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Principal Investigator: Caitlin Anne Orsini
Organization: UNIVERSITY OF TEXAS AT AUSTIN
Fiscal Year: 2024
Award: $547,810
Funding agency: National Institute on Drug Abuse
Project Summary/Abstract
Poor decision making and elevated risk taking may be due to chronic drug exposure and contribute to continued
drug use and/or promote relapse. Animal models have been invaluable in identifying whether such elevated risk
taking arises from drug-induced alterations in neural substrates that govern risk taking in drug-naïve states (i.e.,
prior to drug exposure). Although there has been significant progress in answering such questions, we still face
a significant barrier in translating these findings to the clinical setting. Not only is our understanding of the neural
substrates of risk taking based on studies using only males, but prior studies have also primarily focused on how
hypersensitivity to reward (as opposed to hyposensitivity to punishment) promotes elevated risk taking after drug
use. Little is known about the neural substrates underlying risk taking in females, let alone how such substrates
are altered after drug exposure. The long-term goal of our research is to uncover the neural and hormonal
mechanisms mediating decision making involving risk of punishment in females in order to identify how these
processes become compromised by substance use. To meet this goal, we will use a rat model of risk taking in
which females are more risk averse and exhibit greater sensitivity to risk of punishment than males. In this model,
female risk aversion is largely mediated by estradiol (E2) and such E2-dependent risk aversion requires estrogen
receptor (ER) β. We have also established a role for the basolateral amygdala (BLA) in promoting risk averse
behavior. Preliminary data show activation of D2 dopamine receptors (D2R) in the BLA leads to risk aversion in
females, but not males, suggesting differences in BLA function may underlie sex differences in risk taking. This
would be consistent with greater overall BLA activity in females than males either at baseline or in response to
aversive stimuli. Prior work shows female-specific BLA activity and BLA-dependent behavior are due to E2’s
ability to modulate BLA function. Hence, our overarching hypothesis is that female risk aversion depends on
E2’s ability to regulate BLA excitability via modulation of ERβ and D2R function and suppression of interneuron
activity. This hypothesis will be tested by pursuing three specific aims. Aim 1 will determine the ER mechanisms
in the BLA that contribute to E2-dependent female risk aversion using behavioral pharmacology, in vivo
electrophysiology and RNA interference-mediated ER gene reduction. Aim 2 will identify the contribution of E2
modulation of BLA D2R function to female risk aversion using genetic ablation and optogenetic manipulation of
BLA neurons that selectively express D2Rs. Aim 3 will evaluate the role of BLA parvalbumin-expressing
interneurons in E2-dependent female risk aversion using fiber photometry and optogenetics. Completion of these
experiments will reveal mechanisms by which E2 mediates risk aversion in females. This information will be
significant because it will provide the necessary foundation from which we can assess the efficacy of targeting
E2-dependent neural mechanisms to alleviate elevated risk taking associated with substance use.
Terms: <Ablation><Abstinence><Address><Agonist><Allergy><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Animal Model><Animal Models and Related Studies><Aquadiol><Attenuated><Aversive Stimulus><Behavior><Cell Body><Cells><Chronic><Circulation><Clinical><Cocaine><Cognition><Common Rat Strains><Connector Neuron><D2 receptor><DRD2 Receptor><Data><Decision Making><Differences between sexes><Differs between sexes><Dimenformon><Diogyn><Diogynets><Dopamine D2 Receptor><Drug Exposure><Drug usage><Drugs><ER-BETA><ERalpha><ERbeta><ERα><ERβ><ESR-BETA><ESR1><ESR1 gene><ESR2><ESR2 gene><ESRB><ESTRB><Electrophysiology><Electrophysiology (science)><Endocrine Gland Secretion><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor 2><Estrogen Receptor alpha><Estrogen Receptor beta><Estrogen Receptor α><Estrogen Receptor β><Estrogen Receptors><Exhibits><Female><Fiber><Foundations><Genetic><Goals><Hormonal><Hormones><Hypersensitivity><Impairment><Impoverished><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Investigation><Knowledge><Lead><Mediating><Medication><Modeling><NR3A1><NR3A2><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Ovocyclin><Ovocylin><Parvalbumins><Pb element><Pharmaceutical Preparations><Photometry><Physiologic><Physiological><Position><Positioning Attribute><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Poverty><Process><Progynon><Punishment><RNA Interference><RNA Silencing><RNAi><Rat><Rats Mammals><Rattus><Receptor Activation><Receptor Gene><Receptor Signaling><Regulation><Relapse><Reporting><Research><Rewards><Risk><Risk Taking><Rodent Model><Role><Sequence-Specific Posttranscriptional Gene Silencing><Sex Differences><Sexual differences><Substance Use Disorder><Testing><Therapeutic Estradiol><Therapeutic Hormone><Translating><Work><amygdaloid nuclear complex><attenuate><attenuates><behavioral pharmacology><cost><determine efficacy><drug relapse><drug use><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><electrophysiological><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><in vivo><male><model of animal><neural><neural mechanism><neurobiological mechanism><neuromechanism><neuronal><optogenetics><pharmacobehavioral><pre-clinical study><preclinical study><programs><receptor function><response><selective expression><selectively expressed><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><shRNA><short hairpin RNA><small hairpin RNA><social role><substance use><substance use and disorder><substance user><substance using>