The Prefrontal Cortex as a Key Target of the Visceral Pain Processing in Adult Rats Following Maternal Separation Stress in Infancy

A large body of literature links early life stress (ELS) with a wide range of adult psychopathology. ELS plays an important role in the development of visceral hyperalgesia in irritable bowel syndrome. Neonatal maternal separation (MS) of newborn rats has been shown to trigger a long-term alteration in responses to visceral nociceptive stimuli in rats, and increase colonic motility in response to an acute psychological stressor, mimicking the cardinal features of IBS. Increasing evidence suggests MS can produce long-term changes in brain function. However, the proximate mediator of supra spinal influences on visceral pain processes is missing. Little research has focused on the impact of MS on subsequent visceral pain processing in the limbic forebrain in adulthood.Recently, our serial studies have demonstrated that glutamate in the anterior cingulate cortex (ACC) plays a critical role in the modulation of ACC sensitization and visceral pain in visceral hypersensitive states. Unlike most neurons in the brain, granule cells in the dentate gyrus, continue to be produced during adulthood. Stress in early life inhibits neurogenesis in adulthood. Available evidences showed that MS caused molecular and functional alterations in GABA receptors within CNS suggesting a potential molecular mechanism by which MS may result in altered stress-related behavior. The ACC has a substantial GABAergic termination. Binding studies have reported GABAA and GABAB receptors within the ACC, chronic restraint stress decreased benzodiazepine receptor and GABAA receptor binding in limbic regions.Given the key role of GABA in inhibition of neurotransmission, we hypothesize that reduced GABA and GABAA receptor accompanied with disinhibition in ACC neurons may enhance excitatory transmission in the ACC, which in turn, facilitates visceral pain processing in adulthood. To test this hypothesis, in MS rats the changes in GABAA receptor and GAD67 expression will be detected by immunocytochemistry and Western blot. Electrophysiological recording of ACC neurons will be performed to demonstrate that disinhibition in GABAergic transmission facilitates ACC neuronal responses to noxious visceral stimulation. Further, visceromotor response and conditioned place avoidance will be examined to determine that GABAergic transmissions are directly involved in visceral pain and emotional affective responses to noxious stimuli. Finally, we will focus on genetic overexpression of GABAA receptor in the ACC to prevent the development of visceral hyperalgesia in adult rats following maternal separation stress in infancy. This study will provide a framework to further clarify how cortex neurons modulate visceral hyperalgesia and certain behavioral disturbances associated with early adversity.