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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.

项目摘要精神疾病的发展和流行的性别差异是普遍存在的，这表明在男性和女性中，促进疾病风险和韧性的因素可能是不同的。神经生物学然而，人们对这种可能性背后的机制知之甚少，因为绝大多数前已经在雄性身上进行了临床动物研究。此外，行为结果衡量标准用于了解习得性恐惧主要集中在被动或僵硬的行为上。我们最近确认了一种几乎只发生在雌性大鼠身上的主动的、逃逸样的条件性恐惧反应(“跳跃”) 并与对足部电击无条件刺激的增强反应有关。更好的了解驱动这种行为的潜在的性二态机制可能会开辟新的途径用于治疗在女性中更为普遍的疾病，如创伤后应激障碍。我们已经收集了初步数据前扣带回向中脑导水管周围灰质腹外侧区的投射 (VlPAG)作为一种潜在的新颖的、性别依赖的回路，它将感觉疼痛信息整合到条件化以及无条件的恐惧反应。我们建议在这里探讨这条赛道中的性别差异结构和功能层面。首先，我们将使用逆行示踪剂对ACC- VlPAG投射，然后我们将使用反式-TRANSPESS来表征ACC传入的突触后vlPAG靶点。突触病毒结合荧光免疫组织化学方法。接下来，我们将录制ACC-vlPAG 恐惧条件反射期间的活动使用纤维光度法将活动与刺激呈现和行为反应，最后测试这个电路在使用特定电路驱动飞镖时所起的因果作用化学发生技术。总之，这些研究可以为性别相关的回路机制提供洞察力在压力韧性和脆弱性方面存在潜在的个体差异。