Brain Astrocytes Drive Mood and Cognitive Dysfunction in Chronic Visceral Pain

The clinical connection between pain and the increases in levels of anxiety, depression aswell as cognitive disorders has long been recognized, but the biological basis of theaffective and cognitive changes in visceral pain remains badly understood. Using aviscerally hypersensitive (VH) rat mole, we have demonstrated sensitization of anteriorcingulate cortex (ACC) neurons. Further, ACC activation is critical for memoryprocessing involved in long-term visceral negative affective state. Recently, wecharacterized long-lasting potentiation of local field potential in the medial thalamus(MT)?ACC synapses in VH rats. Higher frequency stimulation in the MT reliablyinduced canonical long-term potentiation (LTP) in normal rat, however, induction ofLTP were impaired in VH states implying chronic visceral pain disrupts emotional andcognitive functions (e.g. decision making) that are associated with ACC. In the currentproposal behavioral studies will be performed to clarify the emotional disorders andcognitive deficits in the visceral pain. We hypothesize that the mechanisms of ACCsynaptic metaplasticity are involved in modifying aversive responses to pain, and affectthe processing learning and memory associated with chronic pain.Proportionately more brain neuronal theta activity (3–8Hz) predicts faster and betterlearning, and learning itself induces the theta activity during training. We will performmultiple-channel recordings to test our hypotheses that a disruption in the theta activityin MT-ACC circuitry may prevent interregional communication, leading to deficits inlearning (gambling task) in later stage of visceral pain.There is now a growing body of evidence indicating that glial cells, particularlyastrocytes, contribute actively to synaptic transmission, neuronal excitability anddepressive and memory behavior. The nature of astrocytic modification dynamicallyvaries with time after the noxious challenge. We will demonstrate that reactiveastrogliosis modify the ACC glutamatergic excitation and contribute to synaptic plasticityin visceral pain. On the other hand, astrocytic and neuronal apoptosis related todegeneration occurs in the chronic visceral pain state.Byproducts of glycogen metabolism are critical for memory formation, astrocytes, butnot neurons, store glycogen, in the last phase of this proposal we will characterize thatan astrocytes-neuron metabolic coupling (e.g. lactate transport) plays a key role inmemory formation, lactate transport is essential for rescue the memory loss, long-termsynaptic plasticity in the chronic visceral pain. These observations would suggest thatthe visceral pain experience may be better explained as a biopsychosocial model of pain.Astrocytes play a vital role in the pain-emotional and cognition interactions.