抗抑郁效应的突触可塑性调控的神经动力学机制

Gradually, to focus the subject in real biological systems has become a progress trend of neurodynamcis. To date, the diagnosis of mental disorders has been based on clinical observation, specifically the identification of symptoms, not on the quantified features from neural systems. Depression is a common mental health problem. Functional neuroimaging and neurobiological studies contribute to find biomarkers for the diagnosis. However, all of these medications must be given for at least several weeks for their antidepressant actions to become manifest. And, most importantly, fewer than 50% of all patients with depression show full remission with optimized treatment. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist, produces a rapid antidepressant response, with effects lasting up to 2 weeks. The present project would aim at elucidating the mechanism of ketamine’s action, both neurobiology and neurodynamcis, from three levels of neural circuits, neuronal network and synaptic plasticity. Before and after ketamine infusion (human), the neural circuit is acquired by analyzing functional brain networks from fMRI datasets. Before and after ketamine perfusion (animal), synaptic plasticity characteristics and spatiotemporal behaviors of neuronal network within a specific brain region are recorded and analyzed. A biologically network model and the complex spatiotemporal behaviors are simulated, composed of pyramidal neurons and interneurons connected by inhibitory and excitatory synapses. Combined the experimental and network simulation results, the neurodynamic mechanism and the related biomarkers are acquired. Furthermore, the potential applications of such response are discuss.

研究实际生物医学问题已经成为神经动力学的发展趋势。目前，精神疾病的临床诊断是基于临床症状的主观量表评估，尚没有实现对神经系统异常活动的本质和规律认识基础上的特征量化。抑郁症是一类常见的精神疾病，功能影像学结合认知神经生物学研究给出了抑郁症相关的客观指征。然而，迄今为止的抗抑郁药存在起效慢、完全缓解率低等问题。最近，氯胺酮引起的一种起效快且稳定的新型抗抑郁效应得到证实。本申请项目拟从神经环路、神经元网络和突触可塑性等不同层次，研究这一新型效应的生物学基础及神经动力学机制。通过采集起效前后功能脑成像数据、分析神经环路功能连接特征，记录分析氯胺酮作用前后特异性脑区突触可塑性变化、神经元网络时空行为，以及建立包括兴奋-抑制突触传递、由锥体神经元和中间神经元构成的皮层神经元网络模型，计算复杂时空动力学行为，实验结合模型研究获得新型抗抑郁效应的神经动力学机制及相关的生物学客观指征，并探讨其应用前景。

通过对抑郁症患者和正常对照人群的脑功能成像数据进行分析，获得了与抑郁症特异性相关的神经环路/脑功能网络，包括与奖赏功能相关的内眶额叶皮层，与记忆相关的海马旁回和内颞叶部位，和与惩罚相关的外眶额叶皮质，提示奖赏相关的记忆功能与抑郁症的相关；实验结合理论模型，研究了神经元放电的转迁规律和信息编码特性，以及抑制性突触调控神经电活动的动力学机制：不只是压制放电而有可能促进放电；构建包含兴奋－抑制突触传递和锥体及抑制性中间神经元的网络，揭示了神经元兴奋性改变、去抑制可以调控网络时空动力学行为转迁和生理/病理功能的变化。研究结果从实验结合理论的角度，揭示了抑郁症的环路/脑网络、神经元网络、神经元和突触层次的动力学特征和可能的机制，为认识氯胺酮等药物对抑郁症的调控作用和机制奠定了基础，也提供了抑郁症的潜在的客观诊断指标。