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.

项目摘要精神疾病发展和患病率的性别差异很普遍，这表明促进疾病风险和韧性的因素在男性和女性中可能是不同的。神经生物学但是，这种可能性的机制知之甚少，因为绝大多数在男性中进行了临床动物研究。另外，行为结果措施曾经了解学习的恐惧主要集中在被动或冻结行为上。我们最近确定了在女性中几乎完全发生的大鼠（“飞镖”）中，一种活跃的，逃脱的条件恐惧反应并与对脚部无条件刺激的增强反应有关。更好了解推动这种行为的潜在性二态机制可能打开新途径用于治疗在PTSD等女性中更普遍的疾病。我们收集了初步数据隐式神经项目从前扣带回（ACC）到腹外侧灰色（VLPAG）作为一种潜在的新型，性依赖性电路，将感觉疼痛信息整合到条件和无条件的恐惧反应。我们在这里提议在这两个电路中探索性别差异结构和功能水平。首先，我们将使用逆行示踪剂进行ACC的定量映射 VLPAG项目，然后我们将使用反式 - 突触病毒方法结合荧光免疫组织化学。接下来，我们将录制ACC-VLPAG 使用纤维光度法在恐惧调节过程中的活动将活性与刺激表现相关联和行为反应，并最终测试该电路使用电路特异性驱动飞镖的因果作用化学发生技术。这些研究共同可以洞悉性别依赖性电路机制压力弹性和脆弱性的个体差异是基本的。