Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute and Research Imaging Center, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R82, Canada.
Department of Psychology, Memorial University of Newfoundland, St John's, NL, A1B 3X9, Canada.
Psychopharmacology (Berl). 2019 Jun;236(6):1917-1929. doi: 10.1007/s00213-019-5177-8. Epub 2019 Feb 22.
The ventral tegmental area (VTA) is implicated in the pathophysiology of depression and addictive disorders and is subject to the detrimental effects of stress. Chronic stress may differentially alter the activity pattern of its different subregions along the rostrocaudal and dorsoventral axes, which may relate to the variable behavioral sensitivity to stress mediated by these subregions.
Here, chronic stress-exposed rats were tested for depressive-like reactivity. In situ hybridization for zif268 as a marker of neuronal activation was combined with in vivo single-unit recording of dopaminergic neurons to assess modifications in the activity of the rostral VTA (rVTA) and caudal VTA (cVTA). Changes in the expression of stress-responsive glucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) were also assessed.
Stress-induced anhedonia-like, hyper-anxious, and passive-like responding were associated with reductions in dopaminergic burst activity in the cVTA and an increase in local GABAergic activity, particularly in GABA receptor sensitivity. On the other hand, stress increased single-spiking activity, burst activity, and zif268 mRNA levels in the rVTA, which were associated with increased glutamatergic tonus and enhanced GR and AMPA receptor (AMPAR) expression. rVTA and cVTA activity differentially correlated with sucrose preference and passivity measures.
These data demonstrate that the rVTA and cVTA respond differently to stress and suggest that while cVTA activity may be related to passivity-like states, the activity of both subregions appears to be related to anhedonia and the processing of incentive value. These region-dependent abnormalities indicate the multi-modular composition of the VTA, which could provide multiple substrates for different symptom features.
腹侧被盖区（VTA）与抑郁症和成瘾障碍的病理生理学有关，并且易受压力的不利影响。慢性应激可能会沿着前后轴和背腹轴改变其不同亚区的活动模式，这可能与这些亚区介导的应激下可变的行为敏感性有关。
在这里，对慢性应激暴露的大鼠进行了抑郁样反应测试。原位杂交法检测神经元激活标志物 zif268，并结合伏隔核中多巴胺能神经元的体内单细胞记录，以评估腹侧被盖区（rVTA）和尾侧腹侧被盖区（cVTA）活性的变化。还评估了应激反应性糖皮质激素受体（GR）和脑源性神经营养因子（BDNF）的表达变化。
应激引起的快感缺失样、过度焦虑和被动样反应与 cVTA 中多巴胺能爆发活动的减少以及局部 GABA 能活性的增加有关，尤其是 GABA 受体敏感性。另一方面，应激增加了 rVTA 中的单峰活动、爆发活动和 zif268 mRNA 水平，这与谷氨酸能张力增加以及 GR 和 AMPA 受体（AMPAR）表达增强有关。rVTA 和 cVTA 的活动与蔗糖偏好和被动性测量呈不同相关性。
这些数据表明，rVTA 和 cVTA 对应激的反应不同，表明虽然 cVTA 活动可能与被动样状态有关，但两个亚区的活动似乎都与快感缺失和激励价值的处理有关。这些区域依赖性异常表明 VTA 的多模块组成，这可能为不同的症状特征提供多个底物。
