Impact of social isolation on cognitive function and neural circuitry abnormalities

社会隔离对认知功能和神经回路异常的影响

• 批准号: 10514594
• 负责人: Susan B Powell
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514594
• 关键词: Address; Adolescence; Agonist; Animal Model; Antipsychotic Agents; Anxiety; Area; Attenuated; Behavior; Behavioral; Biological Markers; Caring; Clinical Research; Cognition; Cognitive; Cognitive deficits; Cognitive remediation; Corpus striatum structure; Data; Deterioration; Development; Early Intervention; Early treatment; Equilibrium; Fiber; Functional disorder; Future; Glutamates; Goals; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Intervention; Long-Term Care; Measures; Mental Depression; Mental disorders; Metabotropic Glutamate Receptors; Military Personnel; Modeling; Neurons; Pathologic Processes; Pathology; Pharmaceutical Preparations; Photometry; Precipitating Factors; Predisposition; Prognosis; Psychoses; Psychotic Disorders; Quality of life; Rattus; Reporting; Research; Resources; Reversal Learning; Risk; Risk Factors; Rodent; Schizophrenia; Severities; Social isolation; Symptoms; Testing; Therapeutic Intervention; Time; Veterans; Weaning; Withdrawal; Work; biomarker identification; clinically relevant; cognitive function; cognitive reappraisal; cost estimate; effective therapy; emerging adult; excitatory neuron; flexibility; frontal lobe; gamma-Aminobutyric Acid; glutamatergic signaling; hospital bed; improved; in vivo; inhibitory neuron; inpatient service; medication compliance; metabotropic glutamate receptor 2; model organism; neural circuit; neurochemistry; neuropathology; neuropsychiatric disorder; neuropsychiatry; neuroregulation; optogenetics; pharmacologic; potential biomarker; preclinical study; predictive marker; prevent; progression marker; severe mental illness; side effect; social; symptom treatment; therapeutic target; therapy development; treatment response

Veterans with schizophrenia are among the most ill of those treated at VA facilities, which presents a great burden on care and VA resources. The inadequacy of treatment response and myriad side effects of current medications makes long-term care and medication adherence difficult. Hence, better treatment of Veterans with psychotic disorders will greatly improve their overall quality of life and long-term care. Recent evidence suggests that social isolation or withdrawal may contribute to the emergence of psychiatric illness, or be a precipitating factor. For example, social withdrawal in schizophrenia occurs prior to symptoms of psychosis and continued social decline predicts conversion to psychosis. Individuals with schizophrenia show disruptions in frontal cortex and hippocampal circuitry, which contribute to negative symptoms and cognitive deficits. Cognitive deficits are particularly debilitating and remain undertreated with current antipsychotic medications. Based on the course of illness it is likely that the severity of social withdrawal/isolation contributes to the neuropathology in schizophrenia; however, the mechanism through which this progression occurs is not known. Because of ongoing deterioration in symptoms and better prognosis with early therapeutic interventions, there is a need to identifying potential risk factors, prodromal symptoms, and biomarkers to help screen military personnel at risk for serious mental illness and provide opportunities for early intervention. The goals of the proposed studies are (1) to determine the impact of social isolation (SI) in rodents on frontal cortex and hippocampal circuitry and behaviors relevant to schizophrenia (e.g. deficits in cognitive flexibility and sensorimotor gating) and (2) identifying biomarkers predictive of susceptibility, and (3) develop more efficacious early interventions for neuropsychiatric disorders, particularly schizophrenia. Aim 1 studies assess the contribution of glutamate and GABA function in cortex and hippocampus to the development of cognitive deficits in socially isolated rats. Studies examine the progression of both cognitive deficits and alterations in markers of excitatory and inhibitory neurons via immunohistochemistry and glutamatergic neuronal activity via in vivo fiber photometry. Aim 2 studies use optogenetics to determine whether neuromodulation of orbitofrontal cortex (OFC) to dorsomedial striatum (DMS) glutamate projections can remediate cognitive deficits in socially isolated rats. Aim 3 studies examine whether early interventions with a metabotropic glutamate receptor agonist, LY379268, to decrease glutamate signaling can prevent the development of cognitive dysfunction associated with social isolation. These preclinical studies will provide a better understanding of the impact of social isolation on neural circuitry and cognitive behavior and identify potential therapeutic targets for future studies in Veterans.

具有精神分裂症的退伍军人是在VA设施中受过治疗的人中最不适的，这表明了很棒的 护理和VA资源负担。治疗反应不足和当前的副作用 药物使长期护理和药物依从性变得困难。因此，更好地对待退伍军人 有了精神病，将大大改善其整体生活质量和长期护理。最近的证据 表明社会隔离或退出可能有助于精神病的出现，或者是 沉淀因子。例如，精神分裂症的社交戒断发生在精神病症状和 持续的社会下降预测转化为精神病。精神分裂症的人在 额叶皮层和海马电路，导致负面症状和认知缺陷。 认知缺陷尤其令人衰弱，并且在当前的抗精神病药物中保持不足。 根据疾病的进程，社会戒断/隔离的严重性可能有助 精神分裂症的神经病理学；但是，这种进展的机制不是 已知。由于症状的持续恶化和早期治疗的预后更好 干预措施，需要识别潜在的危险因素，前驱症状和生物标志物来帮助 筛查有风险严重精神疾病的军事人员，并为早期干预提供了机会。这 拟议的研究的目标是（1）确定啮齿动物对正面皮层的社会隔离（SI）的影响 以及与精神分裂症相关的海马电路和行为（例如，认知灵活性和缺陷 感觉运动门控）和（2）识别可预测易感性的生物标志物，（3）发展更多 神经精神疾病的有效早期干预措施，尤其是精神分裂症。 AIM 1研究评估 谷氨酸和GABA功能在皮质和海马中的贡献对认知的发展 社会孤立的大鼠缺陷。研究检查了认知缺陷和变化的进展 通过免疫组织化学和谷氨酸能神经元活性的兴奋性和抑制性神经元标记 体内纤维光度法。 AIM 2研究使用光遗传学来确定轨道额的神经调节是否是否 皮质（OFC）到背侧纹状体（DMS）谷氨酸望剂投影可以补救社会上的认知缺陷 孤立的大鼠。 AIM 3研究检查是否早期干预代谢性谷氨酸受体 激动剂，LY379268，以减少谷氨酸信号传导可以防止认知功能障碍的发展 与社会隔离有关。这些临床前研究将更好地理解 神经回路和认知行为的社会隔离，并确定未来的潜在治疗靶标 对退伍军人的研究。