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Mission Our Lab Currently Focuses on Deducing the Mechanisms by Which

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Mission Our Lab Currently Focuses on Deducing the Mechanisms by Which Mission Our lab currently focuses on deducing the mechanisms by which alcohol use disorders (AUDs) result in maladaptations of brain function, while exploring several therapeutic possibilities. The effects of AUDs include altered inhibitory transmission mediated by GABAA receptors, increased expression of histone deacetylases (HDAC), excessive corticotropin- releasing factor (CRF) signaling, which in turn dysregulates the hypothalamic-pituitary-adrenal (HPA) axis, and excessive proinflammatory neuroimmune signaling through Toll-like receptors (TLRs) in the innate immune system and the brain. Our lab has investigated several measures to combat these maladaptations, and we have shown that certain HDAC inhibitors and neuroactive steroids stand as potential therapies for alcohol addiction and many other stress-related disorders. 1) GABAergic Corticolimbic Circuit Mechanisms of Ethanol Dependence Numerous studies have implicated adaptations in GABA signaling as a major factor in the pathogenesis of alcohol dependence. Despite the established actions of ethanol on inhibitory control and GABAA receptors, little is known about ethanol adaptations in GABAA receptor expression and signaling that occur in the medial prefrontal cortex (mPFC) and central amygdala (CeA), interconnected brain regions that are implicated in the development of alcohol dependence. Previous work has demonstrated significant adaptations in GABAA receptor expression in cerebral cortex, cultured cortical neurons and CeA neurons, however the impact of these changes on local microcircuitry and functional connectivity of the mPFC and CeA remain unclear. The overarching goal of this component is to examine the role of GABAA receptor adaptations in overall circuit function of mPFC and CeA following chronic ethanol exposure using electrophysiological, biochemical, and molecular methods. We will further investigate the impact of histone deacetylases (HDACs) as the underlying mechanism governing the GABAA receptor adaptations to determine the utility of HDAC inhibition as a potential therapeutic target to selectively reverse pathological changes in GABAAreceptor expression and circuit function. We will also examine the effect of chronic ethanol exposure on functional connectivity between mPFC and CeA using resting state functional magnetic resonance imaging (fMRI). Collectively, the proposed studies will delineate molecular and cellular mechanisms of ethanol dependence in local mPFC and amygdalar microcircuits as well as the mPFC projection to amygdalar subregions. These studies may lead to microcircuit-specific molecular targets for reversal of ethanol dependence pathology. GABA signaling is a key factor in the pathogenesis of alcohol dependence. As such, the Morrow lab would like to delineate the role of GABAA receptor adaptations in the functioning of the medial prefrontal cortex and the central amygdala as a result of chronic ethanol exposure. To do so, the lab will use electrophysiological, biochemical, and molecular methods. Additionally, the Morrow lab would like to investigate the role of histone deacetylases in GABAA mechanisms so as to determine whether their inhibition has the potential to reverse pathological changes in GABAAreceptor expression and circuit function. It is important that we investigate how chronic ethanol exposure affects the functional connectivity between the medial prefrontal cortex and the central amygdala. 2) Gene Delivery to Increase Steroidogenesis in Rat Brain Effective new medications are needed for the treatment of alcoholism. Animal and human studies suggest that elevation of neuroactive steroids may address many of the behavioral pathologies associated with alcohol use disorders. The goal of this project is to evaluate the hypotheses that elevated steroidogenesis in the ventral tegmental area will reduce operant ethanol self- administration and the escalation of voluntary drinkingfollowing deprivation in male and female alcohol preferring (P) rats. Endogenous neuroactive steroids will be elevated by viral vector- mediated gene delivery of the biosynthetic enzyme P450scc that converts cholesterol to pregnenolone. Our recent studies demonstrate that vector-mediated delivery of P450scc to the VTA reduces ethanol self-administration and increases local expression of (3a,5a)-3- hydroxypregnan-20-one (3a,5a-THP, allopregnanolone) (Cook et al., 2014). We now propose targeting the vector to specific cell types in the VTA to determine the neurons responsible for these effects. We will examine both vector and behavioral specificity as well as the persistence of effects. The first aim characterizes rAAV2 vectors with neuron specific promoters for delivery of the steroid synthetic enzyme P450scc to increase neurosteroid biosynthesis in the VTA. Vectors are constructed with the non-specific chicken b-actin (CBA) promotor or neuron-specific promotors to evaluate the effects in tyrosine hydroxylase (TH) vs. glutamate (vGLUT1) neurons. The effects of vector transduction on locomotor and anxiety-like behavior will be measured in the open field and elevated plus maze tests. Aim 2 examines whether non-specific or neuron-specific elevation of steroidogenesis in VTA alters operant ethanol or sucrose self-administration. Aim 3 determines if the elevation of steroidogenesis in VTA alters deprivation-induced elevations in ethanol self- administration in P rats. These studies will increase our understanding of the role of VTA neuroactive steroids in alcohol reinforcement, anxiety-like behavior and escalated drinking following ethanol deprivation. This information may contribute to development of a therapeutic strategy for treatment of alcohol use disorders. 3) Mechanisms of Action of Anti-inflammatory Neurosteroids The mechanism of action by which neuroactive steroids ameliorate symptoms in inflammatory conditions such as trauma, multiple sclerosis, alcohol use disorders, traumatic brain injury, depression and seizures are unknown. Each of these disorders involve elevation of toll-like receptor (TLR) signaling resulting in elevated cytokines, chemokines and tissue inflammation. The goal of this project is to evaluate the overall hypothesis that endogenous neurosteroids inhibit various toll-like receptor (TLRs) activation and signaling pathways in native human macrophages and rat brain. We propose to determine the TLR receptors and pathways involved, determine the structure activity requirements, mechanism(s) of action, and sex differences. These studies will define a new mechanism of endogenous neurosteroid actions on neuroimmune signaling with potential to prevent inflammatory disease. This basic research is relevant to many disease models. Aim 1 examines the effects of neurosteroids pregnenolone, progesterone and 3α,5α-THP (0.1-1.0 mM) in TLR2, TLR3, TLR4 and TLR7 activation by their respective agonists in both native human macrophages and rat brain. We examine expression of the respective inflammatory signals as determined by western blotting or ELISA. Aim 2 determines mechanism(s) of neurosteroid inhibition by evaluation of TLR 2, 3, 4, or 7 interactions with MyD88 or TRIF as well as downstream regulation of pathways, PAMPS and DAMPs associated with each TLR. Aim 3 will evaluate whether neurosteroids inhibit various TLRs in specific brain cell types and assess their interactions. These studies will delineate new mechanisms of neuroactive steroid action in the regulation of innate and activated neuroimmune signaling and may lead to the development of new therapeutics for prevention or treatment of many inflammatory diseases. Person Bio Picture Link to publications Giorgia I am from Sardinia, Italy, where I grew up and completed my studies. I https://pu received a Ph.D. in Neuroscience at the University of Cagliari in 2016, bmed.ncbi investigating a rodent model of anxiety and depression. My dissertation, .nlm.nih.g which was centered around research in rats, considered the effect of chronic ov/?term= stress during adolescence (a time of social isolation) on the Hypothalamic- boero+gio Pituitary-Adrenal axis in adulthood. I used in vivo pharmacology and rgia behavioral tests to study the impact of early-life stress on the regulation of https://sch later stress response, focusing on corticotropin-releasing factor and the olar.googl neuroactive steroid allopregnanolone. I joined the Morrow lab in November of e.com/cita 2017 in order to expand my scientific toolkit, and have gotten a chance to tions?user learn stereotaxic surgery, as well as behavioral and molecular biology in a =E3fMQ rodent model of alcohol addiction. Now, I am studying the role of CMAAA allopregnanolone and corticotropin-releasing factor in extrahypothalamic AJ&hl=en areas that are important in substance use disorders. Outside of the lab, I am a wonderful chef and I love to conduct experiments in the kitchen just as I would at my bench (though without the gloves and with fewer chemicals). I also love to travel, discover new places, experience new cultures, and try different foods. To relax, I like to paint and go to concerts. Todd I am from upstate New York, and I attended the Boston University College of https://www.n cbi.nlm.nih.go Engineering, where I studied biomedical engineering. v/myncbi/1p5 After graduating, I spent some time conducting cardiovascular research in cYGE9op8Aq Berlin, Germany. Now that I work in the Morrow lab, I have several /bibliography/ public/ responsibilities: I work as a research specialist, a lab manager, and a laboratory animal coordinator. I assist
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