Molecular underpinnings of anxiety regulation: Novel insights into the role of the purinergic and oxytocinergic systems within the paraventricular nucleus of the hypothalamus

摘要: Anxiety disorders are the most common psychiatric and although there a number of treatment options available, all have their limitations. Over years, many studies been conducted to discover sites in brain where anxiety-related behaviour is controlled, neural factors that mediate this behaviour. Despite these research efforts, our understanding biology anxiety far from complete, search for better basis effective treatments awaits significant advances field neurobiology anxiety. The paraventricular nucleus hypothalamus (PVN) one key regions involved regulation. Therefore, aims my described thesis were therefore (1) identify new endogenous factor within PVN could be target future pharmacological intervention disorders, (2) determine intracellular processes sustain anxiolytic effect following single OT PVN. By making use microarray performed tissue rats had selected extreme low or high (the LAB HAB rats), I discovered ATP-receptor P2X4R regulates PVN. ligand-gated ion channel, highly permeable Ca2+, thus increases Ca2+-levels downstream signalling when activated. Both mRNA protein expression was strongly up-regulated compared with rats; independent sex. CTP, agonist, decreased anxiety-like Wistar as soon 10 min after local infusion into CTP blocked by pre-treatment selective inhibitor P2X4R, 5-BDBD, supporting involvement Moreover, 5-BDBD rats, respectively, normalisation phenotypes achieved. Intracellular effectors stimulation included activation eEF2, regulator peptide chain elongation, but whether de novo synthesis plays role P2X4R-mediated anxiolysis currently not known. However, data clearly showed novel modulation behaviour. Additionally, examined effects exogenous intra-PVN its hypothalamic cells. This neuropeptide synthesised (among other regions) known both short- long-term properties. found activates via PKC-dependent dephosphorylation vitro cells well vivo, male rats. occurs leads relatively fast increase 30 min. an even greater amount newly proteins detectable 3 h OT-application primary Behavioural testing treated general anisomycin, revealed mid-term (30 min) locally administered depends on synthesis. (3 h) abolished inhibition PVN, suggesting another region connected controlling OT-regulated behaviour. The later time point however, appeared significance OT-induced microRNA Deep Sequencing analysis dozens regulated microRNAs OT-application. By means qPCR, up-regulation essential microRNAs, including miR-124, miR-132, miR-212, validated. MicroRNA regulation completely finding should contribute OT. Thus, assessing purinergic system providing molecular underpinnings oxytocinergic particularly highlighted mediation Taken together, results presented advance knowledge about anxiety, may help develop strategies future.