Neuroscience
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Parkinson's disease is a disorder of adult onset involving the progressive degeneration of selective portions of the central nervous system. It is known that mitochondrial dysfunction is involved in the pathogenesis of PD. Given that PGC-1α induces proliferation of mitochondria via transcription regulation, it is possible that PGC-1α pathway dysregulation is involved in PD pathogenesis. ⋯ Expression of CoxIV, SDHA and Tomm20 also significantly decreased in the ventral midbrains of 10-month-old PGC-1α null mice. Thus, PGC-1α KO in mice induced dopaminergic neuron degeneration in the SNpc and DA deficits in the striatum in an age-dependent manner. Progressive impairment of motor coordination in an age-dependent manner was correlated to the extent of nigrostriatal dopaminergic pathway degeneration and mitochondrial dysfunction.
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Alzheimer's disease (AD) pathology is characterized by amyloid plaques containing amyloid beta (Aβ) peptides, neurofibrillary tangles containing hyperphosphorylated tau protein, and neuronal loss. In addition, Aβ deposition in brain microvessels, known as cerebral amyloid angiopathy (CAA), increases blood-brain barrier (BBB) permeability and induces vascular dysfunction which aggravates AD pathology. The aim of the present study was to characterize neurovascular dysfunction in the Tg-SwDI mouse model of AD. ⋯ In addition, the TJ protein occludin was decreased in Tg-SwDI mice relative to WT mice, which correlated with an increase in BBB permeability in cultured brain endothelial cells. These findings demonstrated that Tg-SwDI mice exhibit Aβ aggregation that is due, in part, to impaired Aβ clearance driven by both a decrease in P-gp and increase in RAGE protein levels in brain capillaries. Aβ aggregation promotes a decrease in the expression of the TJ protein occludin, and as consequence an increase in BBB permeability.
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The dorsomedial nucleus of the hypothalamus (DMH) plays an important role in the regulation of energy intake and expenditure. Numerous appetite-regulatory signals present in the DMH, including nitric oxide (NO) and endogenous cannabinoids (eCBs), act to regulate food intake, but whether these signals are involved in regulating high fat food intake remains unknown. We therefore asked whether NO and eCBs, administered alone or in combination, would influence the consumption of high fat food in rats. ⋯ The l-arginine-induced increase in high fat food intake is dependent on NO synthesis, as it is prevented with the NO synthase inhibitor, l-NAME. We also demonstrate that l-arginine increases glutamate transmission onto DMH neurons, an effect that also requires NO synthesis and is abolished with 2-AG. Together, these data indicate that NO acts in the DMH to regulate the consumption of high fat food, possibly by enhancing glutamate signaling at DMH synapses.
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In the retina, ON- and OFF-type bipolar cells are classified by subtype-specific center responses, which are attributed to differences in glutamate receptor subtypes. However, the mechanisms by which ON- and OFF-type bipolar cells generate subtype-specific surround responses remain unclear. One hypothesis for surround responses is that intracellular Cl concentrations ([Cl-]i) are set at different levels to achieve opposite polarities for GABA responses in ON- and OFF-type bipolar cells. ⋯ Strong NKCC1 activity increased [Cl-]i in rod (ON-) type bipolar cells, while that of KCC2 decreased [Cl-]i in OFF-type bipolar cells. We also confirmed the presence of a [Cl-]i gradient between dendrites and axon terminals in rod (ON-type) bipolar cells. Thus, the subtype-specific control of [Cl-]i is achieved by the activity of NKCC1 relative to that of KCC2 and appears to influence the polarity of surround responses.
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Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. ⋯ Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.