Abstract

Heavy alcohol consumption followed by periods of abstinence (i.e., binge drinking) during adolescence is a concern for both acute and chronic health issues. Persistent brain damage after adolescent intermittent ethanol exposure in rodents, a model of binge drinking, includes reduced hippocampal neurogenesis and a loss of neurons in the basal forebrain that express the cholinergic phenotype. The circuit formed between those regions, the septohippocampal pathway, is critical for learning and memory. Furthermore, this circuit is also altered during the aging process. Thus, we examined whether pathology in septohippocampal circuit and impairments in spatial behaviors are amplified during aging following adolescent intermittent ethanol exposure. Female and male rats were exposed to intermittent intragastric gavage of water (control) or 20% ethanol (dose of 5 g/kg) for a 2 days on/off cycle from postnatal days 25–55. Either 2 (young adult) or 12–14 (middle-age) months post exposure, rats were tested on two spatial tasks: spontaneous alternation and novel object in place. Acetylcholine efflux was assessed in the hippocampus during both tasks. There was no adolescent ethanol-induced deficit on spontaneous alternation, but middle-aged male rats displayed lower alternation rates. Male rats exposed to ethanol during adolescence had blunted behavioral evoked acetylcholine during spontaneous alternation testing. All ethanol-exposed rats displayed suppression of the cholinergic neuronal phenotype. On the novel object in place task, regardless of sex, ethanol-exposed rats performed significantly worse than control-treated rats, and middle aged-rats, regardless of sex or ethanol exposure, were significantly impaired relative to young adult rats. These results indicate that male rats display earlier age-related cognitive impairment on a working memory task. Furthermore, male rats exposed to ethanol during adolescence have blunted behavior-evoked hippocampal acetylcholine efflux. In addition, middle-aged and ethanol-exposed rats, regardless of sex, are impaired at determining discrete spatial relationship between objects. This type of pattern separation impairment was associated with a loss of neurogenesis. Thus, binge-type adolescent ethanol exposure does affect the septohippocampal circuit, and can accelerate age-related cognitive impairment on select spatial tasks.

Highlights

  • Adolescence is a critical period of life that is marked by heightened levels of hippocampal neurogenesis as well as changes in neurotransmitter receptors/transporters and cortical synaptic remodeling (Bayer et al, 1982; He and Crews, 2007; Curlik et al, 2014)

  • The septohippocampal circuit is especially vulnerable to the effects of Adolescent intermittent ethanol exposure (AIE), as previous research has found a significant suppression in basal forebrain neurons expressing the cholinergic phenotype, as well as decreased levels of neurogenesis in the hippocampus (Nixon and Crews, 2004; Broadwater et al, 2014; Vetreno et al, 2014; Fernandez and Savage, 2017)

  • The septohippocampal circuit, and the behaviors associated with it, are a key place to examine the role of developmental ethanol exposure in the progression of age-related cognitive decline

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Summary

Introduction

Adolescence is a critical period of life that is marked by heightened levels of hippocampal neurogenesis as well as changes in neurotransmitter receptors/transporters and cortical synaptic remodeling (Bayer et al, 1982; He and Crews, 2007; Curlik et al, 2014). The rapid rise of blood alcohol to above 80 mg/L in less than 2-h on an episodic time frame, during such a critical developmental epoch can lead to brain pathologies that last well into adulthood (Spear, 2000; Hiller-Sturmhöfel and Spear, 2018). Two of the major brain pathologies observed as a result of AIE are the reduction in basal forebrain neurons expressing the cholinergic phenotype and decreased levels of hippocampal neurogenesis (Crews et al, 2019)

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