嗅觉环路对腹侧背盖区-伏隔核奖励通路的调控在抑郁样行为中的作用机理研究

There is a close relationship between olfactory and emotion, the brain areas processing olfactory and emotion are largely overlapped. Olfactory dysfunction is found in many depressive patients. However, the mechanisms under this are unclear. Our recent study demonstrated that thansgenetic cnga2-/Y mice showed anxiety-like and depressive-like behaviors, and the olfactory piriform cortex projects directly the the ventral tegmental area (VTA). The mid brain reward system is a hot-point in depression researches these year, and the dysfunction of VTA and NAc are related with depressive behaviour, which indicating a modulation effect of olfactory system on VTA-NAc circuit. However, the mechanisms under this are unclear. Here, we will firstly using behavioral and molecular biological method to study the relationships between olfactory deficiency and depression, and to found out whether olfactory deficiency is a cause or result; secondly, the neuronal projection between olfactory system and the reward system will be studied using transsynaptic tracing using pseudrabies virus (PRV); finally, the modulatory effects of olfactory system on the VTA-NAc circuit will be included. Local field potential will be tested simultaneously in piriform cortex and the reward system. In addition, LFP of the VTA-NAc circuit will be tested after olfactory deficiency or olfactory excitation, and the LFP of the piriform cortex will be tested after VTA or NAc inhibition. This study would declare the relationships between olfactory and reward system and the modulation of these two systems in depression, which will establish novel approaches to modeling key symptoms of depression in animals, and could enable the development of antidepressant medications with fundamentally new mechanisms of action.

嗅觉与情绪密切相关，其大脑功能区广泛重叠。临床实践发现抑郁症患者常伴有嗅觉损伤，但二者之间的因果关系及调控机理并不清楚。我们前期研究发现嗅觉离子通道突变的cnga2-/Y转基因小鼠具有典型的抑郁样行为，且嗅觉中枢梨状皮层到中脑腹侧背盖区（VTA）有直接投射。以往研究发现VTA多巴胺能神经元及伏隔核（NAc）神经元活动异常与抑郁有关，提示我们嗅觉损伤可能通过影响奖励系统来调控动物的抑郁样行为，但梨状皮层到VTA和NAc的投射环路对抑郁样行为的调控规律并不清楚。本项目将首先利用行为及分子生物学方法明确嗅觉损伤与抑郁样行为的因果关系；其次利用神经元跨突触逆向示踪及免疫荧光技术探索嗅觉系统与奖励通路的特异性神经投射；最后利用药理学及电生理学技术研究嗅觉环路对VTA、NAc活动的影响。通过上述研究，我们将对嗅觉、抑郁及奖赏系统这三者之间的因果和调控关系产生新的认识，从新的角度阐明抑郁症的发病机理。

许多神经退行性疾病和精神疾病都伴随着嗅觉功能的减退，但其内在神经机制尚不明确。项目成功建立了小鼠可逆性嗅觉损伤的模型，在此基础上研究急性及慢性嗅觉损伤后小鼠学习记忆、焦虑及抑郁样行为，以及嗅觉损伤对海马突触可塑性以及血清皮质酮的影响；通过神经元病毒示踪及电生理研究，我们研究了嗅觉系统与奖励系统之间的神经投射，对嗅觉损伤小鼠奖励系统VTA及NAc脑区的脑电活动及脑电活动相关性进行了研究，进一步阐明了嗅觉对海马及奖励通路的调控。此外，还研究了嗅觉缺失小鼠在慢性束缚应激及慢性不可预知应激作用下认知及情绪的改变。上述研究不仅回答并验证了项目申请书中提出的科学问题，并对相关问题进行了扩展性研究，取得了较好的研究成果。.具体研究结果如下：1）嗅觉损伤对学习记忆的影响具有时程依赖性，损伤1周后Y-迷宫学习记忆及恐惧记忆不受影响，而4周后受损；2）嗅觉损伤时间越长，对海马突触可塑性的损伤就越大，嗅觉损伤1周后，小鼠海马的LTP不受影响，晚期LTD受损，但损伤4周后，海马的LTP和早期LTD 及晚期LTD均受损；3）嗅觉损伤使小鼠长期处于高应激水平，嗅觉损伤后3天、10天、20天检测时小鼠的血清皮质酮水平都升高，正常小鼠抑制嗅球活动后皮质酮水平也升高；4）嗅觉损伤小鼠在长期慢性不可预知应激刺激下，更加容易出现学习记忆损伤及抑郁样行为；5）嗅球对NAc有直接的纤维投射，嗅觉损伤后小鼠VTA、NAc的脑电活动下调，4周后脑电活动恢复但两个脑区之间的相关性下降。 .该研究发现嗅觉损伤对海马的突触可塑性有调控作用，嗅觉损伤小鼠在慢性应激的条件下更加容易抑郁,并且发现嗅觉损伤及抑制嗅球活动能够调控HPA轴，提高小鼠的应激水平。该项目还发现了嗅觉与奖励通路中伏隔核有直接的纤维投射，发现长期嗅觉损伤对奖励系统之间的联系有损伤作用。上述研究为嗅觉与抑郁症、阿尔兹海默症以及帕金森等神经退行性疾病及精神疾病的发病机理研究和治疗提供了线索。