The consequences of alcohol abuse on the American public are profound, both in terms of individual well-being and impact on the family structure, as well as the enormous cost to society in terms of lost productivity and associated health care expenses. Despite increasing efforts, our understanding of the neurobiological mechanisms that underlie the effects of alcohol and the development of alcohol use disorders (AUD) remains incomplete. Epidemiological research has pointed to adolescence as a critical period in the development of alcohol disorders. The prefrontal cortex (PFC) is a brain region that is not yet mature at the onset of human adolescence and continues to develop during this period, during which some individuals may be highly susceptible to the effects of alcohol. The PFC mediates control over goal-directed behaviors and dysfunction of the PFC is thought to underlie compulsive drug-taking and relapse in substance abusers. Binge drinking is highly prevalent in adolescents, and episodes of high alcohol intake have been associated with decreased PFC activity and function (hypofrontality). Imaging studies suggest that hypofrontality persists in chronic alcohol abusers, and may therefore be a contributory factor in the development of AUDs and behavioral pathologies in adulthood. The underlying mechanisms of this PFC hypoactivity are unknown, and the development of robust animal models would therefore be useful in investigating the underlying changes in neuronal excitability. A better understanding of these changes would enable possible molecular and therapeutic interventions in order to prevent the development of alcoholism. One plausible mechanism for hypofrontality involves the depression of persistent activity, a mode of firing that can be observed in recordings from pyramidal neurons in the PFC of rodents. This type of activity is seen at more depolarized membrane potentials and is associated with performance in working memory tasks, and is dependent on the Ih current, which is mediated by a family of hyperpolarization-activated and cyclic nucleotide modulated (HCN) channels. We propose that chronic changes in persistent firing might result from prolonged alcohol exposure. To date there have been few detailed studies of excitability in the PFC after drinking and none in adolescent rodents. In three separate but integrated aims, we plan to test the overall hypothesis that the HCN1 channel that contributes to the Ih current in PFC PNs is important for the regulation of alcohol drinking, and specifically that (a) binge drinking of alcohol during adolescence inhibits persistent firing and excitability in the PFC via reduction of Ih and (b) reduction in HCN1 channel activity in layer 5 of PFC can mimic the effects of alcohol consumption during adolescence, while (c) activation or over-expression of HCN1 channels can restore persistent activity and normal levels of excitability in PFC of binge drinking adolescent animals.

Public Health Relevance

Binge drinking of alcohol during adolescence is a major risk factor for the abuse of alcohol and other drugs later in life. The goal of this proposal is to bettr understand the effects of alcohol on the adolescent brain, which will be accomplished by measuring changes in brain cell activity in the prefrontal cortex of animals that drink alcohol during adolescence. Findings from this work will raise awareness on the vulnerability of the brain to alcohol during adolescence and could lead to the development of medicines and other forms of therapy to prevent or reverse the abuse of alcohol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA023531-03
Application #
9210583
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2015-02-15
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$375,563
Indirect Cost
$140,836
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Harrison, Neil L; Skelly, Mary Jane; Grosserode, Emma K et al. (2017) Effects of acute alcohol on excitability in the CNS. Neuropharmacology 122:36-45
Canetta, S; Bolkan, S; Padilla-Coreano, N et al. (2016) Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol Psychiatry 21:956-68
Avegno, Elizabeth M; Salling, Michael C; Borgkvist, Anders et al. (2016) Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area. Neuropharmacology 110:386-395
Salling, Michael C; Martinez, Diana (2016) Brain Stimulation in Addiction. Neuropsychopharmacology 41:2798-2809