Abstract
Basal forebrain cholinergic neurons mature in adolescence coinciding with development of adult cognitive function. Preclinical studies using the rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55) reveal persistent increases of brain neuroimmune genes that are associated with cognitive dysfunction. Adolescent intermittent ethanol exposure also reduces basal forebrain expression of choline acetyltransferase (ChAT), an enzyme critical for acetylcholine synthesis in cholinergic neurons similar to findings in the post-mortem human alcoholic basal forebrain. We report here that AIE decreases basal forebrain ChAT+IR neurons in both adult female and male Wistar rats following early or late adolescent ethanol exposure. In addition, we find reductions in ChAT+IR somal size as well as the expression of the high-affinity nerve growth factor (NGF) receptor tropomyosin receptor kinase A (TrkA) and the low-affinity NGF receptor p75NTR, both of which are expressed on cholinergic neurons. The decrease in cholinergic neuron marker expression was accompanied by increased phosphorylation of NF-κB p65 (pNF-κB p65) consistent with increased neuroimmune signaling. Voluntary wheel running from P24 to P80 prevented AIE-induced cholinergic neuron shrinkage and loss of cholinergic neuron markers (i.e., ChAT, TrkA, and p75NTR) as well as the increase of pNF-κB p65 in the adult basal forebrain. Administration of the anti-inflammatory drug indomethacin (4.0 mg/kg, i.p prior to each ethanol exposure) during AIE also prevented the loss of basal forebrain cholinergic markers and the concomitant increase of pNF-κB p65. In contrast, treatment with the proinflammatory immune activator lipopolysaccharide (1.0 mg/kg, i.p. on P70) caused a loss of cholinergic neuron markers that was paralleled by increased pNF-κB p65 in the basal forebrain. These novel findings are consistent with AIE causing lasting activation of the neuroimmune system that contributes to the persistent loss of basal forebrain cholinergic neurons in adulthood.
Highlights
Adolescence is a conserved neurodevelopmental period characterized by significant refinement of neurotransmitter systems that parallels the transition of the immature brain to the more efficient adult brain [1]
We report here for the first time that Adolescent intermittent ethanol (AIE) reduces choline acetyltransferase (ChAT)+ neuron populations in the adult (i.e., P80) female basal forebrain similar to males
Neuroimmune involvement in cholinergic neuron loss data, we found that AIE treatment led to a significant reduction of ChAT+IR neurons in the adult (P80) basal forebrain regardless of sex
Summary
Adolescence is a conserved neurodevelopmental period characterized by significant refinement of neurotransmitter systems that parallels the transition of the immature brain to the more efficient adult brain [1]. Adolescence is associated with high levels of alcohol binge drinking [14, 15], which can negatively impact the maturing basal forebrain cholinergic system. Preclinical rat studies find that adolescent basal forebrain cholinergic neurons are sensitive to ethanolinduced neurodegeneration [16]. Adolescent intermittent ethanol (AIE), which models human adolescent binge drinking, causes a loss of cholinergic neurons immediately following the conclusion of AIE treatment that persists well into adulthood (i.e., P220) [16,17,18,19,20]. The heightened vulnerability of the adolescent brain, coupled with the importance of acetylcholine in cognitive functioning, underscores the importance of identifying the mechanism underlying the persistent loss of basal forebrain cholinergic neurons following adolescent binge ethanol exposure
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