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 创伤性脑损伤是导致神经功能障碍的主要原因，也是最常见的认知功能障碍。 兴奋性缺陷影响前额叶皮质(PFC)依赖的功能，如：注意力，工作记忆，社交能力- 以及精神上的灵活性。尽管患病率很高，但对额叶皮质炎的病理生理学知之甚少。 与这些认知缺陷相关的CAL微回路。我们实验室建立了额叶脑萎缩的小鼠模型。 重述创伤后观察到的人类高级认知功能障碍。小鼠展示 在规则逆转行为中测量的异常的社交能力和心理灵活性，意味着对或- 比额叶皮质(OFC)，尽管没有明显的组织丢失。我的初步数据显示有选择性的弱点 OFC内生长抑素阳性(SOM+)抑制神经元。这些神经元表现出Ac-Ac-1的扩大。 动作电位、适应性增加和兴奋性降低，而固有的激发缺陷则不是 在颅脑损伤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内在的 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，我将 用光遗传学技术分析颅脑损伤对锥体神经元SOM+介导的抑制的影响 在试管中。在目标2中，我将评估脑损伤对前馈和反馈抑制的影响，包括前向抑制和反馈抑制。 SOM+抑制神经元介导的锥体神经元间频率依赖性双突触抑制 罗恩。在目标3中，我将探索体内SOM+神经元的光遗传抑制或刺激如何损害或 分别在脑损伤后规则颠倒学习过程中恢复心理灵活性。这些研究将大大增加- Vance和Will对脑损伤后发生的适应不良回路重组的机械性理解 洞察认知缺陷的治疗目标。 这个导师奖将提供作为一名学术医生的独立职业生涯所需的培训。 整体式。我将通过培训脑外伤动物模型、抑制性神经元生理学、OP--来发展技术专长。 在苏珊娜·罗西博士和维卡斯·索哈尔博士的共同指导下， 来自各自领域的专家，以及我的多学科科学和职业咨询委员会的反馈。我 将通过神经电路、光遗传学、统计学和赠款写作等课程来补充这一培训 参加地方研讨会和国家会议，以促进合作。这些活动将会发展 我成为了研究界中受人尊敬的成员，拥有系统神经科学和神经科学的专业知识- 新病理学。

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,