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Principal Investigator: Kathryn Elizabeth Evans
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $53,974
Funding agency: National Institute on Drug Abuse
Project Summary
The central goal of this proposal is to characterize the role of the insular cortex (InsCtx) in encoding
and shaping the physiological drive to consume nicotine in nicotine-dependent mice. The InsCtx
integrates sensory, visceral, and limbic information and is implicated in interoception: the sensing of internal
bodily states. Interoception plays a crucial role in the development of addiction because the rewarding effects
of addictive drugs and the aversive aspects of withdrawal are largely experienced as bodily sensations.
Functional imaging in human smokers shows that InsCtx responses to smoking-related cues increase with self-
reported craving intensity and with the expectancy of receiving nicotine. Intriguingly, after strokes involving the
InsCtx, smokers report increased rates of smoking cessation and fewer nicotine cravings. Nevertheless, it
remains unclear how the InsCtx encodes nicotine-replete and withdrawal states during the development of
nicotine dependence, and if targeted InsCtx manipulations can curb cued nicotine-seeking behaviors. This gap
in understanding is due in part to our inability to track the activity of large numbers of neurons throughout the
development of dependence on and withdrawal from nicotine (or other addictive drugs). I have overcome this
challenge by adapting our lab’s conceptual and technical framework for chronic two-photon calcium imaging of
hundreds of InsCtx neurons during shifts in hunger/thirst to investigate InsCtx encoding of nicotine states and
nicotine-predicting cues. Specifically, I propose to track InsCtx neurons as mice (i) develop nicotine
dependence via home-cage drinking water exposure, and (ii) learn to respond to visual cues in order to receive
oral nicotine rewards. In Aim 1, I will test the hypothesis that as an animal becomes dependent on nicotine, the
pattern of InsCtx ongoing activity encoding states of satiety will change across days to reflect this new bodily
state. Because nicotine has direct effects centrally on the brain as well as peripherally on bodily physiology, I
will use natural and pharmacological manipulations to determine if ongoing InsCtx activity patterns reflect the
central and/or peripheral actions of nicotine. In Aim 2, I will examine how InsCtx responses to nicotine-
predicting cues correlate with concurrent recordings of mesolimbic dopamine release in the nucleus
accumbens, which is known to mediate some of the rewarding aspects of addictive drugs and is profoundly
altered in states of addiction. I will then test the hypothesis that acute optogenetic silencing of the InsCtx will
disrupt learned dopaminergic and behavioral responses to nicotine-predicting cues. These experiments will
advance our understanding of how InsCtx activity patterns change during the emergence of nicotine
dependence, and will define the role of the InsCtx in drug-seeking behaviors. This work will improve our
understanding of how exposure to nicotine modifies the neural representations associated with ‘physiological
satiety’ during the development of drug dependence, and may help establish a basis for novel manipulations of
insular cortex activity that achieve reductions in drug-seeking behaviors in patients with nicotine use disorders.
Terms: <2-photon><Acute><Affect><Animals><Apoplexy><Area><Behavior><Behavioral><Brain><Brain Nervous System><Brain Vascular Accident><Brain region><Calcium><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemical Dependence><Chronic><Cigarette><Clinical><Consumption><Cues><Decision Making><Dependence><Development><Dopamine><Drug Addiction><Drug Dependence><Drug Dependency><Drugs><Encephalon><Esthesia><Expectancy><Food><Functional Imaging><Future><Goals><Gustation><Head><Home><Human><Hunger><Hydrogen Oxide><Hydroxytyramine><Image><Individual><Intake><Interoception><Intracellular Communication and Signaling><Learning><Measurement><Mediating><Medication><Mice><Mice Mammals><Modern Man><Murine><Mus><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nicotine><Nicotine Dependence><Nicotine Use Disorder><Nicotine Withdrawal><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Nucleus Accumbens><Olfaction><Oral><Patient Self-Report><Patients><Pattern><Perception><Peripheral><Pharmaceutical Preparations><Photometry><Physiologic><Physiologic Imaging><Physiological><Physiology><Play><Population><Preparation><Protocol><Protocols documentation><Regulation><Reporting><Rewards><Role><Satiation><Self-Report><Sensation><Sensory><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Smell><Smell Perception><Smoker><Smoking><Stroke><Taste><Taste Perception><Testing><Thirst><Time><Training><Visceral><Visual><Water><Withdrawal><Work><addiction><addictive disorder><after stroke><antagonism><antagonist><behavior response><behavioral response><biological signal transduction><bodily sensation><brain attack><cease smoking><cell cortex><cerebral vascular accident><cerebrovascular accident><craving><developmental><drinking water><drug development><drug seeking behavior><drug/agent><experience><experiment><experimental research><experimental study><experiments><exposure to nicotine><gustatory perception><gustatory processing><gustatory response><hedonic><homes><imaging><imaging study><improved><insight><mouse model><murine model><neural><neuronal><nicotine addiction><nicotine consumption><nicotine craving><nicotine cue><nicotine dependent><nicotine exposure><nicotine reward><nicotine seeking><nicotine seeking behavior><nicotine treatment><nicotine use><novel><odor perception><olfactory perception><optogenetics><pharmacologic><physiological imaging><post stroke><poststroke><preparations><quit smoking><response><satiety><sensory integration><smoking cessation><social role><stop smoking><stroked><strokes><taste processing><taste response><tobacco smokers><two-photon>