Dani Dumitriu, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The mechanisms underlying adult neural plasticity are poorly understood. Estrogen has emerged as a potential candidate to mediate the brain's ability to learn and encode new memories throughout life. Estrogen has been shown to induce spinogenesis and synaptic potentiation in the hippocampus of both female and male rat, and in non-human primates. In addition, estrogen has been implicated in a wide variety of disorders in which neural plasticity is altered, such as Alzheimer's Disease, Parkinson's Disease, depression, and schizophrenia. Although estrogen-induced spinogenesis has been studied for decades, live imaging and characterization of the newly emerged spines has not yet been performed. Here, I propose to use a combination of two-photon imaging and electrophysiological recording in acute hippocampal slices of adult rat to examine the functional properties of these new spines. My main hypothesis is that estrogen induces more "youthful" morphological and electrophysiological profiles in the adult hippocampus, with highly plastic new spines and an increase in silent synapses; however, these changes are permissive in that in the absence of "stabilizing" stimulus such as induction of LTP, the new spines and synapses disappear. The proposed experiments will be important for both investigations of estrogen's functions in the adult CNS [unreadable] as well as the functions of spino- and synaptogenesis in the adult in general. PUBLIC HEALTH RELEVANCE: The brain's ability to learn and form new memories is impaired in many disorders, such as Alzheimer's Disease, Parkinson's Disease, depression, and schizophrenia. Estrogen has been shown to increase the number of synapses, the sites of communications between brain cells. Thus, a better understanding of the mechanisms of estrogen's actions holds great potential for far-reaching [unreadable] clinical applications. [unreadable] [unreadable] [unreadable]

ABSTRACT Like humans, mice subjected to stress can be divided into two phenotypes. Susceptible animals succumb to maladaptive symptoms such as anhedonia and social avoidance, while resilient animals continue to behave indistinguishably from controls. The mechanisms that drive this divergent stress-response remain elusive. Understanding the functional relationship between individual variability in functional and structural connectivity and stress-response is a critical first step in early identification of at-risk individuals and preventative approaches that actively enhance resilience. We will address this relationship at multiple scales of resolution: the whole-brain functional connectivity level using cFos co-activation mapping, the mesoscale structural connectome level using viral-mediated trans-synaptic tracing, the synaptic level using single-cell 3D reconstruction of dendritic spines, and the circuit level using viral-mediated identification and chemogenetic control of a corticolimbic pathway. Multiscale circuits will be studied using a ?time-course? approach, which will provide mechanistic insight into how the functional and structural wiring diagram prior to a stressor contributes to the development of divergent stress-responses. Our behavioral toolbox includes acute and chronic social defeat stress resulting in subpopulations of resilient and susceptible mice, and novel non-stressful predictors of each phenotype. In our preliminary studies, the basolateral amygdala (BLA) and its input from the prelimbic cortex (PL), two regions involved in emotional regulation, have emerged as key players mediating divergent stress-responses. In Aim 1, we will define the contribution of individual variability in BLA connectivity prior to stress-exposure to BLA functional and structural reorganization during acute stress. In Aim 2, we will assess if individual variability in functional and structural BLA connectivity becomes exacerbated following chronic stress. In Aim 3, we will test the hypothesis that circuit rewiring prior to stress-exposure can alter future stress- responses.

ABSTRACT The devastating effects of the COVID-19 pandemic have reverberated through every aspect of our civilization. While SARS-CoV-2, the viral etiology of COVID-19, seems to spare infants in terms of actual infection, it is currently unknown whether maternal infection during pregnancy will have long-term effects on children born during the pandemic. A variety of prenatal insults, including infections and stress, are well-known to lead to increased risk of affective disorders in both mother and child. With its disproportionate reach into already disadvantaged minority communities, the impact of the COVID-19 pandemic on the dyad is currently unknown and potentially of unprecedented magnitude with enduring consequences for women's mental health and children's developmental origins of health and disease (DOHaD). The COVID-19 Mother Baby Outcome (COMBO) initiative, a large multidisciplinary collaborative, was established at Columbia University Irving Medical Center to follow SARS-CoV-2 exposed laboring mothers and their newborns and compare their long- term health outcomes to case-matched dyads without prenatal exposure. This proposal will follow a subset of the larger COMBO cohort to study socioemotional circuits (fronto-limbic) and behavior (caregiving and bonding) in 100 mother-child dyads from prepartum to 18 months postpartum. The team assembled to carry out this study consists of two provider scientists (Dumitriu, pediatrician and neuroscientist, & Monk, clinical psychologist embedded in Ob/Gyn) and neuroscientist/pediatric neuroimager (Marsh). Using an innovative dyadic approach, olfaction testing, multimodal MRI, wearable in-home physiological recordings, observational mother and child assessments (free play, routine care, Harvard Reactivity and Still Face paradigms), this proposal will test the overarching hypothesis that prenatal SARS-CoV-2 exposure affects (1) mother and (2) child brain and behavior, and (3) demonstrate that the socioemotional health of each member of the mother- child dyad is intrinsically related to that of the other. Detecting COVID-19-related early neurobehavioral effects on mothers and the next generation will provide insights into intervention strategies and contribute significantly to DOHaD and stress science.

ABSTRACT The COVID-19 pandemic has highlighted and exacerbated health disparities related to structural racism and discrimination (SRD), economic marginalization, and other social determinants of health (SDOH). Pregnant and postpartum women face unique social and health vulnerabilities related to the pandemic, including risk for stigma, housing, food, income and employment insecurity, psychological distress, and even mortality ? risks and consequences which are disproportionately significant and adverse for women of color and low socioeconomic status (SES). However, the collision of these multiple intersecting 21st century public health crises have not yet been empirically or rigorously studied for inequities in maternal mental health and severe morbidity. The COVID-19 Mother Baby Outcome (COMBO) initiative is a large multidisciplinary collaborative established at Columbia University Irving Medical Center to follow SARS-CoV-2 exposed laboring mothers and their newborns and compare their long-term health and wellbeing to case-matched dyads without prenatal exposure. The focus of the parent NIMH ?COMBO? R01 MH126531 is to understand the effects of SARS-CoV- 2 on mother-infant brain-behavior functioning in a subset of 100 COMBO-enrolled dyads with and without prenatal SARS-COV-2 infections. Responding to key priorities of NOSI NOT-OD-21-071 and leveraging COMBO?s robust infrastructure, this administrative supplement (PA-20-272) expands the parent R01 to study the independent and interactive effects of SRD/SDOH and SARS-CoV-2 on inequities in maternal mental health, taking advantage of COMBO?s unique setting (first pandemic epicenter) and understudied socially disadvantaged sample (>600 mother-infant dyads enrolled to-date, with 63% mothers identifying as racial/ethnic minority and/or low-SES women). By expanding parent R01 brain imaging, surveys, semi- structured interviews, and electronic health record (EHR) extraction, we will test the overarching hypothesis that SRD/SDOH and SARS-CoV-2 independently and additively increase risk of adverse maternal mental health outcomes, with the magnitude of the negative impact being greatest for women of social disadvantage and the health disparity gap ballooning during ? and persisting post ? the pandemic. Findings will inform patient-centered, multi-level interventions to ameliorate the intersecting epidemics of SRD/SDOH and SARS- CoV-2 and their mental health sequelae for women of social disadvantage in NYC and beyond.