Closing the Gap on Substance Use And The Female Brain
Interviewee: Yanaira Alonso Caraballo, PhD, University of Minnesota | Editors: Romina Garcia de leon, Janielle Richards (blog coordinators)
Can you tell us about your research?
My research focuses on understanding how female-specific life experiences, hormonal transitions, and behaviors shape the brain circuits that regulate motivation and reward seeking. During my Ph.D., I investigated how the reproductive cycle and ovarian hormones influence motivation for food-seeking behaviors, with a particular focus on the nucleus accumbens (NAc). The NAc is a key brain region involved in processing food cues and modulating decision-making and reward-seeking behaviors.
In my postdoctoral work, I have expanded my research into the field of opioid use disorder. Specifically, I have been studying opioid relapse after abstinence and the possible underlying brain circuitry. I focused my work on the paraventricular nucleus of the thalamus (PVT) to the NAc pathway, a circuit known to integrate external cues and modulate both appetitive (e.g., reward-seeking) and aversive (e.g., withdrawal symptoms) motivational states. My long-term research aims to define how ovarian hormones shape motivation and reward circuits, how these circuits shift between adaptive and maladaptive states, and how female-specific life experiences remodel the brain’s reward system.
How do you study this?
My research uses rodent models to investigate how motivation and reward-seeking behaviors are regulated by specific brain circuits, particularly in the context of female-specific experiences and opioid use. In these experiments, rodents are trained in operant conditioning chambers (Skinner boxes) equipped with levers that, when pressed, deliver rewards, in my case either food pellets or intravenous opioid infusions. This allows us to measure motivation by assessing lever-pressing behavior in response to different rewards. We also incorporate cue-based paradigms, where a cue (light or noise) signals the drug’s availability. This enables us to measure the urgency and patterns of seeking behavior, including during time periods when the drug is unavailable.
To model abstinence and relapse, animals undergo abstinence periods, which can range from 24 hours to several weeks. In this model of abstinence (called forced abstinence), animals are brought back to their home cages without any exposure to the reward (in this case, opioids). Relapse-like behavior is then measured by how quickly and persistently animals press on a lever upon re-exposure to the previous drug cue but not the drug itself.
Beyond behavior, we examine the underlying neural mechanisms by analyzing glutamatergic plasticity and neuronal excitability, which have been shown to increase during craving states. Using brain slice electrophysiology, we assess changes in neuronal excitability and firing patterns associated with these motivational states. In current studies, I also use in vivo optogenetic circuit manipulation to precisely activate or inhibit specific pathways, such as the PVT-NAc, to test how these circuits drive or suppress motivated behaviors following abstinence.
Are there any findings you can share with us?
When examining sex differences during opioid abstinence, we observed that both males and females exhibited similar neuroadaptations at the 24-hour and 14-day timepoints. However, females displayed significantly greater relapse-like behaviors after 14 days compared to males. At the circuit level, our data revealed that the PVT-NAc pathway undergoes dynamic, time-dependent synaptic adaptations during abstinence, with sex-specific changes emerging in glutamatergic transmission. Notably, females exhibited distinct early-phase synaptic adaptations during abstinence that were absent in males, suggesting that females may engage unique neuroplastic processes that precede and potentially drive the stronger incubation of craving and relapse-like behavior observed after prolonged abstinence.
This temporal profile in females closely aligns with the “incubation of craving” framework, in which relapse vulnerability escalates over time as a result of accumulating neural adaptations. Notably, at extended abstinence periods, both sexes showed enhanced glutamatergic transmission in the PVT-NAc pathway, which may contribute to relapse risk in both sexes. These studies provide the foundation for my ongoing K99/R00 research aimed at dissecting the circuit- and cell-type-specific drivers of opioid motivation and relapse vulnerability.
Where do you see your research heading?
The motivation behind my research stems from the long-standing gap in our understanding of female neurobiology, particularly regarding motivation, reward, and addiction. For decades, both preclinical and clinical studies have predominantly focused on male models, resulting in limited knowledge about how the female brain functions, even in areas critical for developing effective medical treatments.
My scientific goal is to conduct studies emphasizing a female-centered understanding of brain circuits, rather than simply comparing females to males. Going forward, my research will focus on examining female neurobiology on its terms, particularly how hormonal states and life transitions, such as pregnancy, postpartum, and menopause, interact with feeding behavior, drug use, and relapse vulnerability. For example, opioid use engages brain circuits differently in females, yet opioids are frequently prescribed during reproductive events. Despite this widespread use, we have limited understanding of how opioid exposure affects the female brain, especially during sensitive periods like postpartum, and how it may influence maternal behaviors and increase relapse vulnerability in the short and long term. Addressing these critical gaps is central to my research program, which aims to generate mechanistic insights that can inform our understanding of female neurobiology and its implications for mental health.
