Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Behav Brain Res. 2022 Sep 26;434:114028. doi: 10.1016/j.bbr.2022.114028. Epub 2022 Jul 30.
Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including 'response vigor', as a function of present motivational state. In a 'low-motivational state' following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders.
伏隔核（NAc）中的多巴胺（DA）信号通过根据预期的结果价值来调整所付出的努力，从而在一定程度上激发行为。在这里，我们研究了光遗传激活或抑制谷氨酸能腹侧下托（vSub）到 NAc 通路对食物奖励工作动机和运动行为的影响。使用一种将光学刺激与微透析相结合的新型探头，我们发现 ChR2 介导的这些谷氨酸能传入神经的激活增加了 NAc 中的 DA 外排。该方案还通过重新激发杠杆按压选择性地影响了在逐步比率（PR）任务中的觅食动机，但仅在未能获得食物奖励后（即，在 BP 之后）动机降低期间。重要的是，相同的 ChR2 介导的光刺激参数未能影响达到 BP 之前 PR 段中的操作性反应率。相比之下，在达到 BP 之前的剧烈杠杆按压段中，盐敏视蛋白介导的谷氨酸能 vSub-NAc 活性的光遗传学抑制立即并持续抑制了觅食行为。基于这些结果，我们得出结论，谷氨酸能 vSub-NAc 传入神经可以调节觅食行为，包括“反应活力”，作为当前动机状态的函数。在未能获得预期奖励后出现“低动机状态”时，该途径的光遗传刺激可以重新激发杠杆按压行为。反过来，抑制这条谷氨酸能通路似乎会降低动机反应。这些数据可能与包括抑郁症、精神分裂症和物质使用障碍在内的精神疾病中常见的失调动机状态有关。
