Cortical Somatostatin Interneuron Dysfunction after Trauma: Role in Cognitive Flexibility

创伤后皮质生长抑素中间神经元功能障碍：在认知灵活性中的作用

基本信息

批准号：
10023960
负责人：
Amber L Nolan
金额：
$ 3.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023960
关键词：
Action Potentials Advisory Committees Affect Animal Model Animals Anxiety Attention Award Behavior Behavioral Brain Cells Chronic Cognition Cognitive Cognitive deficits Collaborations Communities Contusions Country Data Disease Evoked Potentials Exhibits Feedback Fostering Frequencies Functional disorder Goals Grant Halorhodopsins Human Impaired cognition Impairment In Vitro Injury Interneurons Measures Mediating Memory Mentors Modeling Mus Neurologic Neurologic Deficit Neurons Neurosciences Output Patients Physicians Physiology Positioning Attribute Prefrontal Cortex Prevalence Psyche structure Recurrence Research Reversal Learning Role Schizophrenia Scientist Shapes Short-Term Memory Slice Social Behavior Somatostatin Specificity Synapses System Technical Expertise Techniques Testing Thalamic structure Therapeutic Time Tissues Training Transgenic Mice Translating Trauma Traumatic Brain Injury Work Writing career clinically relevant cognitive testing design disability early life stress experimental study flexibility frontal lobe hippocampal pyramidal neuron in vivo inhibitory neuron insight meetings member mouse model multidisciplinary neural circuit neuronal circuitry neuropathology new therapeutic target optogenetics patch clamp recruit response social statistics therapeutic target treatment strategy

项目摘要

Project Summary Traumatic brain injury (TBI) is a leading cause of neurologic disability and the most common associated cogni- tive deficits affec prefrontal cortex (PFC)-dependent functions such as: attention, working memory, social be- havior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology of frontal corti- cal microcircuits associated with these cognitive deficits. Our lab developed a mouse model of frontal lobe con- tusion that recapitulates higher order cognitive dysfunction observed in humans after trauma. Mice exhibit aberrant sociability and mental flexibility measured in a rule reversal behavior, implying damage to the or- bitofrontal cortex (OFC) despite a lack of overt tissue loss. My preliminary data indicate selective vulnerability of somatostatin-positive (SOM+) inhibitory neurons within the OFC. These neurons exhibit widening of the ac- tion potential, an increase in adaptation rate and a decrease in excitability, while intrinsic firing deficits are not identified in other neuronal types after TBI. With this proposal, I will investigate how these deficits in intrinsic firing propagate through the OFC network to affect synaptic, microcircuit and behavioral function. In aim 1, I will use optogenetic techniques to analyze how SOM+-mediated inhibition in pyramidal neurons is affected by TBI in vitro. In aim 2, I will evaluate the impact of TBI on feedforward and feedback inhibition, including the fre- quency-dependent disynaptic inhibition between pyramidal neurons that is mediated by SOM+ inhibitory neu- rons. In aim 3, I will explore how optogenetic inhibition or stimulation of SOM+ neurons in vivo can impair or restore mental flexibility during rule reversal learning after TBI, respectively. These studies will significantly ad- vance our mechanistic understanding of the maladaptive circuit reorganization that occurs after TBI and will give insight into therapeutic targets for cognitive deficits. This mentored award will provide the training needed for an independent career as an academic physician sci- entist. I will develop technical expertise with training in animal models of TBI, inhibitory neuron physiology, op- togenetics, and cognitive testing under the mutual direction of Drs. Susanna Rosi and Vikaas Sohal, leading experts in their fields, and with feedback from my multidisciplinary scientific and career advisory committee. I will supplement this training with coursework in neural circuits, optogenetics, statistics and grant writing, along with attendance at local seminars and national meetings to foster collaborations. These activities will develop me into a respected member of the research community with expertise in systems neuroscience and neu- ropathology.

项目概要创伤性脑损伤（TBI）是神经功能障碍的主要原因，也是最常见的相关认知障碍主动性缺陷会影响前额皮质（PFC）依赖性功能，例如：注意力、工作记忆、社交能力行为和心理灵活性。尽管这种现象很普遍，但人们对额叶皮质的病理生理学知之甚少。与这些认知缺陷相关的钙微电路。我们的实验室开发了一种小鼠额叶模型概括了在人类创伤后观察到的高阶认知功能障碍。老鼠展在规则逆转行为中衡量的异常社交能力和心理灵活性，意味着对或- 尽管没有明显的组织损失，但双额皮质（OFC）。我的初步数据表明选择性脆弱性 OFC 内生长抑素阳性 (SOM+) 抑制性神经元的数量。这些神经元表现出交流的扩大化潜力，适应率增加和兴奋性下降，而内在的放电缺陷则不会在 TBI 后的其他神经元类型中发现。通过这个提案，我将研究这些内在的缺陷是如何产生的。放电通过 OFC 网络传播，影响突触、微电路和行为功能。在目标1中，我会使用光遗传学技术分析 SOM+ 介导的锥体神经元抑制如何受到 TBI 的影响体外。在目标 2 中，我将评估 TBI 对前馈和反馈抑制的影响，包括频率锥体神经元之间的频率依赖性突触抑制，由 SOM+ 抑制性神经元介导罗恩。在目标 3 中，我将探索体内 SOM+ 神经元的光遗传学抑制或刺激如何损害或分别在 TBI 后的规则逆转学习过程中恢复心理灵活性。这些研究将显着促进提高我们对 TBI 后发生的适应不良回路重组的机制理解，并将深入了解认知缺陷的治疗目标。这个指导奖项将提供作为一名学术医师、科学工作者的独立职业所需的培训。实体。我将通过 TBI 动物模型、抑制性神经元生理学、op- 在博士的共同指导下进行个体遗传学和认知测试。苏珊娜·罗西 (Susanna Rosi) 和维卡斯·索哈尔 (Vikaas Sohal) 领衔各领域的专家，以及我的多学科科学和职业咨询委员会的反馈。我将通过神经回路、光遗传学、统计学和资助写作等课程来补充培训参加当地研讨会和国家会议以促进合作。这些活动将开展我成为研究界一位受人尊敬的成员，拥有系统神经科学和神经科学方面的专业知识病理学。