Neuroscience
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Tg2576 transgenic mice (mice overexpressing the "Swedish" mutation in the human amyloid precursor protein 695) demonstrated a decreased capacity for cell proliferation in the dentate gyrus of the hippocampus compared with non-transgenic littermates at 3 months, 6 months and 9 months of age. Isolation stress induced by individually housing each mouse from the time of weaning further decreased hippocampal cell proliferation in Tg2576 mice as well as in non-transgenic littermates at 6 months of age. Decreases in hippocampal cell proliferation in isolated Tg2576 mice were associated with impairments in contextual but not cued memory. ⋯ These results suggest that Tg2576 mice, a mouse model of Alzheimer disease, have an impaired ability to generate new cells in the dentate gyrus of the hippocampus and that the magnitude of this impairment can be modulated by behavioral interventions and drugs known to have effects on hippocampal neurogenesis in normal rodents. Unexpectedly, isolation stress also appeared to accelerate the underlying process of beta-amyloid plaque deposition in Tg2576 mice. These results suggest that stress may have an impact on the underlying disease process associated with Alzheimer's disease.
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Exercise is increasingly recognized as an intervention that can reduce CNS dysfunctions such as cognitive decline, depression and stress. Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) is increased in the hippocampus following exercise. In this study we tested the hypothesis that exercise can counteract a reduction in hippocampal BDNF protein caused by acute immobilization stress. ⋯ This study demonstrates that CORT modulates stress-related alterations in BDNF protein. Further, exercise can override the negative effects of stress and high levels of CORT on BDNF protein. Voluntary physical activity may, therefore, represent a simple non-pharmacological tool for the maintenance of neurotrophin levels in the brain.
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We examined the effects of repeated stress and D1 receptor activation in the medial prefrontal cortex (mPFC) on acute-cocaine-induced locomotor activity in rats. Male rats were given 7 days of either handling (Controls) or a variety of stressors. After 8-17 days' withdrawal, rats received an intra-mPFC microinjection of the full D1 agonist, SKF 81297: 0, 0.03, 0.1 or 0.3 microg/side followed by an i.p. saline or cocaine injection (15 mg/kg, i.p.). ⋯ In high responders given SFK 81297 into the ventral mPFC, cocaine-induced activity was suppressed in Controls, while stress pretreatment rendered animals resistant to SKF 81297 effects. These results indicate that D1 receptor activation effects in the mPFC are bidirectional depending on whether rats have a high or low locomotor response to cocaine. Further, daily stress alters the sensitivity of the mPFC to SKF 81297, which is dependent on whether the dorsal or ventral mPFC is targeted.
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The ventrolateral preoptic area of the hypothalamus (VLPO) contains a population of sleep-active neurons and is hypothesized to be an important part of the somnogenic process. Adenosine (AD) is an endogenous sleep-promoting factor and may play an important role in promoting natural sleep. We hypothesize that AD may promote sleep, in part, by activating the VLPO sleep-active neurons. ⋯ In contrast, AD decreased EPSC frequency in seven cells (36-73%; mean=59%), increased frequency in five cells (30-236%; mean 83%) and had no effect in six cells. AD application increased the firing rate in two of four cells tested. These data are consistent with the hypothesis that one mechanism which AD may promote sleep is by blocking inhibitory inputs on VLPO sleep-active neurons.
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Recent in vivo electrophysiological studies suggest that chronic dopamine depletion alters profoundly the firing pattern of basal ganglia neurons. These changes may disrupt the processing of cortical information flow from the striatum to the output nuclei, and presumably underlie the clinical manifestations of Parkinson's disease. We have recently reported that chronic nigrostriatal lesions induce changes in the functional state of striatal medium-spiny neurons (MSNs) that could facilitate spreading of cortical synchronous activity (approximately 1 Hz) to striatal target nuclei. ⋯ Following systemic administration of SKF38393 or SKF81279 the membrane potential of striatal MSNs was upheld into a more hyperpolarized value and action potential firing probability decreased. D1 agonists also increased the latency to the cortically driven plateau depolarization and reduced the peak potential of the short latency depolarizing postsynaptic response to a more hyperpolarized value. The present study provides in vivo evidence indicating that pharmacological stimulation of D1-class dopamine receptors can modulate the flow of cortical information through the striatum in the parkinsonian state.