Marianne L. Seney, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): In animals with complex societies, social signals can profoundly influence behavior, physiology, and the nervous system. Naked mole-rats exhibit a strict hierarchical social organization in which breeders are dominant to all non-breeders. Recently, a change in social status has been linked to what appears to be late differentiation of spinal motoneurons. Naked mole-rats live in large colonies consisting of a single breeding female (the queen), one to three breeding males, and a large cohort of reproductively suppressed subordinates. Over 95% of subordinates will remain reproductively inactive for their entire lives. A subordinate can become reproductive, however, if a breeding animal dies or if it is removed from the colony and paired with an opposite-sex mate. This change in social status causes an increase in the number of motoneurons innervating perineal muscles. This project will: 1) determine which factors trigger the changes observed in the spinal cord by independently manipulating gonadal hormones and social status, 2) establish the neurochemical identity of cells within the spinal cord that become large motoneurons in breeders using immunocytochemistry for cell-type markers, and 3) determine the targets of the large motoneurons recruited in breeders by retrograde tract-tracing. The unique social structure and life history of naked mole-rats give us the opportunity to examine neural plasticity in an adult mammal, including the late differentiation or re-specification of neuron subtype in the spinal cord. This information could be used to develop treatments for degenerative diseases characterized by loss or atrophy of motoneurons, such as amyotrophic lateral sclerosis (ALS). [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation. Despite the substantial financial and emotional burden of MDD, understanding the pathological and molecular features of this disorder remains a considerable challenge in neuropsychiatry research. One major risk factor for depression is sex: one in four women, but only one in ten men, will experience a debilitating episode of MDD in the course of a lifetime. A past limitation to investigate this major risk factor and associated mechanisms was the lack of an animal model that not only mimics the complexity of the disorder but also replicates the female vulnerability. In addition to mimicking symptom dimensions, antidepressant reversal, and molecular profile characteristics of human MDD, we now show that unpredictable chronic mild stress (UCMS) in mice recapitulates the female differences in emotionality and vulnerability to depression, making UCMS the appropriate model to investigate underlying mechanisms involved in sex differences in MDD. Emotionality is defined as measured parameters for rodent behavior and physiology that are homologous to human emotions. Although evidence suggests a partial contribution of circulating sex hormones to female emotionality, this proposal aims to use the UCMS model to test the alternative and less investigated hypothesis of a developmental origin of the sexual dimorphism of emotionality and vulnerability to depression. Studies in human subjects and in rodent models suggest a developmental origin for mood disorders. Interestingly, a developmental process also establishes sex differences in the brain, as developmental exposure to testosterone permanently masculinizes the structure of several brain regions, including the amygdala. This project will 1) determine whether developmental organization of the male/female brain (through postnatal testosterone exposure) underlies adult sex differences in baseline and/or stress induced emotionality in mice, and 2) determine whether the developmentally determined molecular correlates underlying altered emotionality in female mice predict similar changes in human female MDD subjects and are reversed by developmental testosterone treatment. PUBLIC HEALTH RELEVANCE: If gender differences in major depression are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of major depression. One major problem with studying depression in rodents has been the lack of models that replicate the well documented human female vulnerability to depression. Importantly, the Sibille lab now shows that the unpredictable chronic mild stress mouse model recapitulates the female vulnerability to major depression, and thus, the proposed studies will use this model to investigate possible biological causes for sex differences in depression.

DESCRIPTION (provided by applicant): Somatostatin, a neuropeptide expressed in a subset of inhibitory neurons in the brain, is decreased in humans across multiple brain disorders, including schizophrenia, bipolar depression and Alzheimer's disease. Somatostatin is also down-regulated in major depressive disorder, and more robustly so in women with depression, hence mirroring the increased female prevalence of the disorder. This proposal follows up on recent findings from the candidate, Dr. Marianne Seney, indicating a role for XY genetic sex in regulating anxiety-like behaviors and expression of somatostatin, and of an opposing effect of adult testosterone on the behavioral effects of XY genetic sex. These translational mouse studies are directly informed by human postmortem findings and will specifically investigate (i) the opposing effect of XY genetic sex and adult circulating testosterone on anxiety-like behavior and on molecular correlates, and (ii) whether manipulating the function of inhibitory neurons that express somatostatin will affect the balance between genetic sex and circulating testosterone in adult behavioral outcomes. The candidate, Dr. Marianne Seney, is the ideal individual to perform the proposed research, based on her previous research experience in the fields of neuroendocrinology and of sexual dimorphism in the rodent brain. The mentor, Dr. Etienne Sibille, will provide expertise in the translational approach to study causality of altered biological pathways or cellular mechanisms involved in the pathophysiology of depression, together offering a unique and synergistic environment in which to study sex differences in depression and anxiety. The co-mentor, Dr. Colleen McClung, will provide essential training in rodent pharmacogenetic techniques to modulate function of specific cell populations in the brain. Co-mentor, Dr. George Tseng, will provide critical support in using state of the art bioinformatics and statistical approaches to interpret large behavioral and molecular datasets. To perform the proposed research and interpret results, Dr. Seney will benefit from a group of internal and external expert consultants, and will obtain additional training in proteomics and in exposure to clinical realities of mood and anxiety disorders. The Department of Psychiatry at the University of Pittsburgh offers a well-funded environment with a nationally and internationally recognized reputation as a premier research institution, making it the ideal location for Dr. Seney to perform her research and gain essential training. At completion of this proposal, Dr. Seney will be poised to lead her own research program aimed at using translational approaches to understand sex differences in mood and anxiety disorders.

Abstract Major depressive disorder (MDD) is a leading cause of disability, affecting more than 300 million people worldwide. There is a well-known sex difference in incidence of MDD, with women being twice as likely to be diagnosed as men. Additionally, the impact of MDD varies between men and women, with sex differences in symptomatology, severity, and number of symptoms. For instance, women are three times more likely to have atypical depression, characterized by hypersomnia and weight gain. These marked differences in symptomatology between depressed men and women led us to hypothesize that MDD differs at the molecular level between men and women. We recently assessed the sex-specific molecular pathology of MDD using human postmortem brain analysis. We showed, for the first time, that depression is not only distinct in men and women, but is characterized by opposite molecular pathology. The strongest opposite effects were in the anterior cingulate cortex (ACC; Brodmann area 25), a brain region consistently implicated in MDD pathology. Our analysis of men with MDD found reductions in markers of synaptic function and increases in markers of microglia and inflammation, consistent with reports of decreased pyramidal cell dendritic spine synapses and increased reactive microglia in depressed men. The molecular changes in MDD males are consistent with a model in which reactive microglia participate in excessive pathologic synapse removal. Surprisingly, our analysis of women with MDD found increased markers of synaptic function coupled with decreased markers of immune function and microglia, which is exactly the opposite of depressed men. However, no study has examined pyramidal cell dendritic spine and microglia changes specifically in depressed women, leaving a major gap in the depression literature. Together, these studies suggest pyramidal cells and microglia are affected in MDD, but in opposite directions in men and women. Notably, studies in rodents report that chronic stress increases reactive microglia and decreases prefrontal cortex dendritic complexity in males, but does exactly the opposite in females. Thus, rodents provide an excellent model system to probe molecular mechanisms underlying the sex-specific pathology observed in human MDD. Here, we will assess pyramidal cell dendritic spines and reactive microglia in the ACC of men and women with MDD, addressing a major gap in the literature (Aim 1). Next, we will assess pyramidal cell- and microglia-specific transcriptional changes that occur in depressed men and women (Aim 2). Finally, we will determine the functional relevance of observed sex-specific MDD spine and microglia pathology using mouse models (Aim 3). These studies are essential for understanding sex- and cell type-specific MDD pathology and determining if these sex differences drive MDD symptoms. In addition, they will assess whether sex-specific treatments alleviate depression-related symptoms and provide key insights for future sex-specific treatment development.

PROJECT SUMMARY Opioid use and dependence prevalence have skyrocketed in the United States. A majority of patients with opioid use disorder (OUD) relapse within months despite treatment. Recent human neuroimaging and postmortem brain studies in OUD reveal the degree of dysfunction within cortical and striatal brain circuits, particularly within dorsolateral prefrontal cortical (DLPFC) and nucleus accumbens (NAc) regions, strongly relates to the opioid use and dependence risk. The PFC provides top-down inhibitory cognitive and emotional control to the NAc, which mediates goal-directed and reward behaviors. Relapse vulnerability in OUD is strongly associated with the severity and persistency of disruptions to sleep and circadian rhythms, raising the possibility that therapeutic interventions which mitigate these disruptions during abstinence may be effective for reducing opioid craving and relapse. However, our understanding of the biological mechanisms underlying the relationships between circadian rhythms and OUD is limited, especially at the molecular level in the brains of people with OUD. We and others have developed novel, innovative approaches using time of death (TOD) to measure molecular rhythms in the human postmortem brain to investigate the mechanistic links between substance use and molecular brain rhythms. Using TOD approaches, we recently found a marked loss of molecular rhythms in the prefrontal cortex associated with normal aging and psychiatric disorders. Notably, we also discovered a gain of rhythmicity in genes within disease-specific molecular pathways, providing novel insights into the biology of brain aging and psychiatric pathology. Preliminary TOD analyses on large-scale gene expression in human subjects with OUD revealed enrichment for pathways related to circadian rhythms in the PFC and NAc. In our proposal, we will directly investigate the relationship between molecular rhythm disruption and opioid use and relapse using both human postmortem brains from subjects with OUD and mouse models of circuit-specific targeting and opioid self-administration. Specifically, we will investigate molecular rhythms in postmortem DLPFC and NAc using RNA-sequencing from a large cohort of subjects with OUD (Aim 1A). We will also examine the impact of specific clinical features (e.g., toxicology reports and overdoses, comorbid psychiatric disorders, history of use, polysubstance use, illness duration) on molecular rhythms in OUD (Aim 1B). We will then directly test the functional relevance of molecular rhythm disruptions in specific brain regions (PFC and NAc; Aim 2A) and circuits (PFC projections to NAc; Aim 2B) during opioid self-administration behavior in mice. Our studies will identify molecular rhythm abnormalities in the brains of subjects with OUD and begin to determine the mechanisms linking circadian rhythms and addiction, which will provide important insight into disease-related pathways and also potential treatment strategies.