L-lactate Release by Optogenetic Activation of Astrocytes Rescues Decision-making Deficit in Visceral Hypersensitive Rats

The clinical connection between visceral pain and the increases in levels of anxiety, depression, as well as cognitive disorders, has long been recognized, however, these emotional and cognitive signs are far less studied than the sensory components of visceral pain. Human brain imaging studies have revealed anterior cingulate cortex (ACC) as a key brain target for mediating visceral pain-cognitive interactions. Recently, we characterized impairments of long-term potentiation (LTP) and spike-field coherence as key electrophysiological features associated with decision-making deficit in visceral hypersensitive (VH) state. Nonetheless, the underlying molecular mechanisms are poorly understood.The brain requires continuous supply of oxygen and energy-yielding substrates involving glucose. A growing body of evidence suggests that L-lactate, byproduct of astrocytic glycolysis, plays a critical role in cognition processing. Astrocytes respond to all forms of CNS damage and disease by undergoing cellular, molecular and functional changes. Our preliminary data showed markedly reactive astrogliosis occurs in ACC in VH rats. We hypothesized that impaired L-lactate release casually involved in cognitive deficit in chronic visceral pain. We find failure of L-lactate release in an activity-dependent manner in chronic visceral pain. VH rats exhibited significant lower lactate level immediately after the cognitive behavioral task (rat gambling task RGT). Next, exogenous L-lactate infusion into ACC repairs the impairments of LTP and decision-making performance in VH rats.Optogenetics can be used to control activity of specifically interested cells by light stimulation. We showed endogenous L-lactate released by optogenetic activating astrocytes rescues the visceral pain related decision-making deficit. Multiple-channel electrophysiological recordings revealed that activation of astrocytes facilitates spike-field coherence in the ACC of VH rats through lactate signaling pathway. Astrocytes neuron metabolic coupling would underscore the importance of functionally connecting these two cell types subserving brain cognitive functions, e.g. decision making. These findings provide new insights into cognitive treatment in clinical chronic visceral pain management.