Research Projects

Project 1: Identify how early adversity can alter risk/resilience for addiction-related phenotypes across development.

Early life trauma can increase the risk for later disorders linked to altered motivation, such as substance use disorder (SUD) and major depression. However, early stress that is not overwhelming can have a later “inoculating” effect, promoting better stress coping and resilience. Our lab uses a rat manipulation of brief early resource scarcity, the limited bedding and nesting (LBN) model, to assess the lasting effects on motivation for drug- and natural- rewards. We have found that in adult male rats exposed to LBN, there is an increase in motivation for natural rewards but a reduction in motivation for opioids. In contrast, in adult female rats, LBN reduces motivation for sucrose, perhaps reflecting anhedonia. We are now pursuing underlying mechanisms by determining how LBN alters cell-type-specific gene transcription and epigenetic changes in key regions of the reward circuit. Additionally, we are beginning to elucidate the developmental trajectory of these effects by characterizing changes in motivated behavior and molecular mechanisms in adolescence. Understanding the mechanisms and developmental timing by which the early environment can alter later motivation may reveal novel targets for treating certain psychiatric disorders. This research is funded by grants from the National Institute on Drug Abuse (NIDA).

Project 2: Identify sex differences in the effects of the stress neuropeptide, corticotropin-releasing factor (CRF), and their cause.

We previously found that the locus coeruleus-arousal system of female rats was more sensitive to CRF than that of male rats due to sex differences in the CRF1 receptor. Currently, we are looking at other regions that are a target of CRF regulation with a focus on cholinergic areas. We found that CRF in the medial septum (a major source of acetylcholine for the hippocampus) impairs spatial learning in male and female rats. However, males are more sensitive, responding to a low dose of CRF in the medial septum that does not affect females. Females may be protected from low levels of CRF in the medial septum, because in this region they have more CRF binding protein, an endogenous protein that sequesters CRF preventing its bioavailability. We are now following up to determine the downstream consequence of CRF on hippocampal acetylcholine release. Additionally, we are using a novel four-core genotype-like rat model to determine whether sex differences in CRF regulation of the medial septum are due to hormone effects or sex chromosome effects. Understanding sex differences in CRF sensitivity may help reveal why women are more likely to suffer from disorders with hyperarousal features, such as PTSD, and men are more likely to suffer from disorders with cognitive deficits, such as schizophrenia. This research is funded by grants from the National Science Foundation and the National Institute of Mental Health.

Project 3: Determine how early resource scarcity causes lasting changes in non-neuronal cells.

In addition to altering motivated behavior, LBN also alters cognition. LBN reduces impulsivity in adult male rats and risky decision-making across sexes. These cognitive processes are regulated by glutamate signaling in the frontal cortex and proper glutamate function relies on astrocytes. A new project in our lab demonstrates that LBN causes lasting changes in astrocyte morphology. Ongoing studies are now linking these structural changes to the function and expanding our work to look at the impact of LBN on other non-neuronal cells. This research is funded by grants from NIDA.

Project 4: Determine how resource scarcity affects maternal behavior and alters the maternal brain.

We have shown that dams in a low-resource environment induced by LBN have altered maternal care such that they increase pup-directed behavior, perhaps to compensate for the low resources. However, this shift towards caring for pups comes at the expense of “self-care”, such that LBN dams rarely rest outside the nest or self-groom. This shift likely reflects a high arousal state in LBN dams. Ongoing projects are extending our behavioral phenotyping of LBN dams to assess the impact on other maternal behaviors (e.g., aggression, pup motivation). We are also exploring how LBN alters circuits involved in maternal behavior. Understanding how low resources affect maternal behavior and the maternal brain is clinically relevant, and these studies may help guide interventions to improve maternal health.

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