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Principal Investigator: JILL M GOLDSTEIN
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $2,400,001
Funding agency: National Institute of Mental Health
OVERALL SUMMARY. Major depressive disorder (MDD) topped heart disease as the number one cause of
disability worldwide, and women have twice the risk of men. MDD is associated with abnormalities in the stress
response circuitry, areas that are among the most sexually dimorphic in the brain. These areas are dense in
sex steroid and glucocorticoid receptors coupled with cytokine receptors. Further, activity in these areas has
been associated with cortisol response, autonomic dysfunction, and immune responses, which we showed
differed by sex. This is important since autonomic dysregulation is significantly associated with cardiovascular
disease. In fact, women are at twice the risk for the co-occurrence of MDD, autonomic dysregulation and heart
disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and
untreated MDD. Thus, understanding early biomarkers for sex differences in MDD and autonomic
dysregulation will provide knowledge for early intervention, attenuating later life disability, in particular for
women who are at higher risk. The scientific mission of this SCORE is to identify stress-immune pathway
abnormalities, beginning in fetal development, that have shared consequences for sex differences in brain
circuitry regulating mood and lifelong recurrent MDD and dysregulation of hormone and immune responses to
stress, and autonomic and neurovascular dysfunction in early midlife. We aim to facilitate transdisciplinary,
translational collaboration among basic and clinical investigators to enhance our understanding of the impact of
sex on MDD and central and peripheral autonomic function and provide the groundwork for translating this
knowledge into sex-selective therapeutics. Further, we aim to serve as an interdisciplinary resource to train
and disseminate findings about sex differences in MDD and autonomic dysregulation to the scientific and
medical communities, policy makers, and the public. To accomplish this, three integrated studies are proposed:
1) a clinical population neuroscience study relating prenatal risk biomarkers to sex differences in brain circuitry
and physiologic deficits in response to stress in MDD in early midlife; 2) clinical study using direct
transcutaneous neuromodulatory stimulation of the vagus nerve, auricular branch (or taVNS) to target the
circuitry associated with stress-immune function and map its neuroanatomic, physiologic and clinical effects in
MDD by sex, in the same subjects as in project 1; and 3) rodent model studies that will map out the central
mechanistic pathways involved in projects 1 and 2. In addition, three cores will contribute to the success of this
SCORE: 1) Leadership Administration Core to administer and oversee the administrative integration of the
studies and cores; 2) Resources Core to provide shared technical expertise across studies; and 3) Career
Enhancement Core, to supplement the training of junior faculty and others on the topic of our SCORE, and
become pedagogical ambassadors to the scientific, medical and public communities about sex differences in
depression and comorbidities with general medicine, a topic with global public health implications.
Terms: <(TNF)-α><ACTH-Releasing Factor><Adult Children><Adult Daughters><Adult Offspring><Adult Sons><Aeroseb-HC><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anterior><Anxiety><Area><Attenuated><Autonomic Dysfunction><Autonomic nervous system><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basic Research><Basic Science><Biological Markers><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain imaging><COBRE><CRF-41><CRH><CRH gene><Cachectin><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cellular Immune Function><Center of Biomedical Research Excellence><Centers of Research Excellence><Cetacort><Clinical><Clinical Investigator><Clinical Research><Clinical Study><Collaborations><Communities><Cornu Ammonis><Cort-Dome><Cortef><Cortenema><Corticoliberin><Corticotropin-Releasing Factor><Corticotropin-Releasing Factor-41><Corticotropin-Releasing Hormone><Corticotropin-Releasing Hormone-41><Cortisol><Cortispray><Cortril><Coupled><Cytokine Receptors><Data Analytics><Dermacort><Developing fetus><Development><Devices><Differences between sexes><Differs between sexes><Disease><Disorder><Dysfunction><Early Intervention><Eldecort><Emotional Depression><Encephalon><Encephalon Diseases><Endocrine Gland Secretion><Faculty><Fetal Development><Functional disorder><Genes><Glucocorticoid Receptor><Gonadal Steroid Hormones><HPA axis><HPGF><Health><Heart Diseases><Hepatocyte-Stimulating Factor><Hippocampus><Hormone secretion><Hormones><Hybridoma Growth Factor><Hydrocortisone><Hydrocortone><Hypothalamic structure><Hypothalamus><Hytone><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune response><Immunes><Immunological response><Interleukin-6><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Knowledge><Leadership><Life><MGI-2><Macrophage-Derived TNF><Major Depressive Disorder><Maps><Medical><Medicine><Mental Depression><Mission><Monocyte-Derived TNF><Moods><Myeloid Differentiation-Inducing Protein><Myocardial Ischemia><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurocyte><Neurons><Neurosciences><Nutracort><Outcome><P50 Mechanism><P50 Program><Paraventricular Hypothalamic Nucleus><Pathway interactions><Peripheral><Physiologic><Physiological><Physiology><Physiopathology><Plasmacytoma Growth Factor><Policy Maker><Population><Prefrontal Cortex><Proctocort><Public Health><Receptor Activation><Recurrence><Recurrent><Research Resources><Resources><Risk><Rodent Model><Scientist><Series><Sex Differences><Sex Disorders><Sex Hormones><Sex Steroid Hormones><Sexual Dysfunction><Sexual differences><Specialized Center><Steroid Receptors><Stress><Study models><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technical Expertise><Technology><Testing><Therapeutic><Therapeutic Hormone><Training><Translating><Translations><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Woman><Women's mortality><amygdaloid nuclear complex><attenuate><attenuates><bio-markers><biologic marker><biological adaptation to stress><biomarker><brain circuitry><brain visualization><cardiac function><cardiac ischemia><cardiovascular disorder><career><cingulate cortex><clinical depression><clinical effect><co-morbid><co-morbidity><comorbidity><coronary ischemia><corticotropin releasing hormone><death among females><death among women><death in females><death in women><death rate among women><death rate in women><death risk><depression><depression symptom><depressive><depressive symptoms><developmental><disability><early biomarkers><early detection biomarkers><early detection markers><effective therapy><effective treatment><female death><female mortality><fetal stress><function of the heart><gonadal steroids><heart disorder><heart function><heart ischemia><high risk><hippocampal><hormonal secretion><host response><hypothalamic><hypothalamic-pituitary-adrenal (HPA) axis><hypothalamic-pituitary-adrenal axis><hypothalmus-pituitary-adrenal axis><immune function><immune system response><immunoresponse><in utero><interferon beta 2><late life><life span><lifespan><major depression><major depression disorder><men><mid life><mid-life><middle age><middle aged><midlife><mortality among females><mortality among women><mortality in females><mortality in women><mortality risk><myocardial ischemia/hypoxia><myocardium ischemia><neural control><neural regulation><neuro-vascular><neuromodulation><neuromodulatory><neuronal><neuroregulation><neurovascular><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><paraventricular nucleus><pathophysiology><pathway><prenatal><prenatal stress><reaction; crisis><respiratory><response><sex><sex based differences><sex dimorphism><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><stress reactivity><stress response><stress; reaction><success><technical skills><therapeutic agent development><therapeutic development><translation><translational study><unborn><vagus nerve stimulation><women's death><women's death rate>