Chen Linghong, Ke Yuting, Ma Hong, Gao Lei, Zhou Yiying, Zhu Huaqiang, Liu Huifen, Zhang Fuqiang, Zhou Wenhua
Zhejiang Provincial Key Laboratory of Addiction, Ningbo Kangning Hospital, School of Medicine, Ningbo University, Ningbo, China.
Laboratory of Behavioral Neuroscience, Ningbo Kangning Hospital, Ningbo, China.
Front Behav Neurosci. 2021 Feb 18;15:602708. doi: 10.3389/fnbeh.2021.602708. eCollection 2021.
The basal forebrain cholinergic system is involved in cognitive processes, but the role of the basal forebrain cholinergic system in depression is unknown. We investigated whether a lesion of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) produces depressive-like behavior and whether fluoxetine or ketamine inhibits such depressive-like behaviors. Here, in rats, we used 192 IgG-saporin to eliminate the cholinergic neurons of the HDB and evaluated depressive-like behaviors using a preference test for sucrose solution and the forced swimming test. Fourteen days after the injection of 192 IgG-saporin into the HDB, the rats exhibited a significantly fewer number of choline acetyltransferase positive cell density in HDB, accompanied with neuronal loss in the entire hippocampus. Meanwhile, these rats significantly reduced preference for sucrose solution, increased immobility time in the forced swimming test, reduced locomotor activity, decreased context dependent memory in fear conditioning and the time spent in the open arms of the plus-maze. A single dose of ketamine (10 mg/kg) increased the sucrose solution consumption, reduced the immobility time in the forced swim test (FST), and increased locomotor activity compared to vehicle-treated rats. Moreover, in rats that were continuously treated with fluoxetine (10 mg/kg/day for 11 days), the sucrose solution consumption increased, the immobility time in the FST decreased, and locomotor activity increased compared to vehicle-treated rats. The present results demonstrate that a lesion of HDB cholinergic neurons results in depressive-like and anxiety-like behaviors and that antidepressants such as fluoxetine or ketamine, can reverse these depressive-like behaviors but not anxiety-like behaviors, and suggest that a lesion of HDB cholinergic neurons and followed hippocampus damage may be involved in the pathogenesis of depression.
基底前脑胆碱能系统参与认知过程，但该系统在抑郁症中的作用尚不清楚。我们研究了布罗卡斜角带水平支（HDB）胆碱能神经元损伤是否会产生抑郁样行为，以及氟西汀或氯胺酮是否能抑制这种抑郁样行为。在此，我们在大鼠中使用192 IgG-皂草素消除HDB的胆碱能神经元，并通过蔗糖溶液偏好试验和强迫游泳试验评估抑郁样行为。向HDB注射192 IgG-皂草素14天后，大鼠HDB中胆碱乙酰转移酶阳性细胞密度显著减少，同时整个海马体出现神经元丢失。与此同时，这些大鼠对蔗糖溶液的偏好显著降低，强迫游泳试验中的不动时间增加，运动活性降低，恐惧条件反射中的情境依赖性记忆减少，在十字迷宫开放臂中的停留时间减少。与给予赋形剂处理的大鼠相比，单剂量氯胺酮（10 mg/kg）增加了蔗糖溶液消耗量，减少了强迫游泳试验（FST）中的不动时间，并增加了运动活性。此外，与给予赋形剂处理的大鼠相比，连续用氟西汀（10 mg/kg/天，共11天）处理的大鼠蔗糖溶液消耗量增加，FST中的不动时间减少，运动活性增加。目前的结果表明，HDB胆碱能神经元损伤会导致抑郁样和焦虑样行为，而氟西汀或氯胺酮等抗抑郁药可逆转这些抑郁样行为，但不能逆转焦虑样行为，这表明HDB胆碱能神经元损伤及随后的海马体损伤可能参与了抑郁症的发病机制。
