Regulation Of Astrocytes On Fear Memory And Its Mechanism

Memory is the record and retention of what we learn over time and is essential to our survival.However,the formed traumatic fearful memory can lead to various psychiatric disorders including post-traumatic stress disorder（PTSD）,panic disorder,phobias,and depression,are major burdens on both affected individuals and society in general.The estimated lifetime prevalence of fear-and stress-related disorders is close to 29%.Yet limiting pathological fear is a considerable challenge since traumatic memories are rapidly acquired and temporally enduring.Fear extinction,such as exposure therapy,is a fundamental behavioral method to reduce fear and anxiety in humans.However,exposure therapy is a context-dependent learning process that does not erase the initial fear memory.Therefore,it is urgent to find new therapeutic strategies for treating these disorders.Astrocytes are the most abundant and morphologically complex glial cells in the central nervous system.Their processes extensively contact and envelop neuronal synapses,making astrocytes capable of having complex network function of modulating and integrating local synaptic information.Calcium level in astrocytes is an important signal,which reflects the received information through Ca²⁺signal,as a result triggering the release of gliotransmitters,which in turn causes feedback regulation of neuronal activity and synaptic function.This bidirectional communication between neurons and astrocytes at the synapse led to the concept of the‘‘tripartite synapse’’,in which contain astrocyte processes,pre-and postsynaptic compartments.Previous studies mostly focused on the interaction between astrocytes and neurons at the synaptic or cellular level,but the role of astrocytes in mammalian behavior remain unclear.Hippocampal pyramidal neurons and interneurons have received much attention related to the contextual fear memory process in the mammalian brain.A few studies have found dynamic morphological and molecular changes in astrocytes during hippocampus-based memory processes,indicating the functional involvement of astrocytes in memory processes.However,as to whether and how astrocyte activity regulates contextual fear memory remains unclear.To explore whether and how astrocyte activity regulates contextual fear memory,we generated GFAP-Ch R2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics,combined with pharmacology,virus injection,electrophysiology,calcium imaging,in vivo microdialysis,behavioral test etc.We found that after memory acquisition within a temporal window,astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavior.Conversely,reducing astrocyte Ca²⁺activity increased fear memory.In vivo microdialysis experiments showed astrocyte photoactivation increased extracellular ATP and adenosine concentrations.Intracerebral blockade of adenosine A₁ receptors（A₁Rs）reversed the attenuation of fear memory induced by astrocyte activation.Furthermore,intracerebral or intraperitoneal injection of A₁R agonist mimicked the effects of astrocyte activation on fear memory and fear-related anxiety behavior.At last,our results also found that A₁R agonist injection within a critical time-window decreased contextual fear memory and fear-related anxiety.Therefore,our findings demonstrate the important regulation role of astrocytes in fear memory and provide a deeper understanding of the astrocyte-mediated regulation of fear memory.More importantly,our results suggest astrocyte activation-based disruption of memory consolidation is a feasible strategy for the treatment of fear memory,and provide a new and important therapeutic strategy against pathological fear-related disorders,such as PTSD.