前额叶皮层星形胶质细胞在焦虑样行为调控中的作用

Successfully seeking rewards and avoiding punishments is an innate and defining characteristic of adaptive behavior. For mammalians, the expression of negative emotions to aversive stimuli is critical for survival, including anxiety and fear. Recent studies demonstrated that the prefrontal cortex (PFC) plays a crucial role in the regulation of anxiety-like behaviors and serves as a brain hub in the interplay between emotions and cognitions. For the anxiety emotion to occur optimally, the neural circuit of PFC must precisely integrate internal motivational states with external information to orchestrate avoidance of aversive stimuli. There is a substantial evidence, including our own findings (Wang, J.; Tu, J.; Cao, B.; Mu, L.; Yang, X.W.; Cong, M.; Ramkrishnan, A.S.; Chan, R.H.M.; Wang, L.P.; Li, Y.; Cell Reports, 2017. 21(9): 2407-2418), demonstrated that astrocytes play an essential role in regulation of neuronal activity and synaptic plasticity. In clinic, it has been well documented that anxiety disorders are associated with astrocytic dysfunctions, however, it still remains unclear whether astrocytes participate in the regulation of anxiety-like behaviors. In the present proposal, we will investigate the activity of astrocytes in response to anxiety-like aversive stimuli by fiber photometry. Further, combining optogenetic and pharmacogenetic approaches to specific manipulate astrocytes, we will clarify the function of prefrontal astrocytes in anxiety-like behaviors. Finally, we will systematically explore the astrocyte-neuronal interaction mechanism underlying regulation of anxiety by in vivo multi-channel recording. This study focuses on astrocytic mechanisms of anxiety-like behaviors. The findings from our proposed studies will advance the theory of prefrontal controlling emotions as well as provide new insights for interventional targets to ameliorate emotional symptoms in psychiatric disorders.

趋利避害是动物本能，高等动物对负面情绪包括焦虑和恐惧的行为反应对于逃避危险至关重要。最近的研究表明前额叶皮层在焦虑样行为调控中具有重要作用，是调节情绪与认知的关键脑区。焦虑样行为的表达依赖于前额叶皮层神经环路的精确控制。越来越多的证据，包括我们自己的研究，表明神经元兴奋性及其功能受星形胶质细胞的调控。此外，焦虑症等情绪类精神疾病伴随有星胶病变。然而，星胶是否参与焦虑样行为调控并不清楚。本项目中，我们将采用钙测量技术研究焦虑样行为表达时星胶的活动规律，结合光遗传学和药理遗传学特异地干预星胶活动来探究星胶在焦虑样行为调控中的作用。在此基础上，我们还将进一步采用在体多通道记录技术分析胶质-神经元互作参与焦虑样行为的具体机制。本项目聚焦于星形胶质参与焦虑样行为调控的机制，其研究结果不仅有助于加深理解前额叶皮层在焦虑情绪加工中的作用机制，也将为焦虑相关情绪类精神疾病的治疗提供新的理论依据和干预靶点。

对于正常人群，焦虑情绪能够帮助我们更好地趋利避害，在确保我们生存繁衍方面起着重要作用；然而，持续的或过度的焦虑会引发焦虑障碍，是目前世界上精神健康面临的最大威胁之一，其发生机制不甚清楚，且目前尚无令人满意的疗法。以往的研究发现脑内多个脑区在焦虑行为调控中发挥重要功能，包括内侧前额叶皮层，目前这些研究多聚焦于这些脑区内神经元及其所组成的神经环路。本项目结合清醒动物钙测量、在体多通道记录、动物行为学、光遗传学以及药理遗传学等神经科学前沿技术深入研究了星形胶质细胞在焦虑状态下的活动规律以及对神经网络的影响。我们采用钙测量技术研究了焦虑样行为表达时星胶的活动规律，结合光遗传学和药理遗传学特异地干预星胶活动探究了星胶在焦虑样行为调控中的作用，并采用在体多通道记录技术分析了胶质-神经元互作参与焦虑样行为的具体机制。此外，我们还进一步探索了前额叶星胶在社会交互与社交焦虑调控中作用及其相关神经环路机制。本项目研究结果不仅有助于加深理解前额叶皮层在焦虑情绪加工中的作用机制，也为焦虑相关情绪类精神疾病的治疗提供了新的理论依据和干预靶点。