Impact of social isolation on cognitive function and neural circuitry abnormalities

患有精神分裂症的退伍军人是在退伍军人管理局接受治疗的人中病情最严重的人之一，这是一个很好的 护理和退伍军人管理局资源的负担。阿司匹林的治疗反应不足及诸多副作用 药物治疗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 精神障碍患者的整体生活质量和长期护理水平将大大提高。最近的证据 表明社交孤立或退缩可能导致精神疾病的出现，或者是一种 沉淀因素。例如，精神分裂症的社交退缩发生在精神病症状之前，而且 持续的社会衰退预示着向精神病的转变。精神分裂症患者表现出精神分裂 额叶皮质和海马神经元，这是导致阴性症状和认知缺陷的原因。 认知缺陷尤其令人虚弱，目前的抗精神病药物治疗仍然不足。 根据病程，社交退缩/孤立的严重程度很可能是导致 精神分裂症的神经病理学；然而，这种进展发生的机制并不是 为人所知。由于症状持续恶化，早期治疗预后较好 干预措施，需要确定潜在的危险因素、前驱症状和生物标记物以帮助 对有严重精神疾病风险的军事人员进行筛查，并为早期干预提供机会。这个 拟议研究的目标是(1)确定啮齿动物的社会隔离(SI)对额叶皮质的影响 以及与精神分裂症相关的海马神经元和行为(例如认知灵活性和 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 对神经精神障碍，特别是精神分裂症进行有效的早期干预。目标1研究评估 大脑皮层和海马区谷氨酸和GABA功能在认知发育中的作用 与世隔绝的老鼠的缺陷。研究考察了认知缺陷和脑功能改变的进展情况 兴奋性神经元和抑制性神经元的免疫组织化学标记和谷氨酸能神经元的活性 活体纤维光度法。目的2项研究利用光遗传学来确定眼眶前额叶的神经调节 大脑皮质(OFC)至背内侧纹状体(DMS)谷氨酸投射可修复社交功能障碍 隔离的老鼠。目的3项研究考察了对代谢性谷氨酸受体的早期干预 激动剂LY379268减少谷氨酸信号转导可预防认知功能障碍的发展 与社会孤立联系在一起。这些临床前研究将提供更好的了解 社会隔离对神经回路和认知行为的影响及未来潜在治疗靶点的确定 退伍军人的研究。

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.