Biology subjects

Bath, K. G.

Publications and source records attributed to Bath, K. G..

4 recordsLinked to original sources

bioRxiv2025

Behavioral Opportunism and Altered Dopamine Dynamics in Mice Exposed to Early Life Adversity

Early life adversity (ELA) confers risk for reward-related psychopathologies. These risks may stem from adaptations optimizing reward pursuit in anticipation of unreliable, resource poor environments. One rational adaptation to poor, unreliable environments is Behavioral Opportunism: updating expectations more slowly and acting vigorously only when reward is immediately available. To systematically test the impact of ELA on behavioral strategies and underlying reward processing mechanisms, we exposed mice to resource restriction (limited bedding and nesting materials for 7 days) to manipulate the reliability and quality of early life care. Subsequently, we tested adults reward learning and decision making in a two-arm bandit task and recorded dopamine signaling using dLight1.2 fiber photometry in the nucleus accumbens core. Exposure to ELA led to poorer choice discrimination, impaired learning, and decreased adaptation to changes in reward availability. Furthermore, ELA mice were slower to choose between levers but were faster to retrieve immediately available rewards when delivered, consistent with a strategy of behavioral opportunism. Dopamine signaling predicted behavior in both rearing conditions, and its fluctuations were strongly predictive of faster retrieval in ELA mice and an increased likelihood of choice repetition, implying that aberrant dopamine signals underlie slowed learning and vigorous action for immediately available rewards. To understand key features of maternal interactions driving these effects, we used home cage video monitoring to quantify maternal behaviors, continuously, across early life. We found that specific experiential outcomes, such as maternal kicking, intensified behavioral opportunism in adults, predicting poorer bandit task performance beyond the group effect of ELA. Behavioral opportunism provides an explanatory framework for interpreting altered reward processing and reward pursuit in adulthood for individuals exposed to ELA.

animal behavior and cognition↗

bioRxiv2025

Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species

Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depressive phenotypes alongside potentially prohedonic effects of NOPR antagonism across species. In Study 1, we evaluated whether exposure to early-life adversity (ELA) upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. In Study 2, we tested whether chronic social defeat altered Pnoc gene expression in reward-related regions. To establish whether direct NOPR modulation is implicated in reward-related behaviors, in Study 3, we assessed whether NOPR antagonism alters reward learning in rats. Finally, in Study 4, we tested whether NOPR antagonism boosts motivation among depressed humans. ELA induced anhedonic behavior and increased Pnoc expression in the VTA; in females (but not males), ELA increased Pnoc expression in the dorsal striatum (Study 1). Furthermore, chronic stress reduced Pnoc-expressing cells in the VTA, dorsal striatum and prefrontal cortex and susceptible rats showed reduced VTA NOPR gene (Oprl1)-expressing cells (Study 2). In a behavioral assay, a single 30-mg dose of a NOPR antagonist (BTRX-246040) boosted reward learning in rats (Study 3). Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties.

neuroscience↗

bioRxiv2023

Early life adversity reduces affiliative behavior towards a distressed cagemate and leads to sex-specific alterations in corticosterone responses

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both mice 20 or 90 minutes after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

neuroscience↗

bioRxiv2020

Early life adversity decreases fear expression in pre-adolescence by accelerating amygdalar parvalbumin cell development

Resource insecurity (e.g., poverty) can be a significant source of stress. Decreased resources during childhood has been associated with increased risk for developing stress-related disorders, including major depressive disorder and anxiety Although the link between early life adversity and increased risk for psychopathology has been well established, the developmental mechanisms remain unclear. Using a mouse model of poverty-like rearing, limited bedding and nesting materials (LB), we tested the effects of LB on the development of fear learning and of key neuronal structures involved in emotional regulation, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). LB delayed the ability of pre-adolescent mice to express, but not form, an auditory conditioned fear memory. LB disrupted typical fear circuit development, accelerating parvalbumin positive (PV+) inhibitory interneuron maturation in the BLA and delaying the maturation of connections between the mPFC and BLA. The decreased fear expression in LB reared mice during early development was rescued through optogenetic inactivation of PV+ cells in the BLA. Together our data demonstrate that LB has profound and deleterious effects on mPFC and BLA development, decreasing threat-associated behavior expression, but not learning, in childhood. The current results provide a model of transiently blunt emotional reactivity in childhood, with fear-associated memories emerging later in adolescence, and possibly contributing to later pathology development.

animal behavior and cognition↗