Neuroscience
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Nerve growth factor (NGF) is an important mediator in the initiation of the inflammatory response and NGF via activation of the p75 neurotrophin receptor (p75(NTR)) and downstream sphingomyelin signaling leads to significant enhancement of the excitability of small-diameter sensory neurons. Because of the interaction between sphingomyelin and cholesterol in creating membrane liquid-ordered domains known as membrane or lipid rafts, we examined whether neuronal NGF-induced sensitization via p75(NTR) was dependent on the integrity of membrane rafts. Here, we demonstrate that the capacity of NGF to enhance the excitability of sensory neurons may result from the interaction of p75(NTR) with its downstream signaling partner(s) in membrane rafts. ⋯ In addition, adding back MβCD with cholesterol restored the NGF-induced sensitization in previously cholesterol-depleted neurons, suggesting that cholesterol and the structural integrity of rafts are key to promoting NGF-mediated sensitization. Using established protocols to isolate detergent-resistant membranes, both p75(NTR) and the neuronal membrane raft marker, flotillin, localize to raft fractions. These results suggest that downstream signaling partners interacting with p75(NTR) in sensory neurons are associated with membrane raft signaling platforms.
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Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). ⋯ After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent.
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The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. ⋯ While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
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Maternal deprivation has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. A growing number of studies demonstrated the importance of childhood experiences in the development of psychosis and schizophrenia in adulthood. Therefore, the present study investigated different behavior responses in rats following maternal deprivation and/or ketamine treatment in adulthood. ⋯ Biochemistry data showed that all doses of ketamine and ketamine plus maternal deprivation increased the acetylcholinesterase (AChE) activity in the prefrontal cortex, hippocampus and striatum. The major doses of ketamine associated with maternal deprivation induced a major increase of AChE activity. Together, our results suggest that animals subjected to maternal deprivation had an increased risk for schizophrenia-like behavior and cholinergic alteration.
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Estrogen receptors (ERs) α and β are involved in the regulation of the nitrergic system in the supraoptic (SON) and paraventricular (PVN) nuclei under basal conditions. In this study we have assessed whether ERs are also involved in the modulation of the nitrergic system in the SON and PVN under acute systemic hypertonic conditions. Adult ovariectomized rats received a single injection of either estradiol, a selective ERα agonist, a selective ERβ agonist, a selective ERα antagonist, a selective ERβ antagonist or vehicle. ⋯ In contrast, the inhibition of ERα enhanced the effect of NaCl, inducing a further decrease in the number of NADPH-diaphorase-positive cells. Moreover, the ERβ agonist enhanced and the ERβ antagonist blocked the effect of NaCl on the number of NADPH-diaphorase-positive neurons in the SON and in the medial magnocellular subdivision of the PVN. These findings indicate that estradiol regulates the nitrergic system in the SON and PVN under acute osmotic stress conditions, but the effects specifically depend on the anatomical subregions and different ERs.