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事务部设施中治疗的最严重的人之一， 负担护理和VA资源。目前的治疗反应不足和无数的副作用， 药物使得长期护理和药物依从性变得困难。更好地对待退伍军人 精神病患者的治疗将大大改善他们的整体生活质量和长期护理。最近的证据 这表明，社会孤立或退缩可能有助于精神疾病的出现，或者是一个 促发因素例如，精神分裂症的社交退缩发生在精神病症状之前， 社会地位的持续下降预示着会转变为精神病。患有精神分裂症的人表现出 额叶皮层和海马回路，这有助于阴性症状和认知缺陷。 认知缺陷特别使人衰弱，并且目前的抗精神病药物治疗不足。 根据病程，社交退缩/孤立的严重程度可能导致 精神分裂症的神经病理学;然而，这种进展发生的机制并不清楚。 知道的由于持续恶化的症状和更好的预后与早期治疗 干预措施，有必要确定潜在的风险因素，前驱症状和生物标志物，以帮助 筛查有严重精神疾病风险的军事人员，并提供早期干预的机会。的 本研究的目的是：（1）确定啮齿类动物社会隔离（SI）对额叶皮层的影响 以及与精神分裂症相关的海马电路和行为（例如认知灵活性的缺陷， 感觉运动门控）和（2）鉴定预测易感性的生物标志物，和（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功能在认知发育中的作用 缺乏社交孤立的老鼠。研究检查了认知缺陷和改变的进展， 兴奋性和抑制性神经元的标记物，通过免疫组织化学， 体内纤维光度法。目的2研究使用光遗传学来确定是否眶额神经调节 皮层（OFC）到背内侧纹状体（DMS）的谷氨酸投射可以修复社交中的认知缺陷， 孤立的老鼠目的3研究是否早期干预与代谢型谷氨酸受体 激动剂LY 379268降低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靶点 研究退伍军人。

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.