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Made available in DSpace on 2022-04-29T08:45:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OX1R) and type 2 (OX2R) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice. The selective blockade of OX1R and OX2R in the PL with SB 334867 (3, 30, 300 nM) and TCS OX2 29 (3, 30, 300 nM), respectively, did not affect general exploratory behavior or reactive fear such as avoidance, jumping or freezing, but significantly enhances tolerance and approach behavior at the highest dose of each antagonist tested (300 nM). We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL. Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP) Neuronal Plasticity Research Group Max Planck Institute of Psychiatry Department of Pharmacology Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP) Department of Anatomy Biomedical Sciences Institute of the University of São Paulo (ICB-USP) Behavioural Neuroscience Institute (INeC) NAP-USP-Neurobiology of Emotions Research Centre (NuPNE) Ribeirão Preto Medical School of the University of São Paulo Central Nervous System Diseases Research Boehringer Ingelheim Pharmaceuticals Die Gesellschaft mit Beschränkter Haftung & Compagnie Kommanditgesellschaft Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP)

The transient receptor potential vanilloid type 1 channel (TRPV1; originally vanilloid receptor VR1) is activated in peripheral terminals of nociceptive fibers by noxious heat, low pH, and natural products such as capsaicin, the pungent ingredient of red-hot chilli peppers. Evidence has been accumulating that TRPV1 is expressed also in the brain, where it seems to be involved in antinociception, locomotor control, and regulation of affective behaviors. This ion channel might be activated by arachidonoyl ethanolamide (anandamide), the endogenous agonist of the cannabinoid type 1 (CB(1)) receptor. However, while CB(1) activation leads to a decrease in intracellular calcium and attenuation of synaptic transmission, anandamide binding to TRPV1 results in elevated calcium levels and potentiated synaptic transmission. This suggests a tripartite regulatory system with antagonistic effects of CB(1) and TRPV1, which are tied together by the same endogenous ligand. Such a system may have important implication for the modulation of behavioral responses. The present commentary elaborates on this interplay between CB(1) receptors and TRPV1 channels in the context of fear- and anxiety-related behaviors.

Only a small percentage of individuals develop posttraumatic stress disorder (PTSD) in the aftermath of a trauma. It is still largely unknown to what extent gene-environment interactions contribute to the inter-individual differences in PTSD susceptibility and resilience and what cellular processes may underlie long-term maintenance of the disorder. Here we employed a mouse model of PTSD to unravel the contribution of genetic background and maternal influences on long-lasting changes in kinase and transcription factor activities in PTSD-susceptible C57BL/6NCrl (B6N) and resilient C57BL/6JOlaHsd (B6JOla) mice. Mice received an inescapable foot shock and were tested for activity changes in the AKT/GSK-3beta/beta-catenin-pathway in specific brain structures 42 days later. To control for prenatal and postnatal environmental (i.e. maternal) factors part of the experiments were performed with animals originating from within-strain and between-strain embryo transfers. In PTSD-susceptible B6N mice, long-term maintenance of contextual and sensitized fear was accompanied by (i) increased levels of phosphorylated AKT within the dorsal hippocampus and (ii) higher levels of phosphorylated AKT and GSK-3beta and increased beta-catenin levels within the basolateral amygdala. In animals originating from embryo transfers, levels of phosphorylated GSK-3beta and of beta-catenin were decreased in the dorsal hippocampus, but increased in the basolateral amygdala of shocked B6N mice compared to shocked B6JOla mice. This was independent of the genotype of the recipient mothers. At the behavioural level, these differences coincided with sustained sensitized and more pronounced contextual fear of B6N compared to B6JOla mice. Taken together our study identifies lasting changes in the AKT/GSK-3beta/beta-catenin cascade within the hippocampus and amygdala as molecular correlates of genetically determined differences in the severity of PTSD-like symptoms.

To investigate the effects of an ethologically-relevant stressor on central and peripheral release of arginine vasopressin and oxytocin, we forced adult male Wistar rats to swim for 10 min and simultaneously measured the release of the two peptides (i) within the hypothalamic supraoptic and paraventricular nuclei (by means of the microdialysis technique) and (ii) into the blood (by chronically-implanted jugular venous catheters). Forced swimming caused a significant rise in the release of arginine vasopressin and oxytocin within both the supraoptic nuclei (four-fold and three-fold, respectively) and the paraventricular nuclei (three-fold and four- to five-fold, respectively). Release patterns measured before, during and after repeated stress exposure on three consecutive days indicated that, at the level of the hypothalamus, the two neuropeptides are critically involved in the rats' stress response in a peptide-, locus- and stress-specific manner. Particularly, despite a general reduction of the recovery of the microdialysis probes over the time, the release of arginine vasopressin within the paraventricular nuclei and of oxytocin within the supraoptic nuclei tended to increase upon repeated stress exposure. Measurement of plasma peptide concentrations revealed that the central release of oxytocin was accompanied by a secretion of this peptide into the systemic circulation. In contrast, arginine vasopressin, assayed in the same plasma samples, failed to respond to the stressor. The latter finding is consistent with a dissociated release of the neuropeptide from different parts of a single neuron (soma/dendrites vs axon terminals). It provides evidence that under physiological conditions plasma hormone levels do not necessarily reflect the secretory activity of central components of the respective neuropeptidergic system.