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: 10665649
• 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/10665649
• 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; experience; experimental study; flexibility; frontal lobe; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; meetings; member; mouse model; multidisciplinary; neural circuit; neuronal circuitry; neuronal excitability; neuropathology; new therapeutic target; optogenetics; patch clamp; recruit; response; 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）是神经疾病的主要原因，也是最常见的相关认知 Tive Adficits AFFEC前额叶皮层（PFC）依赖性功能，例如：注意，工作记忆，社会 Havior和精神灵活性。尽管存在这种流行，但对额叶皮质的病理生理知之甚少。 与这些认知缺陷相关的CAL微电路。我们的实验室开发了额叶的鼠标模型 概括了创伤后人类观察到的高阶认知功能障碍的隆起。小鼠展出 在规则逆转行为中衡量的异常社交性和心理灵活性，这意味着对OR-的损害 尽管缺乏明显的组织损失，但Bitofrontal皮层（OFC）。我的初步数据表示选择性脆弱性 OFC内的生长抑素阳性（SOM+）抑制性神经元这些神经元表现出AC-的扩大 潜在的潜力，适应率的增加和兴奋性降低，而内在的触发不足不是 在TBI之后，在其他神经元类型中鉴定。通过此提案，我将研究这些固有缺陷如何 通过OFC网络发射传播，以影响突触，微电路和行为功能。在AIM 1中，我会 使用光遗传技术分析SOM+介导的锥体神经元中如何受到TBI的影响 体外。在AIM 2中，我将评估TBI对饲喂和反馈抑制的影响，包括频率 由SOM+抑制性neu-介导的锥体神经元之间的抑制性抑制性抑制 罗恩斯。在AIM 3中，我将探讨如何在体内对SOM+神经元的光遗传学抑制或刺激如何损害或 分别在TBI之后分别恢复规则逆转学习期间的心理灵活性。这些研究将显着 万斯我们对TBI之后发生的不良适应电路的重组的机械理解 深入了解认知缺陷的治疗靶标。 该指导奖将为独立职业提供学术医师Sci-提供所需的培训 插入。我将在TBI，抑制性神经元生理学的动物模型中培训技术专长 在DRS的相互指导下进行的tweenetics和认知测试。 Susanna Rosi和Vikaas Sohal，领导 在我的多学科科学和职业咨询委员会的反馈下，他们的领域专家。我 将通过神经回路，光遗传学，统计和赠款写作的课程来补充这种培训 参加当地研讨会和全国会议，以促进合作。这些活动将发展 我成为具有系统神经科学和neu-的专业知识的研究社区的受人尊敬的成员 疾病学。

项目成果

Hyperpolarized 13C metabolic imaging detects long-lasting metabolic alterations following mild repetitive traumatic brain injury.

超极化 13C 代谢成像可检测轻度重复性脑外伤后持久的代谢变化。

• DOI: 10.21203/rs.3.rs-3166656/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Chaumeil,Myriam;Guglielmetti,Caroline;Qiao,Kai;Tiret,Brice;Ozen,Mustafa;Krukowski,Karen;Nolan,Amber;Paladini,MariaSerena;Lopez,Carlos;Rosi,Susanna
• 通讯作者: Rosi,Susanna

Tractography-Pathology Correlations in Traumatic Brain Injury: A TRACK-TBI Study.

创伤性脑损伤中的纤维束成像-病理学相关性：TRACK-TBI 研究。

• DOI: 10.1089/neu.2020.7373
• 发表时间: 2021
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Nolan,AmberL;Petersen,Cathrine;Iacono,Diego;MacDonald,ChristineL;Mukherjee,Pratik;vanderKouwe,Andre;Jain,Sonia;Stevens,Allison;Diamond,BramR;Wang,Ruopeng;Markowitz,AmyJ;Fischl,Bruce;Perl,DanielP;Manley,GeoffreyT;Keene,
• 通讯作者: Keene,