There is a critical need for interdisciplinary and translational scientists to apply sex as a biological variable (SABV) research to address knowledge gaps in the health of women. In 2018, the Office ...of Research on Women's Health (ORWH) partnered with several National Institute of Health (NIH) Institutes and Centers to expand the Specialized Centers of Research (SCOR) Excellence (SCORE) Programs (together referred to as SCOR/E) with an important feature-the Career Enhancement Core (CEC). The SCORE CEC mentors early career investigators to become the next generation of biomedical and behavioral researchers focused on SABV and women's health. In this article, we outline our approach at the Yale University SCORE to support early career trajectories through the provision of salary support, educational curricula, translational mentorship, pilot project funding, and professional development. Using the Yale-SCOR/E CEC Programs as instructional models, we highlight critical measures of academic success, namely grant funding and publications, among early career investigators. At Yale University, 12 pilot projects funded by the SCOR/E Programs resulted in 14 extramural grants, amounting to an $80 return on every $1 invested in "seed" funding. So far, our SCOR/E Programs have resulted in 129 publications, 83% of which were first-authored by trainees, and 100% of trainees continued research careers with an emphasis on SABV. Finally, we provide recommendations on how biomedical scientists can apply SABV in their studies of major medical conditions in an interdisciplinary and integrative way.
Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable ...neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.
BALB/cJ is a strain susceptible to stress and extremely susceptible to a defective hedonic impact in response to chronic stressors. The strain offers much promise as an animal model for the study of ...stress related disorders. We present a comparative hippocampal gene expression study on the effects of unpredictable chronic mild stress on BALB/cJ and C57BL/6J mice. Affymetrix MOE 430 was used to measure hippocampal gene expression from 16 animals of two different strains (BALB/cJ and C57BL/6J) of both sexes and subjected to either unpredictable chronic mild stress (UCMS) or no stress. Differences were statistically evaluated through supervised and unsupervised linear modelling and using Weighted Gene Coexpression Network Analysis (WGCNA). In order to gain further understanding into mechanisms related to stress response, we cross-validated our results with a parallel study from the GENDEP project using WGCNA in a meta-analysis design.
The effects of UCMS are visible through Principal Component Analysis which highlights the stress sensitivity of the BALB/cJ strain. A number of genes and gene networks related to stress response were uncovered including the Creb1 gene. WGCNA and pathway analysis revealed a gene network centered on Nfkb1. Results from the meta-analysis revealed a highly significant gene pathway centred on the Ubiquitin C (Ubc) gene. All pathways uncovered are associated with inflammation and immune response.
The study investigated the molecular mechanisms underlying the response to adverse environment in an animal model using a GxE design. Stress-related differences were visible at the genomic level through PCA analysis highlighting the high sensitivity of BALB/cJ animals to environmental stressors. Several candidate genes and gene networks reported are associated with inflammation and neurogenesis and could serve to inform candidate gene selection in human studies and provide additional insight into the pathology of Major Depressive Disorder.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether ...these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.
Acetylcholine (ACh) signaling in the hippocampus is important for behaviors related to learning, memory and stress. In this study, we investigated the role of two ACh receptor subtypes previously ...shown to be involved in fear and anxiety, the M1 mAChR and the α2 nAChR, in mediating the effects of hippocampal ACh on stress‐related behaviors. Adeno‐associated viral vectors containing short‐hairpin RNAs targeting M1 or α2 were infused into the hippocampus of male C57BL/6J mice, and behavior in a number of paradigms related to stress responses and fear learning was evaluated. There were no robust effects of hippocampal M1 mAChR or α2 nAChR knockdown (KD) in the light/dark box, tail suspension, forced swim or novelty‐suppressed feeding tests. However, effects on fear learning were observed in both KD groups. Short term learning was intact immediately after training in all groups of mice, but both the M1 and α2 hippocampal knock down resulted in impaired cued fear conditioning 24 h after training. In addition, there was a trend for a deficit in contextual memory the M1 mAChR KD group 24 h after training. These results suggest that α2 nicotinic and M1 muscarinic ACh receptors in the hippocampus contribute to fear learning and could be relevant targets to modify brain circuits involved in stress‐induced reactivity to associated cues.
Knockdown of M1 muscarinic or α2 nicotinic ACh receptors in hippocampus impairs cued fear conditioning.
The ability of nicotine to alter firing of dopamine neurons is the first step leading to nicotine reward, but activation of intracellular signaling pathways downstream of nicotinic acetylcholine ...receptors is likely to be critical for longer-term consequences of nicotine exposure, including conditioned reward. The transcription factor cyclic AMP-response element binding protein (CREB) is important for new gene transcription and in its phosphorylated form (pCREB) promotes long-term changes in synaptic strength. Previous studies have implicated nucleus accumbens (NAc) CREB activity in the modulation of cocaine and morphine reward, and have shown that nicotine conditioned place preference (CPP) is associated with NAc CREB activation. It is not clear whether CPP elicits phosphorylation of CREB or if elevations in pCREB support nicotine CPP. In the current study, we investigated levels of CREB and pCREB during Pavlovian conditioning with nicotine in a novel context in the absence of chamber choice. Nicotine context conditioning resulted in elevated pCREB levels in the NAc shell but not the NAc core of mice following placement in the nicotine-paired chamber in the absence of nicotine. To test if CREB activity in the NAc shell contributes to cue-induced responses that may precipitate nicotine-seeking, we used viral-mediated gene transfer of a dominant-negative CREB construct in the NAc shell of C57BL/6J mice and found that disruption of CREB activation before training blocked nicotine place preference across a range of doses. Taken together, these studies identify the NAc shell as a brain region where CREB activity is essential for nicotine CPP.
Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene’s contribution to the constellation of neural phenotypes remain ...elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
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•Systems biology analyses reveal mitochondrial contribution to 7q11.23 CNV syndromes•The 7q11.23 protein DNAJC30 facilitates ATP synthesis in neocortical neurons•Altered behavior and mitochondrial and neuronal physiomorphology in Dnajc30−/− mice•Deficient mitochondrial function and OXPHOS architecture in WS cells and brains
Reduced copy number of DNAJC30, now shown to interact with the mitochondrial ATP synthase, leads to mitochondrial dysfunction underlying neuronal defects in Williams syndrome.
Background Excessive glutamatergic neurotransmission is hypothesized to be associated with depressive-like behaviors and possibly major depressive disorder (MDD). Recent evidence that β-lactam ...antibiotic agents stimulate uptake of glutamate suggests that this class of compounds might possess antidepressant-like activity. Methods Three-month old, male, C57BL/6J mice were administered ceftriaxone (200 mg/kg IP) for 14–18 days, then tested in the tail-suspension, forced swim, and novelty-suppressed feeding tests to determine whether ceftriaxone had similar effects to classical antidepressant compounds in these models. Results Ceftriaxone treatment had an antidepressant-like effect across models. Reduced immobility and decreased freezing were observed in the forced swim and tail suspension tests. The same trend was seen in novelty-suppressed feeding, but the effect was not statistically significant. Conclusion Ceftriaxone demonstrates antidepressant-like effects in several mouse models. This is consistent with the hypothesis that enhanced uptake of glutamate might have antidepressant-like effects.
Background The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are ...administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients. Methods Pharmacological (CSA) and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA shRNA) approaches were used to inhibit calcineurin activity systemically or selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to anxiety and depression. Results Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala using adeno-associated viral-delivered shRNAs targeting calcineurin B increased measures of anxiety-like behavior in the elevated plus maze, the light/dark box, and the open field test. A decrease in locomotor activity was also observed in mice treated systemically with CsA. In the forced swim model of depression-like behavior, both systemic CsA treatment and shRNA-mediated calcineurin blockade in the amygdala significantly increased immobility. Conclusions Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety-like behaviors and to some extent depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and this should be recognized as a potential clinical consequence of treatment to prevent transplant rejection.
Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive ...disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect.
This article is part of the special issue on ‘Vulnerabilities to Substance Abuse.’
•The relationship between stress-related disorders and alcohol use is stronger among women.•Progestogen/androgen-derived neurosteroids underlie both alcohol/stress-related disorders.•Allopregnanolone may reduce alcohol consumption through the reduction of negative affect.
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