Neuroscience
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Anxiety disorder is a major psychiatric disorder characterized by fear, worry, and excessive rumination. However, the molecular mechanisms underlying neural plasticity and anxiety remain unclear. Here, we utilized a mouse model of anxiety-like behaviors induced by the chronic administration of corticosterone (CORT) to determine the exact mechanism of each region of the fear circuits in the anxiety disorders. ⋯ Immunoblot analyses revealed that autophosphorylation of Ca2+/calmodulin-dependent protein kinase (CaMK) IIα at threonine 286 and phosphorylation of cyclic-adenosine-monophosphate response-element-binding protein (CREB) at serine 133 were markedly increased in the BLA of chronic CORT-treated mice after tone stimulation. The protein and mRNA levels of brain-derived neurotrophic factor (BDNF) also significantly increased. Our findings suggest that increased CaMKII activity and synaptic plasticity in the BLA likely account for the aberrant amygdala-dependent fear memory in chronic CORT-treated mice.
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Perineuronal nets (PNNs) are a form of aggregate Extracellular Matrix (ECM) in the brain. Recent evidence suggests that the postnatal deposition of PNNs may play an active role in regulating neuroplasticity and, potentially, neurological disorders. Observations of high levels of PNN expression around somas, proximal dendrites, and axon initial segments of a subtype of neurons have also led to proposals that PNNs may modulate the intrinsic properties of the neurons they ensheathe. ⋯ Low-Threshold Spiking interneurons showed altered rebound depolarizations and decreased frequency of spontaneous synaptic inputs. Putative excitatory neurons; regular spiking, bursting, and doublet phenotypes did not demonstrate any alterations. Our data indicate that chABC-sensitive PNNs may specifically regulate the intrinsic and synaptic physiology of inhibitory interneurons.
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Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. ⋯ Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.
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Prenatal exposure to high-fat diet (HFD) might predispose offspring to develop metabolic and mental disorders later in life. Insight into the molecular and behavioral consequences of maternal HFD on offspring is sparse but may involve both neuroinflammation and a dysregulated neuroendocrine stress axis. Thus, the aim of this work was to: (i) investigate the influence of maternal HFD on memory, anxiety and depression-like behavior in adult offspring and (ii) identify possible biological biomarkers related to neuroinflammation and stress responses. ⋯ This behavioral alteration was accompanied by significantly higher mRNA levels of the hippocampal pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) mRNA and monocyte-chemoattractant protein-1 (MCP-1), both of which correlated with degree of behavioral change. Maternal exposure to HFD increased the offspring's levels of hippocampal, corticosteroid releasing hormone receptor 2 (CRHR2) and kynurenine mono oxygenase (KMO) mRNA, whereas kynurenine aminotransferase I (KAT1) mRNA levels were decreased. The present results suggest that neuroinflammatory and stress axis pathways in the hippocampus may contribute to anxiogenic effects of maternal HFD in offspring.
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Hypobaric Hypoxia (HH) is well-known to cause cognitive impairment and synaptic dysfunction which results in neurodegeneration. Although the role of small conductance calcium-activated potassium channels (SK channels) has been reported in synaptic plasticity, cognition and different neurological disorders; however, the precise role of SK channels in HH-induced memory impairment remains yet to be explored. We, therefore, hypothesized the pivotal role of SK channels in HH-induced cognitive decline and investigated the SK channel expression during different duration of HH exposure (Control, 1, 3, 7 and 14 days) at mRNA and protein level in male Sprague-Dawley rats. ⋯ Immunohistochemical analysis revealed similar pattern in different regions of the hippocampus. Additionally, SK channel inhibition with Apamin prevented HH-induced neurodegeneration and memory impairment as evident from decreased number of Fluoro Jade-positive cells, pyknotic cells, and caspase-3 expression and improved performance in the Morris water maze task. Thus, the present study demonstrates that SK channels play a crucial role in HH-induced cognitive decline and neurodegeneration.