Project 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder

项目 4：易患酒精使用障碍和创伤后应激障碍的啮齿动物模型促进趋同的行为和神经生物学适应

• 批准号: 10526646
• 负责人: JEFFREY L WEINER
• 金额: $ 32.87万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526646
• 关键词: Address; Adolescent; Alcohol consumption; Amygdaloid structure; Animal Model; Animals; Anxiety; Architecture; Behavior; Behavioral; Clinical; Corpus striatum structure; Development; Diagnosis; Disease; Dopamine; Electroencephalography; Electrophysiology (science); Epidemiology; Ethanol; Extinction; Female; Fiber; Fright; Glutamates; Goals; Hippocampus; Individual; Knowledge; Life; Link; Measures; Mediating; Mental Depression; Modeling; Motivation; Neurobiology; Nucleus Accumbens; Opioid Antagonist; Pathway interactions; Phenotype; Photometry; Play; Post-Traumatic Stress Disorders; Procedures; Publishing; Rattus; Risk Factors; Rodent; Rodent Model; Role; Self Administration; Sleep; Sleep Architecture; Sleep disturbances; Social isolation; Stress; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Vulnerable Populations; alcohol research; alcohol risk; alcohol use disorder; anxiety-like behavior; behavioral phenotyping; behavioral study; drinking; early childhood; efficacy evaluation; forest; human subject; in vivo; innovation; kappa opioid receptors; maladaptive behavior; male; multidisciplinary; negative affect; neural; neuroadaptation; neurochemistry; neuromechanism; neuropsychiatric disorder; optogenetics; pharmacologic; receptor function; resilience; sex; stressor; symptomatology; translational study; wireless

PROJECT 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder Jeff Weiner, Sara Jones, Robert Gould, Eva Bach, and Lindsey Kuiper Individuals diagnosed with PTSD are up to four times more likely to develop alcohol use disorder (AUD) and most evidence suggests that PTSD usually precedes the development of AUD. Anxiety, depression, and sleep disruptions are significant risk factors for AUD as well as major symptoms of both disorders. Despite the clinical importance of this problem, the neural mechanisms responsible for the frequent co-occurance of these disorders are not fully understood. The overarching goal of this project is to employ a rodent early life social isolation (eSI) model of AUD vulnerability and a PTSD model, single prolonged stress, to test the hypothesis that both stressors promote similar behavioral phenotypes that are mediated by convergent neural adaptations. These studies will also determine if the “double hit” of eSI + SPS exacerbates these maladaptive changes and test a therapeutic intervention to mitigate these effects. Behavioral studies will focus on measures of anxiety- like behavior and negative affect, deficits in fear extinction, and ethanol self-administration. Neurobiological studies will test the innovative hypothesis that these models strengthen a glutamatergic projection from the ventral subiculum (vSub) to the nucleus accumbens shell (NAc). Extensive evidence suggests that stress enhances vSub-NAc activity and that stimulation of this pathway modulates many AUD/PTSD-related behaviors (e.g. motivation, negative affect) and indirectly increases accumbal dopamine (DA) release. Although this circuit is thought to play an integral role in many neuropsychiatric disorders, it has been largely ignored in the AUD field. To address this knowledge gap, multidisciplinary in vivo and ex vivo approaches will be employed to test the hypotheses that eSI + SPS strengthens vSub-NAc shell synaptic excitation and alters NAc shell DA release dynamics, in part via an increase in kappa opioid receptor function. These studies will also determine if the double hit increases ethanol-stimulated NAc DA release and use closed loop in vivo optogenetics and pharmacological approaches to determine if these synaptic adaptations play a causal role in the ethanol drinking phenotypes promoted by these models. A final aim will use longitudinal wireless EEG to determine if eSI + SPS and ethanol drinking disrupt sleep architecture and duration and whether these changes can be mitigated by a kappa opioid receptor antagonist. Collectively, these studies will provide the first detailed characterization of the effects of eSI and SPS on critical behavioral phenotypes associated with AUD vulnerability and PTSD. Complementary neurobiological studies may identify a relatively uncharacterized hippocamapal-striatal circuitry that contributes to these maladaptive behaviors.

项目4：由啮齿类动物模型促进的趋同行为和神经生物学适应