Pilot Project 1: The impact of adolescent alcohol exposure on pontomesencephalic cholinergic neurons mediating conditioned reinforcement learning
PI: Ewa Galaj (egalaj@colgate.edu)
Binge drinking during adolescence is known to cause prolonged deficits in socio-cognitive functions, attention and memory. One domain that remains poorly investigated is the impact of adolescent intermittent alcohol (AIE) exposure on the acquisition of conditioned reinforcement-the learning about stimuli that gain reinforcement value through association with naturally rewarding stimuli. We have shown that this type of reward-related learning requires cholinergic neurotransmission in the ventral tegmental area (VTA) and is severely impaired by AIE exposure in rats. Although the pedunculopontine nucleus (PPT) is known to provide a major cholinergic input into the VTA and plays a critical role in reward-related learning, to date there is no direct evidence linking the PPT->VTA cholinergics inputs to the conditioned reinforcement learning. Because PPT cholinergic neurons are particularly impacted by alcohol, it is conceivable that AIE exposure weakens the PPT->VTA cholinergic signaling, leading to impairment in conditioned reinforcement learning. If so, one would expect to observe weaker cFos activation in PPT cholinergic neurons projecting to the VTA) and weaker VTA cholinergic neurotransmission during conditioned reinforcement in AIE-treated rats as compared to control. An interesting question then is whether the observed conditioned reinforcement deficit in AIE-treated rats can be reversed by optogenetic manipulation of the PPT->VTA pathway. One hypothesis is that optogenetic stimulation of the PPT->VTA cholinergic neurons can compensate for VTA deficient cholinergic signaling, leading to improvement in conditioned reinforcement learning in AIE-treated rats. We are in the process of testing these hypotheses using a multifaceted approach. These finding will expand our understanding of the AIE exposure impact on the developing brain and provide critical insights into the neurobiology of reward-related learning that is affected by early life alcohol consumption.
Pilot Project 2: Characterizing the effects of binge-like ethanol during adolescence and adulthood on early-and late-stage amyloid deposition in TgF344-AD rats.
PI: Stephen Day (sday4@binghamton.edu)
Alcohol misuse is associated with an increased risk for Alzheimer's disease (AD). However, it is unknown how alcohol misuse during different stages of development drives amyloid-尾. across the lifespan. Binge drinking is characterized by cycles of ethanol consumption followed by periods of abstinence, and binge drinking during adolescence has long-term neurological consequences that include increased AD-related pathology. Previous studies show that adolescent intermittent ethanol (AIE) exposure increases hippocampal A尾42 levels in 6-month old female mice. However, it is unclear whether the developmental period during which binge-like ethanol occurs impacts the progression of amyloid pathology throughout the brain. The overall goal of this project is to characterize how chronic intermittent ethanol (CIE; P90-P120) and adolescent intermittent ethanol (AIE; P30 P60) impacts the progression of AD-related pathology across multiple cortical regions in male and female TgF344-AD rats. We hypothesize that CIE and AIE will exacerbate amyloid pathology, but these effects will be greater in AIE-exposed animals. In addition, we expect specific cortical vulnerability to AIE/CIE induced propagation of AD-pathology as a function of age. This study is highly innovative as it seeks to characterize how binge-like ethanol exposure during two periods of development impacts early-and late-stage amyloid deposition across multiple cortical regions in male and female TgF344-AD rats. Doing so will provide the field with valuable information on how binge-like ethanol, development, and sex interact to alter the progression of AD-like pathology.