Alcohol abuse represents a major clinical condition in the Unites States and worldwide40. Despite the prevalence of alcohol dependence and the well-known adverse effects of chronic alcohol exposure, the neurobiological mechanisms mediating alcohol?s effects in the brain are still not fully understood. The challenge of current and future studies is to understand the neurobiological changes that influence tolerance and dependence in motivational systems that lead to chronic drinking. The amygdala is a major component of the brain involved in the motivational effects of drugs of abuse and alcohol in particular27. Local inhibition is a key element of this circuitry and a critical component of the behavioral effects of acute and chronic ethanol consumption24,27,32. Numerous studies on amygdala circuitry have focused on fear and demonstrated a critical role for local microcircuits in the basolateral amygdala (BLA) in the acquisition and expression of conditioned fear (for review, see Ehrlich et. al15). Despite the thorough investigation of this circuitry in the fear literature and the common thread of negative association and learned behavioral responses between fear and alcohol dependence, much less is known about how ethanol engages and/or alters specific microcircuits in the amygdala to produce long-lasting behavioral effects. Previous studies in the BLA indicate that acute and chronic ethanol alter excitatory and inhibitory transmission28,29,30,36,63,75 however studies examining how these changes impact the activity of specific components of amygdala circuitry are lacking. In addition, no studies have employed parallel cellular and whole-animal approaches to assess how the actions of alcohol are integrated into overall amygdala network function. Recent work by our group demonstrated an important role of the CRF1 system in the effects of ethanol on local circuitry in the central amygdala23. These studies highlight the cell-type specific effects of ethanol on the CRF1 system within the CeA, however how the CRF1 system fits into the BLA network remains unclear. Thus, the major goals of the current proposal are to employ a combined cellular electrophysiological, neuroanatomical, and in vivo microdialysis approach to 1) characterize CRF1+ and CRF1- neurons in two discrete sub-regions of the BLA, the LA and BM, 2) examine the phasic and tonic inhibitory transmission in these neurons and the sensitivity of that transmission to acute ethanol at both the cellular and intact network level, 3) determine the local functional and long-range anatomical connectivity of CRF1+ and CRF1- neurons in the BLA, and 4) determine the effects of chronic ethanol exposure on the activity of this microcircuitry at a cellular and network level.

Public Health Relevance

Despite the prevalence and adverse biological and social effects of alcohol dependence, the neurobiological mechanisms mediating alcohol?s effects in critical brain regions such as the amygdala remain unclear. A better understanding of the neuroadaptations produced by ethanol in the CRF1 system within specific amygdala circuitry would provide important information on the increased vulnerability of certain individuals to the reinforcing properties of ethanol and identify possible therapeutic targets to treat and/or reverse the negative effects of ethanol on this critical brain circuit.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Transition Award (R00)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Liu, Qi-Ying
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University of North Carolina Chapel Hill
Chapel Hill
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Agoglia, Abigail E; Herman, Melissa A (2018) The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry. Alcohol 72:61-73
Borghese, Cecilia M; Herman, Melissa; Snell, Lawrence D et al. (2017) Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes. Sci Rep 7:6230
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Valentino, Rita J; Guyenet, Patrice; Hou, Xun Helen et al. (2017) Central Network Dynamics Regulating Visceral and Humoral Functions. J Neurosci 37:10848-10854
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