Neuroscience
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Anxiety disorder (AD) is characterized by the development of maladaptive neuronal circuits and changes to the excitatory/inhibitory (E/I) balance of the central nervous system. Although AD is considered to be heritable, specific genetic markers remain elusive. Recent genome-wide association studies (GWAS) studies have identified non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), a gene that codes for an intracellular adaptor protein involved in actin dynamics, as an important gene in the regulation of mood. ⋯ Taken together, these data implicate NCK1 in the control of E/I balance in BLA. Our work identifies a novel role for NCK1 in the regulation of sex-specific neuronal circuitry necessary for controlling anxiety-like behaviors. Further, our work points to this animal model as a useful preclinical tool for the study of novel anxiolytics and its significance towards understanding sex differences in anxiolytic function.
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Fully consolidated associative memories may be altered by alternative retrieval dependent memory processes. While a brief exposure to the conditioned stimulus (CS) can trigger reconsolidation of the original memory, a prolonged CS exposure will trigger memory extinction. The conditioned response is maintained after reconsolidation, but is inhibited after extinction, presumably by the formation of a new inhibitory memory trace. ⋯ Also, we observed that a stronger CPC memory engaged reconsolidation after 80 CS instead of limbo, indicating that memory strength affects the parametrical conditions to engage either reconsolidation or limbo. Altogether, these results indicate that limbo is an evolutionary conserved memory process segregating reconsolidation from extinction in the number of CSs space. Limbo appears as an intrinsic component of retrieval dependent memory processing, with a key function in the transition from memory maintenance to inhibition.
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Neuropeptide S (NPS) is a recently discovered peptide signalling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneous Hypertensive Rats (SHR), compared to its control strain, Wistar Kyoto rats (WKY). NPS (0.1 and 1 nmol, intracerebroventricularly (icv)) did not modify the performance in the open field test in both strains; however, NPSR antagonism with [tBu-d-Gly5]NPS (3 nmol, icv) increased, per se, the total distance travelled by WKY. ⋯ Immunoblotting of frontal cortical extracts showed no differences of NPSR density, although SHR had a lower NPS content than WKY. SHR showed higher activity of dopamine uptake than WKY, and NPS (1 nmol, icv) did not change this profile. Overall, the present work shows that the pattern of functioning of the NPS system is distinct in WKY and SHR, suggesting that this system may contribute to the pathophysiology of ADHD.
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In the present study, we examined parvalbumin-immunoreactive cells and axons in the dentate gyrus of surgically resected tissues of therapy-resistant temporal lobe epilepsy (TLE) patients with different etiologies. Based on MRI results, five groups of patients were formed: (1) hippocampal sclerosis (HS), (2) malformation of cortical development, (3) malformation of cortical development + HS, (4) tumor-induced TLE, (5) patients with negative MRI result. Four control samples were also included in the study. ⋯ Significant correlation was found between the level of sprouting of axons and the ratio of ectopic/normally-located parvalbumin-containing cells. Electron microscopy demonstrated that sprouted parvalbumin-immunoreactive axons terminate on proximal and distal dendritic shafts as well as on dendritic spines of granule cells. Our results indicate alteration of target profile of parvalbumin-immunoreactive neurons in HS that contributes to the known synaptic remodeling in TLE.
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Stroke is a major cause of death and long-term disability. Recent evidence suggests that hypoxia-inducible factor 1α (HIF-1α), a transcription factor that regulates oxygen levels, plays a key role in neurological outcomes after ischemic stroke. Accordingly, we investigated the mechanism of HIF-1α on pyroptotic and apoptotic cells during ischemia/reperfusion (I/R). ⋯ YC-1 significantly reduced the mRNA and protein expression of NLRP3, IL-1β, IL-18, and caspase-1; significantly decreased infarction and pyroptotic cell death after 24 h of reperfusion; attenuated the neuroinflammatory response by reducing infiltration of CD68- and MPO-positive cells after 24 h of reperfusion; and reduced apoptotic cell death following ischemic stroke. We found that HIF-1α likely regulates inflammatory responses through the NLRP3 inflammasome complex, thus influencing both apoptotic and pyroptotic cell death after stroke. These findings suggest that future investigations are needed regarding HIF-1α and its role as a potential molecular target in the treatment of acute ischemic stroke.