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Principal Investigator: Samuel Centanni
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $249,000
Funding agency: National Institute on Alcohol Abuse and Alcoholism
PROJECT SUMMARY/ABSTRACT
Alcohol use disorder (AUD) afflicts millions of individuals and their families each year. AUD is frequently
comorbid with anxiety and depression, indicating potential sources for the motivation to consume alcohol.
Alcoholics commonly list stressors and negative affective states as leading triggers of cravings and relapse,
and severity of the disease state correlates with relapse susceptibility. The health and financial burden
associated with AUD highlights the pressing need for more research focused on understanding the interaction
between AUD and negative affective disturbances. Identifying key neuroadaptations driving this debilitating
disease is essential for developing better diagnostic tools and treatments for affective symptoms in alcohol
abstinence. Converging evidence suggests the transition from social use to negative reinforcement-driven
alcohol seeking involves a set of brain structures collectively referred to as the extended amygdala. The bed
nucleus of the stria terminalis (BNST), a component of the extended amygdala network, is a critical node for
stress-related disorders such as anxiety, depression, and addiction. The BNST plays a prominent role in many
facets of alcohol addiction including binge drinking and cravings in withdrawal. The BNST interacts with many
cortical, subcortical, midbrain, and hindbrain regions to determine general affect. Our recent work identified a
functional connection between the insular cortex (insula) and the BNST. The insula is involved in interoceptive
awareness, cognitive control, and sensory processing, and mounting evidence suggests a role for the insula in
alcoholism and negative affective disturbances. We used a mouse model of chronic drinking followed by forced
abstinence (CDFA) to outline a definitive role for the insula-BNST pathway in abstinence-induced negative
affect, and this proposal will significantly build on this foundational evidence. We will combine in vivo calcium
fiber photometry and ex vivo electrophysiology with genetic mouse lines and a variety of sophisticated viral-
genetic techniques to isolate circuit-specific neuronal ensembles. The mentored (K99) phase will provide
training in fiber photometry and complex viral-genetic manipulation strategies to determine the functional and
physiological state of BNST neurons receiving insular inputs (Aim 1) and insular neurons that project to the
BNST (Aim 2) in the protracted abstinence phase of CDFA. The independent (R00) phase will identify 2nd order
inputs onto insulaàBNST neurons, with the goal of further delineating the complex neurocircuitry regulating
abstinence-induced negative affect. The proposed studies and related career development training plan in this
Pathway to Independence Award collectively provide the ideal mechanism to transition the applicant to a
career as an independent addiction neuroscientist. The results will significantly advance our understanding of
the neural adaptations that occur in protracted abstinence following chronic alcohol abuse.
Terms: <Abstinence><Affect><Affective><Affective Symptoms><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcohol dependence><Alcoholic><Alcoholism><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anterior><Anxiety><Anxiety Disorders><Automobile Driving><Award><Awareness><Bed Nucleus of Stria Terminalis><Behavior><Boozer><Brain><Brain Nervous System><Brain imaging><Calcium><Cell Nucleus><Central Lobe><Characteristics><Chronic><Chronic Phase><Complex><Connector Neuron><Coupled><DNA Recombination><DREADDs><Data><Dependent drinker><Diagnostic><Disease><Disorder><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><EtOH abuse><EtOH drinking><EtOH use><Exhibits><Family><Fiber><Financial Hardship><Food><Genetic><Genetic Recombination><Genetic Technics><Genetic Techniques><Goals><Health><Heterogeneity><Hind Brain><Human><Hyperactivity><Individual><Insula><Insula of Reil><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Island of Reil><Link><Major Depressive Disorder><Mental Depression><Mental disorders><Mental health disorders><Mentors><Mesencephalon><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Modern Man><Motivation><Murine><Mus><Negative Reinforcements><Nerve Cells><Nerve Unit><Neural Cell><Neural Pathways><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus><Output><PTSD><Pathway interactions><Patients><Pattern><Phase><Photometry><Physiologic><Physiological><Play><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Predisposition><Psychiatric Disease><Psychiatric Disorder><Recombination><Regulation><Relapse><Reporting><Research><Rhombencephalon><Role><Sensory><Severities><Severity of illness><Somatosensory Cortex><Source><Stress><Stria Terminalis Nucleus><Structure><Structure of terminal stria nuclei of preoptic region><Susceptibility><Symptoms><Synapses><Synaptic><Testing><Thalamic structure><Thalamus><Therapeutic><Time><Training><Viral><Viral Genetics><Virus><Withdrawal><Work><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><addiction><addictive disorder><affective disturbance><alcohol abstinence><alcohol addiction><alcohol co-abuse><alcohol dependency><alcohol dependent><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol seeking><alcohol seeking behavior><alcohol use><alcohol use disorder><alcoholic beverage consumption><alcoholic drink intake><amygdaloid nuclear complex><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><associated symptom><binge alcohol consumption><binge drinking><brain visualization><career><career development><cell type><clinical depression><co-morbid><co-morbid symptom><co-morbidity><co-occuring symptom><cognitive control><comorbid symptom><comorbidity><concurrent symptom><cooccuring symptom><craving><depression><designer receptors exclusively activated by designer drugs><diagnostic tool><disease severity><disturbance in affect><drinking><driving><electrophysiological><episodic drinking><ethanol abstinence><ethanol abuse><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol seeking><ethanol use><ethanol use disorder><ethanol-seeking behavior><feeding><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><hazardous alcohol use><hindbrain><in vivo><major depression><major depression disorder><mental illness><mood alteration><mood and affect disturbance><mood disturbance><mood dysfunction><mouse model><murine model><negative affect><negative affectivity><neural><neural adaptation><neural circuit><neural circuitry><neural imaging><neuro-imaging><neuroadaptation><neurocircuitry><neuroimaging><neurological imaging><neuronal><novel><pathway><post-trauma stress disorder><posttrauma stress disorder><problem alcohol use><problem drinker><problem drinking><problematic alcohol consumption><problematic alcohol use><prophylactic><psychiatric illness><psychological disorder><side effect><social><social role><somesthetic sensory cortex><stress related disorder><stressor><symptom association><symptom comorbidity><synapse><synaptic circuit><synaptic circuitry><thalamic><therapeutic target><traumatic neurosis><virus genetics>