The long-term goal of this project is to map neural circuits in order to understand how adult neurogenesis accounts for cognition and mental stability, as well as how dysfunctions of neural circuits of new neurons underlie neurological, affective, addictive, and psychiatric diseases. The persistent production and incorporation of new neurons into hippocampal circuits (neurogenesis) plays a key role in learning and memory, but almost nothing is understood about how adult neurogenesis can impact and contribute to normal and pathological brains. In this application, we propose to understand the role of new neurons in cognition and emotion at the circuitry level. To understand neural circuits formed by neurogenesis in normal and pathological brains, we will determine the precise connectivity of new neurons in normal and alcoholic brains. Alcohol use disorder (AUD) is one of the most prevalent and devastating neurological and addictive disorders causing cognitive impairments. We hypothesize that chronic alcohol abuse negatively regulates proliferation and neuronal production of neural stem cells (NSCs), and that aberrant neural circuit formation of hippocampal newborn neurons may underlie cognitive and addictive behaviors of alcoholic mice. In order to understand how chronic alcohol abuse contributes to aberrant neural circuits of new neurons, we will apply a novel rabies virus-mediated retrograde transsynaptic system to determine altered brain inputs into newborn neurons.
In Aim 1, we will test the hypothesis that chronic alcohol abuse disrupts proliferation and neuronal differentiation of NSCs.
In Aim 2, we will test the hypothesis that chronic alcohol interferes with synapse formation of input neurons and physiological maturation of new neurons.
In Aim 3, we will determine aberrant neural circuits caused by hippocampal newborn neurons in order to test the hypothesis that chronic alcohol induces abnormal circuit formation of hippocampal newborn neurons. We will particularly investigate whether chronic alcohol disrupts and reinforces circuits for cognition and addiction, respectively.
In Aim 4, we will test impaired cognitive behaviors of alcoholic mice in order to understand the consequence of abnormal neural circuit formation induced by chronic alcohol exposure. These studies will provide mechanistic insights into the role of new GCs and the abnormal circuits involved in alcohol-induced behavior deficits, which will likely suggest potential therapeutic targets for AUD. Furthermore, this knowledge has direct implications for the potential therapeutic modulation of neurogenesis in a variety of brain diseases.

Public Health Relevance

The development of new therapies for neural circuit disorders including affective, addictive, and neurodegenerative diseases requires a better understanding of the brain circuits altered in these conditions. The present proposal applies a novel tracing system to dissect out neural circuits of new GCs in normal and chronic alcohol abuse mouse models. Our studies will provide both qualitative and quantitative information on neural circuits of new GCs, with an unprecedented specificity and resolution.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA022377-01A1
Application #
8694664
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Regunathan, Soundar
Project Start
2014-09-05
Project End
2019-08-31
Budget Start
2014-09-05
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$356,625
Indirect Cost
$131,625
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195