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.

患有精神分裂症的退伍军人是在退伍军人管理局设施接受治疗的患者中病情最严重的人之一，这提供了一个很好的机会 护理和退伍军人管理局资源的负担。当前治疗反应的不足和无数的副作用 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 精神障碍患者将大大改善他们的整体生活质量和长期护理。最近的证据 表明社会孤立或退缩可能导致精神疾病的出现，或者是一种 促发因素。例如，精神分裂症的社交退缩发生在精神病症状和症状之前。 持续的社会衰退预示着会转变为精神病。精神分裂症患者表现出精神分裂 额叶皮层和海马回路，导致阴性症状和认知缺陷。 认知缺陷尤其使人衰弱，并且目前的抗精神病药物治疗仍然不足。 根据病程，社交退缩/孤立的严重程度可能会导致 精神分裂症的神经病理学；然而，这种进展发生的机制并不 已知。由于症状持续恶化以及早期治疗的更好预后 干预措施时，需要确定潜在的危险因素、前驱症状和生物标志物来帮助 对有严重精神疾病风险的军事人员进行筛查，并提供早期干预的机会。这 拟议研究的目标是（1）确定啮齿类动物的社会隔离（SI）对额叶皮层的影响 以及与精神分裂症相关的海马回路和行为（例如认知灵活性和行为能力的缺陷） 感觉运动门控）和（2）识别预测易感性的生物标志物，以及（3）开发更多 对神经精神疾病，特别是精神分裂症进行有效的早期干预。目标 1 研究评估 皮层和海马谷氨酸和 GABA 功能对认知发展的贡献 社会孤立大鼠的缺陷。研究考察了认知缺陷和认知改变的进展情况 通过免疫组织化学检测兴奋性和抑制性神经元的标记物，通过谷氨酸能神经元活性 体内光纤光度测定。目标 2 研究使用光遗传学来确定眶额神经调节是否 皮质（OFC）到背内侧纹状体（DMS）的谷氨酸投射可以修复社交认知缺陷 孤立的老鼠。目标 3 研究检验代谢型谷氨酸受体的早期干预是否有效 激动剂 LY379268，减少谷氨酸信号传导可预防认知功能障碍的发展 与社会孤立有关。这些临床前研究将有助于更好地了解 社会隔离对神经回路和认知行为的影响，并确定未来潜在的治疗目标 退伍军人研究。