Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects

Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stress-induced plasticity in the amygdala. BDNF overexpression also causes antidepressant effects, because transgenic mice exhibit improved performance on the Porsolt forced-swim test and an absence of chronic stress-induced hippocampal atrophy. Thus, structural changes in the amygdala and hippocampus, caused by genetic manipulation of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders

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

Corticosterone attenuates zinc-induced neurotoxicity in primary hippocampal cultures

Primary hippocampal cultures derived from newborn rats were exposed to zinc chloride at 50, 75, 100, 150 and 200 μM concentrations. Neuronal injury was assessed morphologically and by the lactate dehydrogenase (LDH) efflux assay. Zinc exposure increased LDH efflux in a concentration-dependent manner. Exposure to 100 μM zinc for 24 h resulted in beading of neurites and swelling of neuronal soma. When cultures were co-exposed to zinc at 100 μM and corticosterone in the range of 10-5 to 10-7 M, degeneration of neurons caused by zinc was attenuated. Our study suggests that corticosterone can protect neurons from zinc-induced neurotoxicity at low doses

Enhanced metabolic activity coincides with survival and differentiation of cultured rat retinal ganglion cells exposed to glutamate

Neurotransmitters are prominent candidates for trans-cellular signals that influence the development of the CNS. The present study has examined the effect of glutamate on survival, differentiation and metabolic activity of cultured rat retinal ganglion cells at 3 days in vitro. Retinal cultures from neonatal Wistar rats were treated with glutamate for 48 h. The metabolic activity was markedly increased in the retinal ganglion cells exposed to 20 μM glutamate. This was accompanied by an enhanced survival of these neurons. The number of differentiated retinal ganglion cells as determined by microtubule-associated protein-2 labeling was significantly increased following exposure to low but not higher doses of glutamate. The effect of glutamate on the metabolic activity and differentiation was blocked by tetrodotoxin. The results of the present study shows that glutamate has a significant effect on survival, differentiation and metabolic activity. An increase in the metabolic activity indicates an enhancement in the electrical activity. Thus, our results are consistent with the hypothesis that glutamate is critically involved in the regulation of electrical activity in developing rat retinal ganglion cells

Long-lasting structural changes in CA3 hippocampal and layer V motor cortical pyramidal neurons associated with self-stimulation rewarding experience: a quantitative Golgi study

Self-stimulation (SS) rewarding experience induced structural changes in CA3 hippocampal and layer V motor cortical pyramidal neurons in adult male Wistar rats has been demonstrated. In the present study, whether these structural changes are transient or of a permanent nature was evaluated. Self-stimulation experience was provided for 1 h daily over a period of 10 days through bilaterally implanted bipolar electrodes in the lateral hypothalamus and the substantia nigra-ventral tegmental area. Following 10 days of SS experience, the rats were sacrificed after an interval of 30 and 60 days for the quantitative analysis of the dendritic morphology in Golgi stained CA3 hippocampal and layer V motor cortical pyramidal neurons. The results revealed a significant increase in the dendritic branching points and intersections in apical and basal dendrites in both types of neurons in 30 days post-SS group compared to sham control. The total number of apical and basal dendrites were significantly increased in both 30 and 60 days post-SS groups of rats. This study suggests that SS experience induced structural changes are sustainable, even in the absence of rewarding experience

Self-stimulation rewarding experience induced alterations in dendritic spine density in CA3 hippocampal and layer V motor cortical pyramidal neurons

Self-stimulation rewarding experience induced alterations in the numerical density of spines in CA3 hippocampal and layer V motor cortical pyramidal neurons in adult male Wistar rats was evaluated. Self-stimulation experience was provided 1 h daily over a period of 10 days through stereotaxically implanted bipolar stainless steel electrodes bilaterally in lateral hypothalamus and substantia nigra-ventral tegmental area. After 10 days, rats were killed and the hippocampus and motor cortex were processed for rapid Golgi staining procedure. The dendritic spine densities were studied in CA3 hippocampal and layer V motor cortical pyramidal neurons. The spine densities were quantified in five successive segments of 15.2 μm up to a distance of 76 μm. Apical dendrites were classified as mainshaft, sub branch, oblique shaft-I, oblique shaft-II, primary branch; and basal dendrites as main shaft, primary branch and secondary branch. A grand total of 864 CA3 hippocampal and 1 008 layer V motor cortical dendrites were analysed for spine counting in different groups of rats. The results revealed a significant (P<0.001; ANOVA, F-test) increase in the number of spines in all the categories of dendrites in apical and basal regions in both hippocampal and motor cortical neurons in self-stimulation group of rats. Such changes were not observed either in sham control, experimenter-administered or normal control groups of rats. The self-stimulation induced increase in the spine density suggests an increase in the postsynaptic receptive field in CA3 hippocampal and layer V motor cortical neurons. This might enhance the efficacy of synaptic transmission in these neurons. Our study clearly demonstrated the self-stimulation rewarding experience induced postsynaptic plasticity in hippocampal and motor cortical pyramidal neurons

Alterations in the density of excrescences in CA3 neurons of hippocampus in rats subjected to self-stimulation experience

Self-stimulation (SS) rewarding experience induced alterations in the density of excrescences in the apical dendrites of CA3 neurons were studied in adult male Wistar rats. SS experience was provided daily for an hour over a period of 10 days, through bipolar stainless steel electrodes implanted bilaterally in lateral hypothalamus and substantia nigra-ventral tegmental area. The results revealed a significant (P<0.001) increase in the number of excrescences in both main shaft and sub branches of the apical dendrites in SS experienced group compared to control groups of rats. The increased number of excrescences in CA3 neurons might be due to an enhancement in the synaptic transmission in the mossy fiber pathway following SS experience

Self-stimulation of lateral hypothalamus and ventral tegmentum increases the levels of noradrenaline, dopamine, glutamate, and AChE activity, but not 5-hydroxytryptamine and GABA levels in hippocampus and motor cortex

Self-stimulation (SS) rewarding experience induced structural changes have been demonstrated in the hippocampal and motor cortical pyramidal neurons. In the present study, we have evaluated whether these changes are accompanied by neurochemical alterations in the hippocampus and motor cortex in SS experienced rats. Self-stimulation experience was provided one hour daily over a period of 10 days through stereotaxically implanted bipolar stainless steel electrodes, bilaterally in lateral hypothalamus and substantia nigra-ventral tegmental area. Self-stimulation experience resulted in a significant (P < 0.001) increase in the levels of noradrenaline, dopamine, glutamate and AChE activity but not 5-hydroxytryptamine and GABA levels in hippocampus and motor cortex. Such alterations in the levels of neurotransmitters may enhance the cognitive functions in the ss experienced

The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed 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