Journal Article

Adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons and neuroimmune activation are prevented by exercise and indomethacin

Crews, Fulton T., Vetreno, Ryan P.

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetylcholine / Acetyltransferase / Activation / Adolescents / Affinity / Alcohol / Alzheimer's disease / Alzheimers disease / Animal cognition / Animals / Anti-inflammatory agents / Basal forebrain / Basal Forebrain - drug effects / Basal Forebrain - growth & development / Basal Forebrain - immunology / Basal Forebrain - pathology / Binge Drinking - immunology / Binge Drinking - pathology / Binge Drinking - prevention & control / Biology and Life Sciences / Brain / Central Nervous System Depressants - adverse effects / Child development / Choline / Choline O-acetyltransferase / Cholinergic nerves / Cholinergic Neurons - drug effects / Cholinergic Neurons - immunology / Cholinergic Neurons - pathology / Cognitive ability / Disease Models, Animal / Dosage and administration / Ethanol / Ethanol - adverse effects / Exercise / Exercise Therapy / Exposure / Female / Females / Forebrain / Forebrain (basal) / Gene expression / Growth factors / Health aspects / Hypotheses / Immune system / Indomethacin / Indomethacin - pharmacology / Inflammation / Kinases / Lipopolysaccharides / Male / Markers / Medicine and Health Sciences / Nerve growth factor / Neurodegeneration / Neuroimmunomodulation - drug effects / Neuroimmunomodulation - physiology / Neurons / Neuroprotective Agents - pharmacology / Neurosciences / NF-κB protein / People and Places / Phosphorylation / Physical Sciences / Random Allocation / Rats, Wistar / Rodents / Running - physiology / Sexual Maturation / Shrinkage / Studies / Teenagers / TrkA protein / TrkA receptors / Tropomyosin / Underage Drinking / Volition / Wheel running