Abstract
Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generated GFAP-ChR2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics. 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. 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. Furthermore, intracerebral or intraperitoneal injection of A1R agonist mimicked the effects of astrocyte activation. Therefore, our findings provide a deeper understanding of the astrocyte-mediated regulation of fear memory and suggest a new and important therapeutic strategy against pathological fear-related disorders.
Highlights
Astrocytes are the most abundant glial cells in the central nervous system (Allen and Barres, 2009; Bushong et al, 2002) and are recognized for their classical supportive, metabolic, and protective roles (Allaman et al, 2011; Oliveira et al, 2015)
NECA and CCPA in the dorsal CA1 did not affect spontaneous locomotor activity or center zone exploration time in the open-field test (OFT) (Figure 4—figure supplement 1A–E). These results showed that the activation of A1 receptors (A1Rs) after memory acquisition mimicked the effects of astrocyte activation on contextual fear memory, indicating that A1Rs mediate the contextual fear memory attenuation
Astrocyte activation paired with ARL 67156 reversed the freezing level to that of controls, showing that the attenuation effect of astrocyte photostimulation on fear memory was almost totally blocked by ARL 67156 (Figure 5F). These results indicate that the fear memory attenuation induced by astrocyte activation is abrogated with diminished levels of adenosine
Summary
Astrocytes are the most abundant glial cells in the central nervous system (Allen and Barres, 2009; Bushong et al, 2002) and are recognized for their classical supportive, metabolic, and protective roles (Allaman et al, 2011; Oliveira et al, 2015). Astrocytes respond to neuronal activity with a transient increase in the cytosolic Ca2+ concentration, as a result triggering the release of gliotransmitters, which in turn causes feedback regulation of neuronal activity and synaptic transmission (Araque et al, 2014; Zhang et al, 2003). Most of these studies were performed at the synaptic or cellular level, and the roles of astrocytes in mammalian behavior remain incompletely understood.
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