增强背侧海马锥体神经元兴奋抑制外周神经损伤引起的神经病理性疼痛的作用及其机制研究

Our previous work has shown that peripheral nerve injury (spared nerve injury, SNI) can result in neuropathic pain, impairment of long term potentiation (LTP) in CA1 downregulation of BDNF and reduced NMDA current. However, it is still not clear whether hippocampal activity can direct control neuropathic behaviors. Here we show that activation of pyramidal neurons in dorsal hippocampus of SNI rats, either by glutamate microinjection or by chemogenetics, could alleviate neuropathic pain behaviors induced by SNI. These results indicate that exciting the pyramidal neurons in dorsal hippocampus can reverse neuropathic pain induced by peripheral nerve injury, yet the mechanisms are still not clear. Using a new methodology (chemo-fMRI), where we combine awake resting state brain imaging with viral vector mediated chemogenetic activation (PSAM/PSEM), we could demonstrate that increased excitability of dorsal hippocampus pyramidal neurons altered resting state functional connectivity within circuitry specifically related to the extent of diminution of neuropathic behavior (mechanical allodynia). The identified circuitry was hippocampal-thalamic, striatal, and cortical. In the present project, firstly, we are going to investigate whether peripheral nerve injury decreased glutamatergic transmission and decreased the intrinsic excitability of pyramidal neurons in dorsal hippocampus. Next, we will investigate whether NMDAR-ERK1/2-CREB signaling pathway is involved in the activation and deactivation of the circuitry that we identify using chemo-fMRI. Thus, the present study will elucidate a novel causal role for the dorsal hippocampus mediated circuitry controlling neuropathic pain behavior.

我室以往的工作表明，外周神经损伤（SNI）的病理性疼痛大鼠海马CA1区LTP 被抑制， BDNF表达下降，NMDA电流减小。然而海马的活动是否能直接控制神经损伤引起的痛行为尚不清楚。本项目的预实验发现，背侧海马内注射谷氨酸钠或利用化学遗传学方法特异性地兴奋背侧海马锥体神经元均可短暂抑制SNI引起的机械痛敏，提示兴奋海马锥体神经元可抑制痛行为，但机制不清。进一步fMRI实验表明，化学遗传学方法兴奋背侧海马锥体神经元改变了海马与丘脑、纹状体及皮层之间的静息态功能连接强度。本项目拟首先明确兴奋背腹侧海马锥体神经元在抑制机械痛敏中的作用是否存在差异，进一步探讨兴奋背侧海马锥体神经元是否通过NMDAR，激活ERK1/2-CREB信号途径，进而改变了海马与疼痛相关脑区之间的功能连接强度。研究有助于阐明海马对神经病理性疼痛的调制作用及其机制。

我室以往的工作表明，外周神经损伤（SNI）的病理性疼痛大鼠海马CA1区LTP 被抑制，BDNF表达下降，NMDA电流减小。然而海马在神经病理性疼痛动物及病人具体的功能变化尚不清楚。海马是否能直接控制痛行为亦未明确。在本研究中，我们进一步发现：神经病理性疼痛情况下背侧海马产生了显著的功能下降，包括锥体神经元内在兴奋性在神经病理性疼痛动物产生了显著下降及负性的静息态功能连接在慢性腰背痛的病人产生的明显降低。用不同方法，包括注射化学药物，化学遗传学，光遗传学等方法激活背侧海马锥体神经元可缓解神经病理性疼痛及其共病记忆障碍。其作用是通过作用于阿片受体，影响海马的输出效应，进一步调节疼痛相关脑区，包括丘脑，皮层，纹状体,前额叶等的活动。最后，我们发现神经病理性疼痛情况下背侧海马锥体神经元的兴奋性降低是星形胶质细胞释放的乳酸减少导致的。这些结果提示外周神经损伤导致背侧海马功能的降低，而激活背侧海马可缓解痛行为。