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(ASD)包括一组典型的严重神经发育障碍 由沟通障碍和社会损害造成。鉴于症状出现在3岁之前，它是 大部分人都同意，神经元功能障碍发生在大脑发育的早期。发育中的大脑显示出 对经验的塑性变化的非凡能力；因此，它的发展最容易受到 环境因素会破坏正常的大脑功能。暴露在早期生活压力中，表现为 大脑发育的关键时期的虐待/忽视表现出行为和心理上的 在动物模型和人类研究中都存在与自闭症症状非常相似的缺陷。因此，这是至关重要的。 确定早期生活应激导致的社会功能障碍的神经机制，以促进 ASD儿童复杂行为缺陷的治疗策略。最近的研究表明，早期 啮齿动物的生活压力会导致长期的大脑变化，类似于自闭症患者的缺陷， 包括前额叶皮质(PFC)的功能障碍和起源于大脑的压力/奖赏相关回路 腹侧被盖区(VTA)已知在PFC中兴奋性突触的形成在最初的 功能神经回路的建立。相反，突触发育受阻会损害PFC功能 并被认为是多种神经发育障碍的病理基础。PFC是密集的 由多巴胺能轴突终末支配，并与可能是 在自闭症等疾病中受到干扰。在这份R21提案中，我们使用了一种新的方法组合，包括 早期社会剥夺应激范式和双光子成像和去功能化来检验我们的假设 生活应激诱导的PFC投射多巴胺神经元的调节失调构成了一种神经机制，通过这种机制 生命早期的不良事件改变了PFC的功能，并可能导致成年后的行为障碍。指导原则 强劲的初步数据，我们将在两个具体目标上检验这一假设：1)定义 早期生活应激后投射PFC的VTA多巴胺神经元。2)确定多巴胺的作用机制- 诱导早期生活应激后前额叶皮质的突触发育。这些研究的结果将进一步推动我们的 了解多巴胺调节大脑发育的独特而详细的机制， 与神经发育障碍的细胞基础的关键相关性。大约每100名儿童中就有1名 在美国是虐待和忽视的受害者。我们预计我们的结果将突出新的途径进入 早期扰动所致神经发育障碍的病理生理学研究 多巴胺信号。

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