Neuroscience
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The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses and specialized to allow for precise neuron-to-neuron transmission of information. ⋯ Glutamatergic synaptic dysfunction affecting PSD morphology and signaling events have been described in many neurodegenerative disorders, either sporadic or familial forms. Thus, in this review we describe the main protein players forming the PSD and their activity, as well as relevant modifications in key components of the postsynaptic architecture occurring in Huntington's, Parkinson's and Alzheimer's diseases.
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The preclinical multicomponent free-choice high-fat high-sucrose (fcHFHS) diet has strong validity to model diet-induced obesity (DIO) and associated maladaptive molecular changes in the central nervous system. fcHFHS-induced obese rats demonstrate increased sensitivity to intracerebroventricular infusion of the orexigenic Neuropeptide Y (NPY). The brain region-specific effects of NPY signaling on fcHFHS diet component selection are not completely understood. For example, fcHFHS-fed rats have increased intake of chow and fat following intracerebroventricular NPY infusion, whereas NPY administration in the nucleus accumbens, a key hub of the reward circuitry, specifically increases fat intake. ⋯ This effect was mediated specifically by chow intake in fcHFHS-fed rats. The orexigenic effects of intra-LHA NPY were prevented by NPY1R and NPY5R antagonism in chow-fed rats, but only by NPY5R antagonism in fcHFHS-fed rats. Thus, NPY signaling has brain region-specific effects on fcHFHS component selection and LHA NPYR sensitivity is dysregulated during consumption of a fcHFHS diet.
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The consequences of excessive fructose intake extend beyond those of metabolic disorder to changes in emotional regulation and cognitive function. Long-term consumption of fructose, particularly common when begun in adolescence, is more likely to lead to deleterious consequences than acute consumption. These long-term consequences manifest differently in males and females, suggesting a sex-divergent mechanism by which fructose can impair physiology and neural function. ⋯ When exposed to an acute energetic challenge, the pattern was reversed. Taken together, these data indicate that diet-induced alterations to neural function and physiology are sex-specific and highlight the need to consider sex as a biological variable when treating metabolic disease. Furthermore, these data suggest that synaptic mitochondrial function may contribute directly to the behavioral consequences of elevated fructose consumption.
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Amylin is a pancreatic peptide, which acts as a key controller of food intake and energy balance and predominately binds to three receptors (AMY 1-3). AMY 1-3 are composed of a calcitonin core receptor (CTR) and associated receptor-activity modifying proteins (RAMPs) 1-3. Using RAMP1, RAMP3 and RAMP1/3 global KO mice, this study aimed to determine whether the absence of one or two RAMP subunits affects food intake, glucose homeostasis and metabolism. ⋯ While female mice generally weighed less than male mice, only RAMP1 KO showed a clear sex difference in meal pattern and food intake tests. Lastly, a decrease in CTR fibers did not consistently correlate with a decrease in amylin- induced c-Fos expression in the area postrema (AP). Ultimately, the results from this study provide evidence for a role of RAMP1 in mediation of fat utilization and a role for RAMP3 in glucose homeostasis and amylin's anorectic effect.
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Extensive research over the past decades has characterized multiple forms of synaptic plasticity, identifying them as key processes that allow the brain to operate in a dynamic manner. Within the wide variety of synaptic plasticity modulators, kainate receptors are receiving increasing attention, given their diversity of signaling mechanisms and cellular expression profile. Here, we summarize the experimental evidence about the involvement of kainate receptor signaling in the regulation of short- and long-term plasticity, from the perspective of the regulation of neurotransmitter release. In light of this evidence, we propose that kainate receptors may be considered homeostatic modulators of neurotransmitter release, able to bidirectionally regulate plasticity depending on the functional history of the synapse.