The consumption of alcohol during adolescence is a significant risk factor for development of an alcohol use disorder (AUD) as an adult. Adolescent alcohol use is thought to uniquely prime reward learning and alcohol- cue conditioning systems. Classically conditioned cue associations can be modeled in rodents with a fear conditioning paradigm in which a mild foot shock is paired with a tone, the conditioned cue. Extinction learning that the tone no longer predicts a shock, is mediated by an infralimbic (IfL) cortex and basolateral amygdala circuit. Our lab has shown that adolescent intermittent ethanol (AIE) exposure in rats slows extinction learning and impairs extinction recall when tested in adulthood. Intriguingly, extinction learning can be enhanced by disruption of the specialized extra cellular matrix, perineuronal nets (PNN) in the amygdala. PNNs form preferentially around parvalbumin positive interneurons well into young adulthood in the prefrontal cortex (PFC) including the IfL, making them vulnerable to AIE. Studies show adult repetitive drug and alcohol use increases PNN density around parvalbumin positive interneurons. Our preliminary data suggest that AIE follows this pattern and increases PNN density in the medial PFC. The current proposal is designed to test the hypothesis that impairment of fear extinction learning and recall in male rats after adolescent alcohol exposure is mediated by increases in PNN density in the IfL cortex. It is further hypothesized that females will be resistant to AIE induced deficits in fear extinction recall, due to protection by higher circulating levels of estradiol compared to males.
Aim 1 is designed to confirm preliminary results of PNN increases after AIE that persist into adulthood. Utilizing immunohistochemical and confocal techniques these data will also examine mature sulfonation patterns of PNNs in the PFC. These data are critical for understanding the mechanisms by which alcohol affects the developing PFC.
Aim 2 is designed to dissect alterations in parvalbumin positive interneuron activity and coordination in the PFC that may be influenced by altered PNN configurations. Using fiber photometry will allow for the determination of the pattern of population firing in the IfL during fear extinction learning. Furthermore, by using a wireless multielectrode array targeting the IfL and BLA we will examine the parvalbumin interneuron coordination within the IfL and how activity coordinates with activity in downstream amygdala. These experiments will provide novel insight into the mechanisms by which of adolescent ethanol exposure may lead to later alcohol misuse and inform the development of efficacious treatments.
The prefrontal cortex is a brain area that plays a critical role in behavioral control, and accumulating evidence indicates that dysfunction of this brain region may contribute to the progression from intermittent adolescent alcohol abuse to an alcohol use disorder in adulthood. The transition from juvenile to adult prefrontal cortex function is in part due to the stabilization of synaptic configurations by perineuronal nets, a specialized extra cellular matrix. Our preliminary data suggest that adolescent ethanol exposure increases perineuronal nets prematurely. The project proposed in the current application will examine how this increase in perineuronal nets impairs prefrontal cortex driven fear extinction.
