Hardingdwyer5403

The cellular and molecular mechanisms underlying neuropsychiatric and neurodevelopmental disorders show that most of them can be categorized as synaptopathies-or damage of synaptic function and plasticity. Synaptic formation and maintenance are orchestrated by protein complexes that are in turn regulated in space and time during neuronal development allowing synaptic plasticity. However, the exact mechanisms by which these processes are managed remain unknown. find more Large-scale genomic and proteomic projects led to the discovery of new molecules and their associated variants as disease risk factors. Neuronal glycoprotein M6a, encoded by the GPM6A gene is emerging as one of these molecules. M6a has been involved in neuron development and synapse formation and plasticity, and was also recently proposed as a gene-target in various neuropsychiatric disorders where it could also be used as a biomarker. In this review, we provide an overview of the structure and molecular mechanisms by which glycoprotein M6a participates in synapse formation and maintenance. We also review evidence collected from patients carrying mutations in the GPM6A gene; animal models, and in vitro studies that together emphasize the relevance of M6a, particularly in synapses and in neurological conditions.Exposure to early adversity (EA) is associated with long-lasting dysregulations in cognitive processes sustained by brain regions that are sensitive to stress hormones the hippocampus, the amygdala, and the prefrontal cortex. The Life Cycle Model of Stress highlights the importance of considering the timing at which EA began, as these brain regions follow distinct developmental trajectories. We aimed to test this hypothesis by assessing whether adults exposed to EA exhibit different cognitive patterns as a function of the age at which they were first exposed to EA. Eighty-five healthy men and women aged 21-40 years old (y/o) exposed to EA, as assessed by the Adverse Childhood Experience Questionnaire, were grouped based on the age of first exposure to EA 0-2 y/o ("Infancy" hippocampal development), 3-7 y/o ("Early childhood" amygdala development) and after the age of 8 ("Childhood/Adolescence" frontoamygdala connectivity development). Declarative memory, attentional bias to threat and emotion regulation were measured. Results revealed increased attentional bias to threat in women first exposed to EA after 8 years. This result is in line with the Life Cycle Model of Stress and highlights the importance of considering the age at exposure to EA when investigating the effects of EA on cognitive processes.The nervous system uses oscillations to convey information efficiently. Inter-muscular coherence in the 15-35 Hz range is thought to represent common cortical drive to muscles, but is also in the frequency band in which electrical stimulation is applied to restore movement following neurological disease or injury. We wished to determine if, when stimulation is applied at the peak frequency of the coherence spectra it was still possible to determine voluntary effort. Using healthy human subjects we stimulated muscles in the arms and legs, separate experiments, while recording EMG activity from pairs of muscles including the stimulated muscles. Offline coherence analysis was performed. When stimulation is greater than motor threshold, and applied at the peak of the coherence spectra a new peak appears in the spectra, presumably representing a new frequency of oscillation within the nervous system. This does not appear at lower stimulation levels, or with lower frequencies. The nervous system is capable of switching oscillatory frequencies to account for noise in the environment.Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer's disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p less then 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p less then 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.The preoptic area of the hypothalamus is a homeostatic control center. The heterogeneous neurons in this nucleus function to regulate the sleep/wake cycle, reproduction, thirst and hydration, as well as thermogenesis and other metabolic responses. Several recent studies have analyzed preoptic neuronal populations and demonstrated neuronal subtype-specific roles in suppression of thermogenesis. These studies showed similar thermogenesis responses to chemogenetic modulation, and similar synaptic tracing patterns for neurons that were responsive to cold, to inflammatory stimuli, and to violet light. A reanalysis of single-cell/nucleus RNA-sequencing datasets of the preoptic nucleus indicate that these studies have converged on a common neuronal population that when activated, are sufficient to suppress thermogenesis. Expanding on a previous name for these neurons (Q neurons, which reflect their ability to promote quiescence and expression of Qrfp), we propose a new name QPLOT neurons, to reflect numerous molecular markers of this population and to capture its broader roles in metabolic regulation.