Amygdala Metabotropic Glutamate Receptor 1 Influences Synaptic Transmission To Participate In Fentanyl-Induced Hyperalgesia In Rats

The underlying mechanisms of opioid-induced hyperalgesia (OIH) remain unclear. Herein, we found that the protein expression of metabotropic glutamate receptor 1 (mGluR1) was significantly increased in the right, but not in the left laterocapsular division of central nucleus of the amygdala (CeLC) in OIH rats. In CeLC neurons, the frequency and the amplitude of mini-excitatory postsynaptic currents (mEPSCs) were significantly increased in fentanyl group which were decreased by acute application of a mGluR1 antagonist, A841720. Finally, the behavioral hypersensitivity could be reversed by A841720 microinjection into the right CeLC. These results show that the right CeLC mGluR1 is an important factor associated with OIH that enhances synaptic transmission and could be a potential drug target to alleviate fentanyl-induced hyperalgesia.

Analyzing Transverse Momentum Spectra by a New Method in High-Energy Collisions

We analyzed the transverse momentum spectra of positively and negatively charged pions (π+ and π−), positively and negatively charged kaons (K+ and K−), protons and antiprotons (p and p¯), as well as ϕ produced in mid-(pseudo)rapidity region in central nucleus–nucleus (AA) collisions over a center-of-mass energy range from 2.16 to 2760 GeV per nucleon pair. The transverse momentum of the considered particle is regarded as the joint contribution of two participant partons which obey the modified Tsallis-like transverse momentum distribution and have random azimuths in superposition. The calculation of transverse momentum distribution of particles is performed by the Monte Carlo method and compared with the experimental data measured by international collaborations. The excitation functions of effective temperature and other parameters are obtained in the considered energy range. With the increase of collision energy, the effective temperature parameter increases quickly and then slowly. The boundary appears at around 5 GeV, which means the change of reaction mechanism and/or generated matter.

Smaller Amygdala Subnuclei Volume in Schizophrenia Patients with Violent Behaviors

Objective To investigate the association between the volume of amygdala subnuclei and violent behaviors in patients with schizophrenia (SCZ). Methods In the present study, we recruited 40 SCZ patients with violent behaviors (VS), 26 SCZ patients without violent behaviors (NVS), and 28 matched healthy controls (HC) who completed T1-weighted magnetic resonance imaging. Both the total amygdala and amygdala subnuclei volumes were estimated with FreeSurfer. Results When comparing the whole SCZ patients with HC, SCZ patients had smaller volume of the left amygdala and the left basal nucleus. Further, the VS patients had smaller volume of the amygdala central nucleus as compared to the NVS group. Conclusions Our findings suggested that a smaller volume of the amygdala central nucleus might be relevant to violence risk in SCZ patients.

Anatomical and Functional Characterization of Central Amygdala Glucagon-Like Peptide 1 Receptor Expressing Neurons

Glucagon-like peptide 1 receptors (GLP-1Rs) are highly expressed in the brain and are responsible for mediating the acute anorexigenic actions of widely prescribed GLP-1R agonists. Neurobiological efforts to localize the hypophagic effects of GLP-1R agonists in the brain have mainly focused on the hypothalamus and hindbrain. In this study, we performed a deep anatomical and neurophysiological characterization of GLP-1Rs in the central nucleus of the amygdala (CeA). At an mRNA level, we found that Glp1r is diffusely coexpressed in known CeA subpopulations like protein kinase c δ (Prkcd), somatostatin (Sst), or tachykinin2 (Tac2). At a cellular level, we used Glp1r-Cre mice and viral Cre-dependent tracing to map the anatomical positions of GLP-1R cells across the rostral-caudal axis of the CeA and in CeA subdivisions. We found that Glp1rCeA cells are highly enriched in the medial subdivision of the CeA (CeM). Using whole cell patch clamp electrophysiology, we found that Glp1rCeA neurons are characterized by the presence of Ih-like currents and resemble a low threshold bursting neuronal subtype in response to hyperpolarizing and depolarizing current injections. We observed sex differences in the magnitude of Ih-like currents and membrane capacitance. At rest, we observed that nearly half of Glp1rCeA neurons are spontaneously active. We observed that active and inactive neurons display significant differences in excitability even when normalized to an identical holding potential. Our data are the first to deeply characterize the pattern of Glp1r in the CeA and study the neurophysiological characteristics of CeA neurons expressing Glp1r. Future studies leveraging these data will be important to understanding the impact of GLP-1R agonists on feeding and motivation.

Going beyond Cryptocurrencies: The Social Representation of Blockchain

This study investigates the social representation of Blockchain from the perspective of professionals in Brazil, herein considered as a proxy for emerging markets, and then compares the results found with the existing academic literature on the concept of Blockchain. To do that, the social representation theory was applied, operationalized through the words evocation technique. Security, bitcoin and decentralization were the categories located in the central nucleus of the social representation of Blockchain, while innovation, data, network, cryptocurrency, and technology were the categories located in the peripheral system. Based on the results obtained, there was a perceived strong association of Blockchain with bitcoin, one of its applications, and a dissonance between the existing academic literature and the perception of Brazilian professionals about the concept of Blockchain, as the latter is a privilege of the technical and operational issues of Blockchain to the detriment of its strategic potential. This dissonance can cause Blockchain initiatives to have results below expectations. Finally, Brazilian professionals did not realize the potential for inclusion of Blockchain in an emerging market such as Brazil and did not notice the need and relevance of a specific legal governance for Blockchain, an issue also forgotten by academia.

Sex-dependent effects of traumatic stress on social behavior and neuronal activation in the prefrontal cortex and amygdala

Social behavior is complex and fundamental, and deficits in social behavior are common pathological features for a variety of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress has a negative impact on social behavior, and these effects may vary based on sex. The aim of this study was to explore the effect of footshock stress on the sociability of male and female C57Bl/6J mice. Animals were divided into two main groups of footshock exposure or context exposure control. Each group had mice that were treated with either the benzodiazepine alprazolam, or vehicle. Neuronal activation during social interaction was assessed using immunohistochemistry against the immediate early gene product cFos. Footshock stress induced a significantly increased latency to approach a social interaction counterpart in both sexes. Stress-induced increases in defensive tail-rattling behavior elicited during the sociability test were sex-dependent and alleviated by alprazolam. Alprazolam also lowered social exploration and neuronal activation in the infralimbic medial prefrontal cortex. Social interaction induced sex-dependent differences in cFos activation in the lateral subdivision of the central nucleus of the amygdala and ventromedial intercalated cell clusters. Overall, our results suggest that acute footshock stress induces alterations in sociability and patterns of cFos activation in a sex-dependent manner.

Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

An Enriched Environment Reduces Chronic Stress-Induced Visceral Pain Through Modulating Microglial Activity in the Central Nucleus of the Amygdala

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders, however, the underlying mechanisms of CBT remain to be explored. Previously we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We sterotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days following CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment and the expression of synaptic pruning-related signals C1q, C3 and C3R were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared to control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.

Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner

Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.

Mechanical Stretch Induces Annulus Fibrosus Cell Senescence through Activation of the RhoA/ROCK Pathway

Background. Intervertebral disc is responsible for absorbing and transmitting mechanical compression. Under physiological conditions, the peripheral annulus fibrosus (AF) cells are subjected to different magnitudes of transverse mechanical stretch depending on the swelling of the central nucleus pulposus tissue. However, the biological behavior of AF cells under mechanical stretch is not well studied. Objective. This study was performed to study the effects of mechanical tension on AF cell senescence and the potential signaling transduction pathway. Methods. Rat AF cells were made to experience different magnitudes of mechanical stretch (2% elongation and 20% elongation for 4 hours every day at 1 Hz) in a 10-day experiment period. The inhibitor RKI-1447 of the Rho-associated coiled-coil–containing protein kinases (ROCK) was added along with culture medium to investigate its role. Cell proliferation, cell cycle, telomerase activity, and expression of senescence markers (p16 and p53) were analyzed. Results. We found that 20% elongation significantly decreased cell proliferation, promoted G0/G1 cell cycle arrest, decreased telomerase activity, and upregulated mRNA/protein expression of p16 and p53. Moreover, the inhibitor RKI-1447 partly resisted effects of 20% elongation on these parameters of cell senescence. Conclusion. High mechanical stretch obviously induces AF cell senescence through the RhoA/ROCK pathway. This study provides us a deeper understanding on the AF cell’s behavior under mechanical stretch.