the effects of bromocriptine in the presence or absence of restraint stress.
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.
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.
Our study shows that amelioration of stress-induced learning impairment correlates with restoration of dopamine levels by bromocriptine treatment.
[show abstract][hide abstract] ABSTRACT: Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
Proceedings of the National Academy of Sciences 08/2007; 104(27):11489-94. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: The amygdala, which exerts a regulatory influence on the stress response, is itself affected by stress. It has been reported that the serine protease tissue-plasminogen activator (tPA), a key mediator of spine plasticity, is required for stress-induced facilitation of anxiety-like behavior. Importantly, tPA is also involved in stress-induced activation of molecular signals that have the potential to contribute to neuronal remodeling in the medial amygdala (MeA). However, little is known about the precise nature of, and specific role played by tPA in, stress-induced structural plasticity in the MeA. Hence, we compared the impact of chronic restraint stress on spine density of medium spiny stellate neurons in MeA in wild-type mice with mice in which the tPA gene is disrupted (tPA-/-). In wild-type mice, chronic stress caused significant reduction in MeA spine density, which was in contrast to enhanced spine density in the neighboring basolateral amygdala (BLA). Strikingly, tPA-/- mice exhibited significant attenuation of stress-induced spine retraction in the MeA, but BLA spinogenesis was not affected. Therefore, tPA-dependence of stress-induced modulation in spine density was restricted to the MeA. Further, MeA neurons in tPA-/- mice, even when challenged with repeated stress, were able to maintain levels of spine density that were comparable to that of wild-type mice without stress. Our findings provide novel evidence for a permissive role for tPA in amygdalar spine plasticity elicited by behavioral stress.
[show abstract][hide abstract] ABSTRACT: 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.