Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex

Abstract

Adolescence has been identified as a vulnerable developmental time period during which exposure to drugs can have long-lasting, detrimental effects. Although adolescent binge-like ethanol (EtOH) exposure leads to a significant reduction of forebrain cholinergic neurons, EtOH’s functional effect on acetylcholine (ACh) release during behavior has yet to be examined. Using an adolescent intermittent ethanol exposure model (AIE), rats were exposed to binge-like levels of EtOH from postnatal day (PD) 25–55. Three weeks following the final EtOH exposure, cholinergic functioning was assessed during a spontaneous alternation protocol. During maze testing, ACh levels increased in both the hippocampus and prefrontal cortex. However, selectively in the prefrontal cortex, AIE rats displayed reduced levels of behaviorally-relevant ACh efflux. We found no treatment differences in spatial exploration, spatial learning, spatial reversal, or novel object recognition. In contrast, AIE rats were impaired during the first attentional set shift on an operant set-shifting task, indicative of an EtOH-mediated deficit in cognitive flexibility. A unique pattern of cholinergic cell loss was observed in the basal forebrain following AIE: Within the medial septum/diagonal band there was a selective loss (30%) of choline acetyltransferase (ChAT) positive neurons that were nestin negative (ChAT+/ nestin−); whereas in the Nucleus basalis of Meynert (NbM) there was a selective reduction (50%) in ChAT+/ nestin+. These results indicate that early adolescent binge EtOH exposure leads to a long-lasting frontocortical functional cholinergic deficit, driven by a loss of ChAT+/ nestin+ neurons in the NbM, which was associated with impaired cognitive flexibility during adulthood.

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

“…Historically, AIE has been shown to reduce populations of ChAT+IR neurons in the basal forebrain of adult male rodents [ 16 – 18 , 57 ], but to date no studies have assessed the effect of AIE on ChAT expression in the basal forebrain of adult females. In the present study, we found that expression of ChAT in control male and female Wistar rats did not differ as a function of sex, which is consistent with data reporting similar numbers of basal forebrain ChAT+IR neurons in aging male and female rats (i.e., 12 mo—25 mo; [ 58 ]).…”

Relationship of Wine Consumption with Alzheimer’s Disease

“…Chronic intake of alcohol is linked, other than to cardiac and liver problems, to cognitive impairments and brain damage. The characteristics of dementia due to excessive alcohol drinking have received increased interest, and both neuropathological and imaging studies have suggested that excessive and prolonged use of alcohol may be responsible for structural and functional brain damage [70][71][72]. Chronic or excessive alcohol consumption may cause damage to the temporal lobe similar to that observed in AD [73].…”

Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function

“…Rats were returned to standard pair-housing conditions after VEx/Stat for 9 days prior to being handled daily for an additional 5 days prior to behavioral testing as a 14-day period has been demonstrated to be needed to see exercise-induced changes in the forebrain cholinergic system (see Hall and Savage, 2016 ). Spontaneous alternation testing procedures, in conjunction with microdialysis collection of hippocampal ACh efflux, was conducted with procedures published in our previous work (see Anzalone et al, 2010 ; Hall and Savage, 2016 ; Fernandez and Savage, 2017 ). Spontaneous alternation is a spatial task that is sensitive to the cholinergic system as well as the functioning of the hippocampus and basal forebrain (for review, see Lalonde, 2002 ).…”

“…Thus, we developed a brightfield co-labeling stain to assess the Nestin/ChAT populations of neurons as well as the overlap in the Nestin and ChAT neuronal populations. Six sections from every subject (sampling every 5th section) spanning the MS/DB were treated with a standardized ICC protocol (see Roland and Savage, 2009 ; Hall and Savage, 2016 ; Fernandez and Savage, 2017 ). Following rinsing (PB), quench and blocking steps, sections were first processed with the ChAT primary antibody (1:200, goat polyclonal anti-ChAT, cat# AB144P; Millipore, Billerica, MA, United States), and where then incubated in a secondary antibody (biotinylated anti-goat IgG 1:100, cat# BA-5000; Vector Laboratories, Burlingame, CA, United States).…”