Dissecting neural circuits underlying early life stress-induced PFC dysfunction

剖析早期生活压力引起的 PFC 功能障碍的神经回路

• 批准号: 10381735
• 负责人: Won Chan Oh
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381735
• 关键词: Address; Adult; Adverse event; Age; Animal Model; Animals; Axon; Behavior; Behavior Disorders; Behavioral; Brain; Calcium Signaling; Cells; Characteristics; Child; Chronic stress; Communication; Complex; Data; Dendrites; Dendritic Spines; Development; Disease; Dopamine; Dopamine Receptor; Electrophysiology (science); Environmental Risk Factor; Equilibrium; Event; Excitatory Synapse; Exhibits; Exposure to; Functional disorder; Glutamates; Goals; Growth; Human; Image; Impairment; Investigation; Life; Link; Mediating; Methods; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurotransmitters; Outcome; Pathology; Patients; Pharmacology; Play; Prefrontal Cortex; Presynaptic Terminals; Property; Psychopathology; Receptor Activation; Receptor Signaling; Research; Rewards; Risk; Rodent; Role; Signal Transduction; Social Behavior; Stress; Symptoms; Synapses; Synaptic plasticity; Testing; Time; Ventral Tegmental Area; Vertebral column; Work; abuse neglect; abuse victim; autism spectrum disorder; autistic; autistic children; cognitive process; critical period; density; dopaminergic neuron; early experience; early life adversity; early life stress; emotional functioning; experience; hippocampal pyramidal neuron; improved; in vivo; in vivo calcium imaging; in vivo imaging; infancy; maltreated children; neural circuit; neurobiological mechanism; neuromechanism; neuronal excitability; neurophysiology; novel; preference; presynaptic; psychologic; relating to nervous system; response; social; social deficits; social deprivation; synaptic function; synaptogenesis; therapy development; treatment strategy; two-photon

Project Summary Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to the environmental factors that can derail normal brain function. Exposure to early life stress in the form of abuse/neglect during a critical period of brain development has demonstrated behavioral and psychological deficits that closely resemble autistic symptoms in both animal models and human studies. Thus, it is essential to identify the neural mechanisms underlying early life stress-induced social dysfunction for the development of treatment strategies for complex behavioral deficits in children with ASD. Recent studies have shown that early life stress in rodents induces long-lasting brain alterations similar to the deficits seen in patients with ASDs, including dysfunctions in the prefrontal cortex (PFC) and the stress/reward-related circuitry originating in the ventral tegmental area (VTA). Formation of excitatory synapses in the PFC is known to be essential for the initial establishment of functional neural circuits. Conversely, disrupted synapse development impairs PFC function and is thought to underlie the pathology of multiple neurodevelopmental disorders. The PFC is densely innervated by dopaminergic axon terminals and associated with higher cognitive processes that may be disrupted in illnesses such as ASDs. In this R21 proposal, we utilize a novel combination of methods including early social deprivation stress paradigm and two-photon imaging and uncaging to test our hypothesis that early life stress-induced dysregulation of PFC-projecting dopamine neurons constitutes a neural mechanism by which adverse events early in life alter PFC function and may cause behavioral dysfunction in adulthood. Guided by strong preliminary data, we will examine this hypothesis in two specific aims: 1) Define functional changes in PFC-projecting VTA dopamine neurons following early life stress. 2) Determine mechanisms of dopamine- induced synapse development in the PFC following early life stress. Results from these studies will further our understanding of the unique and detailed mechanisms by which dopamine regulates brain development, with critical relevance to cellular underpinnings of neurodevelopmental disorders. Approximately 1 per 100 children in the U.S. is a victim of abuse and neglect. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying neurodevelopmental disorders resulting from early perturbation of dopamine signaling.

项目摘要 自闭症谱系障碍（ASDS）包括一组严重的神经发育障碍 通过沟通不足和社会障碍。鉴于症状发作到3岁时发生，这是 在很大程度上同意，在早期大脑发育过程中会出现神经元功能障碍。一个发育的大脑显示 塑料变化的显着能力响应经验；因此，它的发展最容易受到影响 可能使正常脑功能脱轨的环境因素。暴露于早期生活压力的形式 在大脑发育的关键时期，虐待/忽视表明了行为和心理 在动物模型和人类研究中都非常类似于自闭症症状的缺陷。因此，这是必不可少的 确定早期生活压力引起的社会功能障碍的神经机制以发展 ASD儿童的复杂行为缺陷的治疗策略。最近的研究表明，早期 啮齿动物的生命胁迫会引起长期的大脑改变，类似于ASDS患者的缺陷， 包括前额叶皮层（PFC）中的功能障碍以及源自应力/奖励相关的电路 腹侧对段区域（VTA）。已知PFC中兴奋性突触的形成对于初始 建立功能性神经回路。相反，突触开发破坏了PFC功能 并被认为是多种神经发育障碍的病理。 PFC密集 由多巴胺能轴突终端支配并与可能是较高的认知过程有关 被ASD等疾病中断。在此R21提案中，我们利用了包括 早期的社会剥夺压力范式和两光子成像和脉冲成像，以检验我们早期的假设 生命应力引起的PFC投射多巴胺神经元的失调构成了一种神经机制 生命早期的不良事件会改变PFC功能，并可能导致成年后的行为功能障碍。指导 强大的初步数据，我们将以两个具体的目的检查这一假设：1）定义功能变化 PFC投射VTA多巴胺神经元在早期胁迫之后。 2）确定多巴胺的机制 在生命早期压力之后，PFC诱导突触发育。这些研究的结果将进一步 了解多巴胺可以调节大脑发育的独特和详细机制， 与神经发育障碍的细胞基础的关键相关性。每100名儿童大约有1个 在美国，是虐待和忽视的受害者。我们希望我们的结果将重点介绍新的途径 对早期扰动引起的潜在神经发育障碍的病理生理学的研究 多巴胺信号传导。

项目成果

MDGA1 negatively regulates amyloid precursor protein-mediated synapse inhibition in the hippocampus.

• DOI: 10.1073/pnas.2115326119
• 发表时间: 2022-01-25
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Kim J;Kim S;Kim H;Hwang IW;Bae S;Karki S;Kim D;Ogelman R;Bang G;Kim JY;Kajander T;Um JW;Oh WC;Ko J
• 通讯作者: Ko J

Induction of input-specific spine shrinkage on dendrites of rodent hippocampal CA1 neurons using two-photon glutamate uncaging.

• DOI: 10.1016/j.xpro.2021.100996
• 发表时间: 2021-12-17
• 期刊: STAR protocols
• 作者: Jang J;Anisimova M;Oh WC;Zito K
• 通讯作者: Zito K

Fetal cannabidiol (CBD) exposure alters thermal pain sensitivity, problem-solving, and prefrontal cortex excitability.

• DOI: 10.1038/s41380-023-02130-y
• 发表时间: 2023-08
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Swenson, Karli S.;Gomez Wulschner, Luis E.;Hoelscher, Victoria M.;Folts, Lillian;Korth, Kamryn M.;Oh, Won Chan;Bates, Emily Anne
• 通讯作者: Bates, Emily Anne