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Principal Investigator: Constanza Garcia Keller
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $248,999
Funding agency: National Institute on Drug Abuse
Converging epidemiological studies indicate that a life-threatening event increases the incidence of post-
traumatic stress disorder (PTSD), which carries a 30-50% comorbidity with substance use disorders (SUDs).
Such comorbidity results in greater drug use and poorer treatment outcomes. The proposed research builds
upon my recent publication, where I showed a remarkable overlap between the enduring neuroadaptations
produced in nucleus accumbens core (NAcore) excitatory transmission after acute restraint stress and drug use.
Recently, I paired a stressful event with a novel odor and found that the stress-conditioned odor alone induced
cocaine seeking. In NAcore, ~95% of neurons are medium spiny neurons (MSNs) chemically coded as
selectively expressing D1 or D2 dopamine receptors. Different studies showed that D1 activation generally
promotes and D2 activation inhibits behaviors during drug seeking. At molecular level, I observed that activated
matrix metalloproteases signal through β3-integrins and are required for the transient synaptic plasticity (t-SP)
characteristic of drug seeking elicited by cocaine cues. Here, I will examine the role of D1- and D2-MSN neuronal
activity in response to stress-conditioned cues and determine if the changes in neuronal activity encode coping
behavior or cocaine seeking. Furthermore, I will determine if changes in activity in D1- and D2-MSNs are integrin-
mediated. To accomplish this, I will be trained in vivo single cell Ca2+ transients in real time. I will also use
DREADDS technology for cell-type specific modulation and Cre-dependent shRNA for cell-specific target protein
knockdown. In the K99 aims, I propose to determine if exposure to stress-conditioned cues elicit different patterns
of activity during defensive burying (DB) (Aim 1). I will selectively inactivate D1- or D2-MSNs during restraint
stress to evaluate the necessity of each cell type for encoding coping during DB (Aim 2A) and I will evaluate if
the activity in either cell type is dependent upon β3-integrin signaling using Cre-dependent shRNA knockdown
(Aim 2B). MUSC provides an ideal research environment in which to attain this training and complete these aims,
as it boasts one of the leading neuroscience departments for addiction research with multi-PI center grants. This
training will enhance my qualifications for transitioning to an independent tenure-track faculty position at a major
research institution, which is my ultimate goal. Moreover, Dr. Kalivas is a well-established mentor who has
demonstrated abundant success in facilitating the transition of his postdoctoral trainees to faculty positions. Once
I achieve a faculty appointment during the R00 period, I will determine if the changes in Ca2+ transient in D1- or
D2-MSNs during stress-conditioned cues are similar to those observed during stress-induced cocaine seeking
(Aim 3). I will examine the necessity of each cell type for encoding cocaine seeking (Aim 4A) and I will evaluate
if the activity in either cell type is dependent upon β3-integrin signaling (Aim 4B). These experiments have the
potential to reveal novel neurobiological mechanisms of PTSD that induce the increased vulnerability to SUDs.
Understanding this link will enhance our ability for rational drug design to treat comorbid PTSD and SUDs.
Terms: <Acute><Animal Model><Animal Models and Related Studies><Animals><Appointment><Behavior><Biological><Brain><Brain Nervous System><CD61><CD61 Antigens><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Chemicals><Chemosensitization><Chemosensitization/Potentiation><Cocaine><Code><Coding System><Common Rat Strains><Coping Behavior><Corpus Striatum><Corpus striatum structure><Cues><D2 receptor><DRD2 Receptor><DREADDs><Diagnosis><Dopamine D2 Receptor><Drug Design><Drug usage><Drugs><Encephalon><Environment><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Event><Excitatory Synapse><Exposure to><Faculty><GP IIIa><GP3A><GPIIIa><Glutamates><Goals><Grant><History><ITGB3><ITGB3 gene><Image><Incidence><Individual><Institution><Intake><Integrin Beta 3><Integrin beta3><Integrin β3><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><L-Glutamate><Life><Link><LoxP-flanked allele><Mediating><Medication><Mentors><Metallopeptidases><Metalloproteases><Metalloproteinases><Molecular><NAIT><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuronal Transmission><Neurons><Neurosciences><Nucleus Accumbens><Odors><PTP gene><PTSD><Pattern><Pharmaceutical Preparations><Phase><Platelet Fibrinogen Receptor, Beta Subunit><Platelet GPIIIa><Platelet Glycoprotein IIIa><Platelet Membrane Glycoprotein IIIa><Play><Position><Positioning Attribute><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Postdoc><Postdoctoral Fellow><Posttraumatic Neuroses><Potentiation><Predisposition><Prevalence><Proteins><Publications><Qualifying><Rat><Rats Mammals><Rattus><Recording of previous events><Regulation><Research><Research Associate><Role><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Stressful Event><Striate Body><Striatum><Structure><Substance Use Disorder><Susceptibility><Synapses><Synaptic><Synaptic plasticity><Technology><Testing><Time><Training><Transmission><Trauma><Treatment outcome><acute stress><addiction><addictive disorder><avoidance behavior><axon signaling><axon-glial signaling><axonal signaling><biologic><biological signal transduction><cell type><co-morbid><co-morbidity><cocaine cue><cocaine seeking><cocaine use><comorbidity><coping><designer receptors exclusively activated by designer drugs><drug relapse><drug use><drug use vulnerability><drug/agent><epidemiologic investigation><epidemiology study><experience><experiment><experimental research><experimental study><experiments><floxed><floxed allele><glia signaling><glial signaling><glutamatergic><histories><imaging><in vivo><insight><knock-down><knockdown><model of animal><nerve signaling><neural adaptation><neural mechanism><neural signaling><neuroadaptation><neurobiological mechanism><neuromechanism><neuronal><neuronal signaling><neurotransmission><novel><post-doc><post-doctoral><post-doctoral trainee><post-trauma stress disorder><posttrauma stress disorder><prevent><preventing><programs><research associates><response><restraint stress><selective expression><selectively expressed><shRNA><short hairpin RNA><small hairpin RNA><social role><stress disorder><stressful experience><stressful life event><stressful life experience><striatal><substance use and disorder><success><synapse><tenure process><tenure track><transmission process><traumatic event><traumatic neurosis><vulnerability to drug use>