Infralimbic circuit control over a sex-dependent switch in threat responding

边缘下电路控制威胁响应中的性别依赖性开关

基本信息

批准号：
10620853
负责人：
REBECCA M SHANSKY
金额：
$ 44.53万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620853
关键词：
Amygdaloid structure Anatomy Animal Experimentation Aversive Stimulus Behavior Behavioral Clinical Complex Conditioned Reflex Crete Data Development Disease Disease susceptibility Dorsal Equilibrium Exhibits Extinction FOS gene Female Freezing Fright Genetic Goals Immunofluorescence Immunologic Individual Differences Investigation Learning Link Machine Learning Measures Mediating Mediator Mental disorders Modeling Neurobiology Odors Outcome Outcome Measure Pain Pattern Performance Phenotype Post-Traumatic Stress Disorders Pre-Clinical Model Prediction of Response to Therapy Prevalence Rattus Risk Factors Risk Marker Role Sex Differences Shock Stimulus Stress Synapses Techniques Testing Viral Woman Work behavioral outcome behavioral response cohort conditioned fear conditioning coping disorder risk flexibility genetic approach improved insight machine vision male men midbrain central gray substance neural neural circuit neurobiological mechanism novel pharmacologic postsynaptic pre-clinical predictive marker prevent recruit resilience response selective expression sex sexual dimorphism stress resilience success tool translational goal translational neuroscience trauma exposure

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 predictive of improved extinction retention. 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 propose here to define the neural circuitry that drives the selection of conditioned darting vs. freezing, and how that integrates with known extinction circuits to promote extinction retention. Our preliminary data implicate the infralimbic cortex (IL) in this role, and we will use pharmacological, chemogenetic, and viral techniques to probe how descending IL projections to the dorsal and ventral periaqueductal gray (PAG) may mediate a strategic switch between active and passive responding and drive long-term behavioral flexibility through putative collaterals in the amygdala. We will then use sophisticated machine vision and machine learning-based tools to define the broader behavioral repertoires within which darting exists, thereby identifying a multifaceted phenotype that could provide insight into the 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预测了改善的扩展保留率。更好地理解潜在的性二态推动这种行为的机制可以为治疗疾病的新途径开放在女性中普遍存在，例如PTSD。我们在这里建议定义驱动选择的神经回路有条件的飞镖与冰点，以及如何与已知的扩展电路集成以促进扩展保留。我们的初步数据牵涉到该角色的漏皮层（IL），我们将使用药物，化学生成和病毒技术，以探测IL向背侧和腹侧投射的下降螺旋灰色（PAG）可以调节主动反应和被动响应之间的战略切换和驱动长期通过杏仁核中推定的副源性的行为灵活性。然后，我们将使用复杂的机器视觉和基于机器学习的工具来定义更广泛的行为曲目存在飞镖，从而识别一个多方面的表型，该表型可以提供对机制的见解压力弹性和脆弱性的个体差异是基本的。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Darting across space and time: parametric modulators of sex-biased conditioned fear responses.

DOI：
10.1101/lm.053587.122
发表时间：
2022-07
期刊：
LEARNING & MEMORY
影响因子：
2
作者：
Mitchell, Julia R.;Trettel, Sean G.;Li, Anna J.;Wasielewski, Sierra;Huckleberry, Kylie A.;Fanikos, Michaela;Golden, Emily;Laine, Mikaela A.;Shansky, Rebecca M.
通讯作者：
Shansky, Rebecca M.

Sounding the Alarm: Sex Differences in Rat Ultrasonic Vocalizations during Pavlovian Fear Conditioning and Extinction.