Girotti Milena, Boehmer-Cortez Maisie G, Tuite Kathleen, Morilak David A
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Int J Neuropsychopharmacol. 2025 Jul 23;28(7). doi: 10.1093/ijnp/pyaf043.
Motor impulsivity is a symptom shared by several psychiatric disorders. Stress exacerbates impulsivity, but the neurocircuits involved are unknown. We have shown that the orbitofrontal cortex (OFC) is activated during a rodent motor impulsivity task and that chronic unpredictable stress (CUS) increases premature responding. In this study, we examine the role of the OFC projection to dorsal medial striatum (DMS) in motor control, and test whether this pathway mediates the effects of stress on impulsive action.
Motor impulsivity was measured with the 1-choice serial reaction time test (1-CSRTT). To determine if OFC-DMS projections are involved in controlling impulsivity, we used pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated chemogenetic manipulation during 1-CSRTT. We examined stress effects on OFC-DMS neuronal activation using Fos immunohistochemistry. To assess if stress increases impulsivity through OFC-DMS projections, we chemogenetically manipulated the pathway in stressed rats during behavior.
We found OFC-DMS projections inhibit premature responding in a well-mastered task. Stress attenuated OFC neuronal activation, including the OFC-DMS projection neurons, during behavior. However, selectively activating the projection in stressed rats was not sufficient to abolish the stress effects. Finally, the response to stress depended on baseline trait impulsivity. Rats with low trait impulsivity were more vulnerable to stress and showed attenuated activation of OFC-DMS neurons but increased activation of other OFC cell populations.
These results suggest the OFC-DMS pathway modulates impulsivity in concert with other OFC neuronal populations. Furthermore, stress effects are baseline-dependent and affect only low-impulsivity rats, possibly by altering the balance of activation in functionally opposing neuronal populations.
运动冲动是几种精神疾病共有的症状。压力会加剧冲动，但相关的神经回路尚不清楚。我们已经表明，在啮齿动物运动冲动任务中眶额皮质（OFC）会被激活，并且慢性不可预测应激（CUS）会增加过早反应。在本研究中，我们研究了OFC向背内侧纹状体（DMS）的投射在运动控制中的作用，并测试该通路是否介导压力对冲动行为的影响。
用单选择序列反应时测试（1-CSRTT）测量运动冲动。为了确定OFC-DMS投射是否参与控制冲动，我们在1-CSRTT期间使用了由设计药物专门激活的通路特异性设计受体（DREADD）介导的化学遗传学操作。我们使用Fos免疫组织化学检查压力对OFC-DMS神经元激活的影响。为了评估压力是否通过OFC-DMS投射增加冲动性，我们在行为过程中对应激大鼠的该通路进行化学遗传学操作。
我们发现OFC-DMS投射在一项熟练掌握的任务中抑制过早反应。在行为过程中，压力减弱了OFC神经元的激活，包括OFC-DMS投射神经元。然而，在应激大鼠中选择性激活该投射不足以消除压力影响。最后，对应激的反应取决于基线特质冲动性。特质冲动性低的大鼠对应激更敏感，OFC-DMS神经元的激活减弱，但其他OFC细胞群的激活增加。
这些结果表明，OFC-DMS通路与其他OFC神经元群协同调节冲动性。此外，压力影响是基线依赖性的，并且仅影响低冲动性大鼠，可能是通过改变功能相反的神经元群中的激活平衡。
