Research

Current projects

• Effects of social isolation on the brain and social behavior

In 2023, U.S. Surgeon General Dr. Vivek Murthy declared a national epidemic of loneliness and social isolation, drawing attention to studies showing that a significant portion of Americans currently lack adequate social support. This declaration echoes a growing body of research identifying social isolation as a major risk factor for mental health conditions, including anxiety, depression, psychosis, and cognitive decline. To develop effective and targeted interventions for social isolation, it is crucial to first understand how isolation impacts the brain. 

My current research investigates the effects of social isolation on mental health through the lens of social behavior, as disruptions in social behavior are a core feature of mental disorders associated with social isolation. Previous studies in both humans and non-human animals have shown that short-term isolation increases social engagement, while long-term isolation leads to social withdrawal. Despite this well-documented contrast, the underlying brain mechanisms that promote social engagement after short-term isolation, and how they are altered over long-term isolation to eventually lead to social withdrawal remain unclear. 

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In my recent work (Zhao et al., PlosONE, 2021; Zhao et al., eLife, 2025), I found that short-term (3-day) isolation of female mice significantly enhances social investigation, mounting, and the production of ultrasonic vocalizations (USVs) during subsequent interactions with a novel female mouse. This behavioral paradigm is particularly valuable because it focuses on female-female interactions, an affiliative social context that has been largely overlooked in previous research that predominantly included male subjects. This paradigm also provides a unique opportunity to investigate how the brain is rapidly reshaped to promote social behaviors following social isolation. Using immediate-early gene mapping and TRAP2-based activity-dependent viral labeling, I identified a population of neurons in the preoptic area of the hypothalamus (POAsocial neurons) that increase their activity following same-sex interactions in single-housed females. Silencing POAsocial neurons using DREADDs attenuates the effects of isolation on social behavior in single-housed females, while activation of these neurons recapitulates the effects of isolation on promoting social behaviors in group-housed females. These findings reveal neural plasticity in the POA as a key mechanism in mediating the effects of social isolation on social behaviors. In humans, the POA also plays a critical role in regulating socioemotional behavior. My work provides an entry point for further exploring the therapeutic potential of POAsocial neurons in restoring disrupted social behaviors observed in neuropsychiatric disorders. 

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Previous Projects

• Social environments as source of individual variation in responses to testosterone’s rewarding effects and its rapid effect on social-decision making.

Testosterone has rewarding properties that influence a wide range of behaviors and brain functions. Previous research in both animals and humans suggests individual differences in testosterone's rewarding capacity. In my PhD thesis, I explored the source of these individual differences by demonstrating how changes in social environment, such as isolation and pair-bonding, influence animals' responses to testosterone's rewarding effects. Using California mice (Peromyscus californicus), a monogamous social species, I found that social isolation increased testosterone's rewarding effects by encouraging animals to spend more time in the environment where testosterone was administered, a phenomenon known as conditioned place preference. Conversely, pair-bond formation dampened testosterone's rewarding effects in inducing a place preference for a novel environment but increased it for a familiar environment associated with testosterone administration. These findings suggest that changes in social connections may interact with environmental familiarity to influence an individual's response to testosterone's rewarding effects. At the neurobiological level, my research revealed elevated levels of androgen receptors in the hypothalamus of isolated male mice, which correlated with changes in conditioned place preference. This demonstrates the role of POA androgen signaling as a mechanism to mediate the impact of isolation on an individual's sensitivity to testosterone's rewarding properties. 

Beyond testosterone’s rewarding effects, my research also provided the first empirical evidence suggesting testosterone has rapid effects on an animal's social decision-making in challenge/opportunity situations. Specifically, a testosterone injection quickly altered male California mice's behavior, redirecting their focus from a mating opportunity (a female mouse) to confronting a potential threat (a novel male intruder). Notably, pair-bonded males showed a significantly reduced response to these rapid testosterone-induced changes in social decision-making. This finding, in conjunction with my earlier work, illuminates the critical role of social environments in shaping an individual's response to testosterone's effects.

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• Effects of environmental enrichment on early-life adversity

Environmental enrichment (EE) involves creating stimulating environments that offer a variety of sensory, cognitive, and social experiences. While known to enhance brain function, the effects of EE on early-life adversity remain incompletely understood. I addressed this knowledge gap using a mouse model of maternal immune activation (MIA)—a type of early-life adversity associated with heightened neurodevelopmental disorder risk in offspring. Specifically, my research uncovered that EE can alleviate the disruptive effects of MIA on the social motivation of offspring. I also uncovered the molecular and cellular mechanisms underlying this mitigation, showing that EE can reduce elevated plasma corticosterone levels and normalize the dysregulation of multiple hippocampal mRNA markers related to the hypothalamic-pituitary-adrenal axis. In addition to demonstrating the benefits of EE, my research also revealed that social isolation, when experienced following prolonged exposure to EE, can act as a stressor to exacerbate the effects of MIA on cognitive performance assessed through a visual pairwise discrimination paradigm. My research also unveiled potential roles of parvalbumin neurons surrounded by perineuronal nets, along with neural markers associated with GABA/glutamate signaling within the prefrontal cortex, in mediating the effects of immune activation and environmental manipulations. Furthermore, I tested the idea that accelerated puberty might serve as a link between the adverse effects of MIA and the development of psychopathological conditions; my results supported this hypothesis. Importantly, my research emphasized that the consequences of MIA on puberty acceleration could be effectively mitigated through lifelong environmental enrichment. Collectively, my work reinforces the concept that EE can yield practical advantages and interventions that positively impact the well-being of both humans and animals.