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

• 批准号: 10445310
• 负责人: Amber L Nolan
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445310
• 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

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.

项目摘要 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功能障碍。 情感缺陷影响前额叶皮层（PFC）依赖的功能，如：注意力，工作记忆，社会行为， 灵活性和精神灵活性。尽管这种流行，很少有人知道的病理生理学额叶皮质- 与这些认知缺陷相关的微电路。我们的实验室开发了一个额叶皮质的小鼠模型- 在人类创伤后观察到的高级认知功能障碍的重演。小鼠表现出 在规则逆转行为中测量的异常社交能力和精神灵活性，意味着对或- 双额叶皮层（OFC），尽管缺乏明显的组织损失。我的初步数据显示 的生长抑素阳性（SOM+）抑制神经元内的OFC。这些神经元表现出AC的扩大- 动作电位，适应率的增加和兴奋性的降低，而内在的放电缺陷不是 在TBI后的其他神经元类型中发现。有了这个提议，我将研究这些缺陷是如何在内在的， 放电通过OFC网络传播以影响突触、微电路和行为功能。在目标1中，我将 使用光遗传学技术分析TBI如何影响锥体神经元中SOM+介导的抑制 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fre- 由SOM+抑制性神经元介导的锥体神经元之间的频率依赖性双突触抑制， 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刺激SOM+神经元。 分别恢复TBI后规则逆转学习过程中的心理灵活性。这些研究将大大提高- 万斯我们的机械理解不良电路重组后发生的创伤性脑损伤， 让我们深入了解认知缺陷的治疗靶点。 这个指导奖将提供一个独立的职业生涯所需的培训，作为一个学术医生科学， 实体主义者我将开发技术专长与培训TBI，抑制性神经元生理学，OP- 在Susanna Rosi博士和Vikaas Sohal博士的共同指导下， 他们的研究来自于各自领域的专家，以及我的多学科科学和职业咨询委员会的反馈。我 我将用神经回路、光遗传学、统计学和拨款写作等课程来补充这一培训，沿着 参加地方研讨会和全国性会议，以促进合作。这些活动将发展 我成为一个受人尊敬的成员，研究界的专业知识，在系统神经科学和神经- 病理学