Neuroscience
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Benzodiazepines are one of the most commonly prescribed anxiolytic drugs in America, and between 2006 and 2015 prescription rates increased by an estimated 27.1%. Weight gain is a common side effect of these drugs and it may result from increased feeding caused by drug-enhanced food palatability. We investigated the role of specific GABAA receptor subtypes involved with benzodiazepine-induced food consumption through third ventricle injections of L-838,417, a partial agonist of GABAA α2, α3, and α5 subunits, and a full antagonist of the α1 receptor subunit. ⋯ These results indicate that nuclei in proximity to the ventricles respond to GABAA α2, α3, or α5 activation to induce motivation to feed, absent of α1 receptor subunit activation. Furthermore, activation of the α1 subunit is not necessary for benzodiazepine hyperphagia and may instead contribute to the oromotor depressant and sedative properties of classic benzodiazepine agonists. Hypothalamic nuclei such as the paraventricular nucleus may be involved in the benzodiazepine-increased motivation to feed, while the parabrachial nucleus of the hindbrain could contribute to benzodiazepine-induced enhancement of taste palatability.
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Voltage-gated Ca2+ channels (VGCCs) play key roles in auditory perception and information processing within the inner ear and brainstem. Pharmacological inhibition of low voltage-activated (LVA) T-type Ca2+ channels is related to both age- and noise induced hearing loss in experimental animals and may represent a promising approach to the treatment of auditory impairment of various etiologies. Within the LVA Ca2+ channel subgroup, Cav3.2 is the most prominently expressed T-type channel entity in the cochlea and auditory brainstem. ⋯ Our results, based on a self-programmed automated wavelet approach, demonstrate that both heterozygous and Cav3.2 null mutant mice exhibit age-dependent increases in hearing thresholds at 5 months of age. In addition, complex alterations in WI-IV amplitudes and latencies were detected that were not attributable to alterations in the expression of other VGCCs in the auditory tract. Our results clearly demonstrate the important physiological role of Cav3.2 VGCCs in the spatiotemporal organization of auditory processing in young adult mice and suggest potential pharmacological targets for interventions in the future.
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Before movement onset, during the reaction time, excitability of M1 is selectively modulated by somatosensory inputs, only in the movement-related muscle. If a similar mechanism operates before the onset of mental movements, then somatosensory afferent inputs are exploited during cognitive representation of movement. We assessed sensorimotor modulation through short latency afferent inhibition (SAI) paradigm before the onset of executed and imagined movements. ⋯ There was a positive correlation between the individual degree of sensorimotor modulation during executed and mental movements and between the sensorimotor modulation during mental movements and motor imagery ability. Sensorimotor modulation operates during the cognitive representation of movement with selective disinhibition of the cortical representation of the muscle involved in the task. Sensorimotor modulation mechanisms prior to mental and executed movements likely share overlapping circuits.
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Inflammation aggravates the lethal consequences of intracerebral hemorrhage. Recently, many studies have found that nuclear factor-κB (NF-κB) is a crucial transcription factor that initiates inflammation in the perihematomal region of ICH. NF-κB essential modulator (NEMO)-binding domain (NBD) peptide, a cell-permeable peptide spanning the NBD of IKKα or IKKβ, functions as a highly specific inhibitor of NF-κB. ⋯ We found that NBD peptides suppressed microglia inflammation and lowered the expression of TNF-α and IL-1β in both in vivo and in vitro experiments. Further experiments were performed in mice and cultured microglia, which treated with NBD peptides in the presence of p65 siRNA confirmed that the specificity of NBD peptides inhibit ICH-induced NF-κB activation. This study demonstrated that NBD peptides exert a neuroprotective role after ICH and might be a potential candidate for a novel therapeutic strategy for ICH.
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Creatine (Cr) is a small metabolite with a central role in energy metabolism and mitochondrial function. Creatine deficiency syndromes are inborn errors of Cr metabolism causing Cr depletion in all body tissues and particularly in the nervous system. Patient symptoms involve intellectual disability, language and behavioral disturbances, seizures and movement disorders suggesting that brain cells are particularly sensitive to Cr depletion. ⋯ Moreover, our data suggest possible abnormalities of dendritic spines, synaptic function and plasticity, network excitability and neuroinflammatory response. Intriguingly, the alterations occurred in coincidence with the developmental onset of neurological symptoms. Thus, cerebral mitochondrial alterations could represent an early response to Cr deficiency that could be targeted for therapeutic intervention.