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Psychological stress contributes to the onset and exacerbation of nearly all neuropsychiatric disorders. Individual differences in stress-regulatory circuits can therefore dramatically affect vulnerability to these illnesses. Here we identify neural circuit mechanisms underlying individual differences in vulnerability to stress using a murine model of chronic social defeat stress. In chronically stressed mice, we find that the degree of prefrontal cortex (PFC) control of amygdala activity predicts stress susceptibility in individual mice. Critically, we also find that individual differences in PFC activation (that is, reactivity) during exposure to an aggressor mouse predict the emergence stress-induced behavioural deficits in stress-naïve mice. Finally, we show that naturally occurring differences in PFC reactivity directly correspond to the intrinsic firing rate of PFC neurons. This demonstrates that naturally occurring differences in PFC function underlie individual differences in vulnerability to stress, raising the hypothesis that PFC modulation may prevent stress-induced psychiatric disorders. Connectivity between the prefrontal cortex (PFC) and the amygdala (AMY) is implicated in responses to stress and regulation of affect. Here, the authors show that stress is regulated by changes in PFC–AMY coherence, PFC oscillatory activity and AMY oscillatory activity across the 2–7 Hz frequency band.

It has long been recognized that there are comorbidities between migraine and psychiatric disorders, especially major depressive disorder (MDD). Often this relationship is attributed to the psychological risk of having an intermittent debilitating disorder that causes a great deal of suffering. However, as evidence mounts about the mechanisms underlying each disorder, mechanistic overlap is beginning to emerge that suggests some shared underlying etiology. These findings span biochemical, genetic, physiological, neuroanatomical, and environmental levels of analysis. Here we review evidence for shared biological mechanisms between migraine and MDD by first searching for mechanisms of each disorder separately across levels of analysis, with an emphasis on current and historic treatments for each disorder. Search terms included each disorder separately largely across NIMH Research Domain Criteria (RDoC) levels of analysis, adding “environment” to genes, molecules, cells, circuits, and physiology. In order to focus our efforts on shared underlying mechanisms, we included studies in preclinical models of these disorders. This review was written to highlight the emergent themes with the most mechanistic overlap between the two disorders across levels of analysis. We prioritized reporting of the findings with more mechanistic detail, which often comes from preclinical studies with carefully controlled variables and tests of causality. As such, this review is aimed at providing new insight by identifying features that are shared between these disorders, including those that have largely not been previously recognized. By emphasizing preclinical studies and mechanisms of underlying constructs relating these disorders, such as sensory gain and processing of emotional stimuli, we intend for this review to stimulate new areas of investigation at both clinical and preclinical levels of research.

Recent breakthroughs in gut microbiome-derived technologies and therapies, coupled with the lack of invasiveness associated with them, provide attractive routes of biomarker and therapeutic development. Alongside such breakthroughs, an ever-growing body of literature indicates a strong connection between brain activity and microbial populations in the gut. The paucity of effective psychiatric therapies makes the gut microbiota/brain connection a particularly enticing field. This article reviews some of the mechanisms of connection between the gut and the brain, their potential relationship to psychiatric disorders, and the therapeutic potential that arises from them.

ABSTRACT Mentoring is a developmental experience intended to increase the willingness to learn and establish credibility while building positive relationships through networking. In this commentary, we focus on intentional mentoring for underrepresented mentees, including individuals that belong to minority racial, ethnic and gender identity groups in Science, Technology, Engineering, Mathematics and Medicine (STEMM) fields. Intentional mentoring is the superpower action necessary for developing harmony and comprehending the purpose and value of the mentor/mentee relationship. Regardless of a mentor's career stage, we believe the strategies discussed may be used to create a supportive and constructive mentorship environment; thereby improving the retention rates of underrepresented mentees within the scientific community. This article discusses how to be an intentional mentor in the 21st Century.

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies.

ABSTRACT While it is commonly thought that microaggressions are isolated incidents, microaggressions are ingrained throughout the academic research institution (Young, Anderson and Stewart 2015; Lee et al. 2020). Persons Excluded from science because of Ethnicity and Race (PEERs) frequently experience microaggressions from various academicians, including graduate students, postdocs and faculty (Asai 2020; Lee et al. 2020). Here, we elaborate on a rationale for concrete actions to cope with and diminish acts of microaggressions that may otherwise hinder the inclusion of PEERs. We encourage Science, Technology, Engineering and Mathematics (STEM) departments and leadership to affirm PEER scholar identities and promote allyship by infusing sensitivity, responsiveness and anti-bias awareness. This article focuses on how mentors can be allies against microaggressions in STEM.

In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

Migraine is a disorder of severe, recurrent headaches and debilitating sensory, cognitive and affective symptoms, often triggered by stress. Early life stress in childhood has been shown to increase the likelihood of migraine in adulthood in humans. Calcitonin-gene relate peptide (CGRP) has been shown to reliably and acutely induce migraine or migraine-like behavior in both humans and rodent models. Here we investigate the impact of early life stress and CGRP on migraine-related neural circuitry, as well as the impact of early life stress on CGRP-mediated migraine-like activity in order to better understand the mechanisms by which early life stress predisposes neural circuitry to migraine brain activity. We implemented an early life stress paradigm in the outbred strain of mice, CD1. We evaluated the impact of peripheral CGRP on migraine-like behavior and employed multi-site in vivo neurophysiology in freely behaving mice. A changepoint analysis was used to dissect differences in individual CGRP-induced responses. We found that early life stress exacerbated migraine-related behavioral and network physiology. CGRP alone caused disruptions in neural oscillatory activity across a network of brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), thalamus (Po, VPM, and MDthal), and parabrachial nucleus (PBN). We found that power across the network was lowered within 10 minutes of peripheral CGRP exposure, which was sustained for ∼40-50 min. Coherence was mostly disrupted in amygdalar brain region pairings, and took on a shorter timecourse, with partial rescue of these responses by migraine abortive, sumatriptan. We found that early life stress exacerbated most of these responses, especially AMY-thalamic coherence pairings, although early life stress in the absence of CGRP demonstrated no impact on the network overall. We further identified individual mice with brain-network activity hypersusceptible to migraine. Our findings demonstrate that early life stress confers vulnerability to migraine, simultaneously impacting behavior and brain network activity responses to peripheral CGRP.

Migraine is a disorder consisting of severe, recurrent headaches and debilitating sensory symptoms which often include affective symptoms or comorbidities such as depression, anxiety, and irritability. As such, migraine is a complex nervous system disorder that involves integration of many modalities across the brain. This makes migraine a complex systems neuroscience problem represented by the confluence of sensory, pain, cognitive, autonomic, and affect-related circuits. Thus, it is essential to understand how neuronal activity across various brain regions implicated in migraine is coordinated during migraine pathophysiology. Using a calcitonin gene-related peptide (CGRP) mouse model of migraine, we probed neural oscillatory activity in the anterior cingulate cortex, amygdala (BLA and CeA), thalamus (Po, VPM, and MDthal), and parabrachial nucleus following peripheral administration of CGRP. We identified three frequency bands in which directional signals occur in this network and found that power in these frequencies across the network was lower than vehicle within 10 minutes of peripheral CGRP exposure, which was sustained for (~40-50 min). Coherence, on the other hand, was mostly disrupted in CeA brain region pairings, and took on a shorter timecourse. Sumatriptan partially blunted or reversed these CGRP-induced network responses, especially with regard to amygdala power and coherence pairings. Early life stress, which has been shown to increase the likelihood of migraine in adulthood in humans, exacerbated CGRP-induced migraine-related behavioral phenotypes and induced corresponding network changes in LFP power in the CeA and Po and coherence in Po-related pairings. Clustering based on a changepoint analysis of coherence identified individual mice hypersusceptible to migraine. Overall, our findings demonstrate coordinated brain-wide network activity by which migraine is mediated in the brain in response to peripheral CGRP.Competing Interest StatementThe authors have declared no competing interest.

Heterotrimeric G proteins play invaluable roles in cellular processes involving transmembrane signaling, particularly at sites of neuronal connectivity within the central nervous system (CNS). Gαz is a member of the Gαi subfamily of heterotrimeric G proteins that displays unique biochemical characteristics and is primarily expressed in neuronal and neuroendocrine cells. Studies in Gz-null mice over the past decade reveal that Gz significantly impacts responses to psychoactive drugs, and is capable of coupling to D2 dopamine, 5-HT1A serotonin, μ-opioid, and α2A-adrenergic receptors. These studies have suggested that Gz may play a critical role in diseases and disorders involving disruptions of monoamine neurotransmitter signaling in the brain such as depression, anxiety, drug abuse, ADHD, schizophrenia, drug addiction, and pain sensitivity. Much is still unknown about the roles and mechanisms of action of Gz in biology. In this thesis, I have built on what is known regarding Gαz biochemistry by conducting a series of studies that provide further understanding of its role in the CNS, particularly in neuronal development and seizure susceptibility. Gz interacts with several proteins that act as regulators and effectors: RGSZ, adenylyl cyclase, EYA2, and Rap1GAP being the best characterized. A finding regarding its impact of Gz on neurotrophin signaling through RAP1GAP in particular has led to much of the work described here. The studies presented in this thesis indicate that Gαz inhibits BDNF-stimulated axon growth in cortical neurons, establishing an endogenous role for Gαz in regulation of neurotrophin signaling in the CNS that may have important implications for development and plasticity. Furthermore, Gαz was shown to be uniquely distributed to synaptic vesicles suggesting that one mechanism underlying Gz biology may be the regulation of vesicle loading, docking, or release. Finally, I demonstrate that Gz-null mice are hypersusceptible to pilocarpine-induced seizures, and provide histology data indicating increased levels of zinc in the hippocampus. Taken together, these findings suggest that Gz plays a regulatory role at the intersection of neurotrophin and GPCR signaling in the CNS.