Andre Der-Avakian, Ph.D. - US grants

DESCRIPTION (provided by applicant): Mood disorders are the leading cause of disability in the U.S. and constitute an immense burden on society. The broad, long-term objectives of this proposal are to understand how environmental stressors may precipitate the development of mood disorders and their behavioral manifestations, such as anhedonia, using a translational approach in both humans and rats. The first aim of this proposal is to determine whether prior life stressors predict the expression of anhedonic symptoms in a clinical sample that is presenting major depressive episodes. This goal will be accomplished by using objective, laboratory-based assessments of both life stress and anhedonia to measure the severity of these factors in bipolar subjects in a depressed state. The development of a rat model that is analogous to the human condition will facilitate the investigation of the neurobiological mechanisms responsible for the development of these disorders. Thus, the second aim is to develop and refine valid preclinical models of depression-like behaviors by using a psychosocial stressor to induce anhedonia, a core symptom of mood disorders. This goal will be accomplished by repeatedly exposing rats to social defeat, then assessing anhedonia using quantitative operational measures of reward and motivation. Finally, loss of volume and activity in certain regions of the medial prefrontal cortex (mPFC) and dysregulated GABA(B) receptor function are associated with mood disorders. Thus, the third aim is to use the preclinical model from the second aim to explore the role of GABA(B) receptors in the mPFC during the expression of these hedonic and motivational deficits. The goal of this aim is to discover novel neurobiological targets for pharmacotherapy. Collectively, this work is consistent with the mission of NIMH, which is to "reduce the burden of mental illness through research on mind, brain, and behavior." PUBLIC HEALTH RELEVANCE: A better understanding of the factors that are involved in the precipitation and expression of mood disorders will aid in the development of more relevant and valid animal models of these disorders. Such models will greatly facilitate 1) our understanding of the underlying neurobiological mechanisms that are involved and 2) the discovery of novel pharmacotherapies that target these mechanisms.

RFA-AA-17-016 states that ?Studies examining alcohol related behaviors in current models of PTSD and potentially in novel animal models of PTSD are sought?. Animal models of PTSD are on the cutting edge of exploiting individual differences to understand mechanisms underlying resilience and susceptibility to psychopathology. Validated models of PTSD recapitulate the prevalence of PTSD in trauma-exposed individuals (~15-30% depending on trauma). We will use 2 well-validated animal models of PTSD, social defeat stress and predator stress, to understand in what biological contexts trauma and subsequent enduring stress response provokes drinking behavior. Predator stress models the enduring effects of a severe single traumatic event while social defeat stress models effects of chronic physical and emotional stress. Both models produce variance in enduring response rates to trauma exposure, (30-50% of animals exhibit prolonged behavioral and neurobiological change), providing etiological validity for PTSD. We propose to examine if two highly translatable markers of trauma-symptom development, sleep disturbance and increased peripheral immune signaling, predict development and/or maintenance of drinking after stress in rodents. This approach addresses the RFA mandate to ?identify biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse.? The goal is to (1) develop robust cross-species biomarkers of long term-trauma effects associated with increased alcohol consumption and (2) identify biomarkers that are predictive for treatment response. We will test the hypothesis that sleep and inflammation abnormalities after trauma predict increased drinking and treatment response. To test this hypothesis we will use a large (N=200/model) prospective, longitudinal design based on clinical research approaches. This strategy enables use of sophisticated statistical models to identify biological predictors of drinking behavior. We will assess clinical relevance by comparing these findings to humans by leveraging our clinical database of a prospective, longitudinal study of trauma in active duty service members (N=2600). This database includes data on trauma, PTSD symptoms, alcohol dependence, sleep and peripheral inflammation both before and after a combat deployment. Once validated, sleep and immune biomarkers identified in our animal models and validated in humans can be used to screen for prophylactic and therapeutic treatment effects of novel pharmacotherapies.

PROJECT SUMMARY Deficits in motivation and effort (i.e., avolition) are defining characteristics of several psychiatric and neurological disorders; have adverse effects on functional recovery, disease chronicity, and morbidity; and lack effective treatments. Research and development of novel treatments for avolition has been hindered by the lack of well-validated functional measures of target engagement that are similar across human and non-human model species, possibly due to the use of different approaches in laboratory animals and humans that lack translation. Importantly, neurophysiological recordings enable direct observation of synchronized neural activity with high (ms) temporal resolution and are argued to have higher validity for cross-species comparison of the effects of drugs on behavior compared to cellular or molecular measures. In this regard, and in line with RFA- MH-19-235 and the NIMH RDoC initiative, the current application proposes to optimize, evaluate, and mechanistically test neurophysiological and behavioral assays of physical and cognitive effort in a manner that will enable preclinical pipelines to develop novel and efficacious treatments for avolition in clinical populations In Aim 1, we will optimize rodent behavioral assessments of physical and cognitive effort using the physical effort task (PET) task and cognitive effort task (CET), respectively. Combined behavioral and electrophysiological evaluation will determine the neural substrates of physical and cognitive effortful decision making. In Aim 2, we will validate these models using pharmacological challenges (modafinil and tolcapone) to potentiate the behavioral and neurophysiological correlates of effortful decision making. Finally, in Aim 3, we will investigate the mesostriatal and mesocortical mechanisms underlying drug-induced potentiation of effortful decision making using a combination of optogenetic manipulations in genetically defined neurons, electrophysiological recording, and behavioral pharmacology. Collectively, this application will delineate the precise contributions of mesolimbic and mesocortical dopamine circuits in the mediation of different forms of effortful behavior, identifying neural substrates that can be targeted to ameliorate impairments in motivation that are core to several psychiatric and neurological disorders.