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Sex-dependent pain processing circuitry in classical Pavlovian fear conditioning

经典巴甫洛夫恐惧调节中的性别依赖性疼痛处理电路

基本信息

批准号：
10572183
负责人：
REBECCA M SHANSKY
金额：
$ 23.55万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10572183
关键词：
Address Animal Experimentation Animals Anterior Auditory Automobile Driving Behavior Behavioral Biological Assay Cells Clinical Conditioned Reflex Conditioned Stimulus Data Development Disease Disease Marker Disease susceptibility Exposure to FOS gene Female Fiber Freezing Fright Genetic Techniques Goals Immunohistochemistry Individual Individual Differences Investigation Label Lateral Learning Link Maps Measures Mediating Mediator Mental disorders Methodology Modeling Neuroanatomy Neurobiology Neurons Outcome Outcome Measure Pain Phenotype Photometry Play Post-Traumatic Stress Disorders Prefrontal Cortex Prevalence Proxy Rattus Reporting Risk Factors Rodent Role Sex Bias Sex Differences Shock Stimulus Stress Stressful Event Synapses Testing Time Tracer Trauma Viral Withdrawal Woman awake behavioral outcome behavioral response cell type cingulate cortex conditioned fear designer receptors exclusively activated by designer drugs disorder risk experience experimental study foot insight male men midbrain central gray substance neglect neural neurobiological mechanism novel pain model pain processing postsynaptic pre-clinical predict clinical outcome predictive marker presynaptic prevent resilience response sensory integration sensory stimulus sex sexual dimorphism stress resilience translational goal translational neuroscience trauma exposure traumatic event

项目摘要

Project Summary Sex differences in the development and prevalence of mental illnesses are widespread, suggesting that the factors that promote disease risk and resilience may be distinct in men and women. The neurobiological mechanisms underlying this possibility are poorly understood, however, because the vast majority of pre- clinical animal research has been conducted in males. In addition, the behavioral outcome measures used to understand learned fear have focused predominantly on passive, or freezing behavior. We recently identified an active, escape-like conditioned fear response in rats (“darting”) that occurred almost exclusively in females and was associated with an augmented response to the foot shock unconditioned stimulus. A better understanding of potentially sexually dimorphic mechanisms that drive this behavior could open new avenues for treatment of disorders that are more prevalent in women, like PTSD. We have collected preliminary data implicating the neural projections from the anterior cingulate (ACC) to ventrolateral periaqueductal gray (vlPAG) as a potentially novel, sex-dependent circuit that integrates sensory pain information into conditioned and unconditioned fear responses. We propose here to explore sex differences in this circuit at both the structural and functional level. First, we will use a retrograde tracer to perform a quantitative mapping of ACC- vlPAG projections, then we will characterize the post-synaptic vlPAG targets of ACC afferents using trans- synaptic viral approaches combined with fluorescent immunohistochemistry. Next, we will record ACC-vlPAG activity during fear conditioning using fiber photometry to correlate activity to stimulus presentation and behavioral responses, and finally test the causal role this circuit plays in driving darting using circuit-specific chemogenetic techniques. Together, these studies can provide insight into sex-dependent circuit mechanisms underlying individual differences in stress resilience and vulnerability.

项目摘要在精神疾病的发展和流行方面，性别差异很普遍，这表明，促进疾病风险和复原力的因素在男子和妇女中可能不同。的神经生物学然而，这种可能性背后的机制却知之甚少，因为绝大多数的前在雄性动物中进行了临床动物研究。此外，行为结果测量用于了解习得性恐惧主要集中在被动或冻结行为上。我们最近发现大鼠中几乎仅在雌性中发生的一种活跃的、类似逃跑的条件性恐惧反应（“快速移动”）并且与对足部电击无条件刺激的增强反应相关。更好的了解驱动这种行为的潜在性二态性机制可能会开辟新的途径用于治疗女性更常见的疾病，如创伤后应激障碍。我们已经收集了初步数据暗示前扣带回（ACC）到中脑导水管周围灰质腹外侧的神经投射（vlPAG）作为一种潜在的新颖的、性别依赖的回路，其将感觉疼痛信息整合到条件反射中。和无条件的恐惧反应我们建议在这里探讨性别差异，在这两个电路结构和功能水平。首先，我们将使用逆行示踪剂进行ACC的定量映射- vlPAG投射，那么我们将使用trans-vlPAG来表征ACC传入的突触后vlPAG靶。突触病毒方法结合荧光免疫组织化学。接下来，我们将记录ACC-vlPAG 使用纤维光度测定法将活动与刺激呈现相关联，行为反应，最后测试因果关系的作用，这个电路在驱动飞镖使用特定的电路化学遗传学技术总之，这些研究可以提供对性别依赖性回路机制的深入了解潜在的压力恢复力和脆弱性的个体差异。