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Open Access Publications from the University of California

Scholarly Works (58 results)

  • Article
  • Peer Reviewed
UC Davis Previously Published Works (2024)
Oxytocin is a versatile neuropeptide that modulates many different forms of social behavior. Recent hypotheses pose that oxytocin enhances the salience of rewarding and aversive social experiences, and the field has been working to identify mechanisms that allow oxytocin to have diverse effects on behavior. Here we review studies conducted on the California mouse (Peromyscus californicus) that shed light on how oxytocin modulates social behavior following stressful experiences. In this species, both males and females exhibit high levels of aggression, which has facilitated the study of how social stress impacts both sexes. We review findings of short- and long-term effects of social stress on the reactivity of oxytocin neurons. We also consider the results of pharmacological studies which show that oxytocin receptors in the bed nucleus of the stria terminalis and nucleus accumbens have distinct but overlapping effects on social approach behaviors. These findings help explain how social stress can have different behavioral effects in males and females, and how oxytocin can have such divergent effects on behavior. Finally, we consider how new technological developments and innovative research programs take advantage of the unique social organization of California mice to address questions that can be difficult to study in conventional rodent model species. These new methods and questions have opened new avenues for studying the neurobiology of social behavior.
    Cover page: Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2020)
    Our review focuses on findings from mammals as part of a Special Issue "30th Anniversary of the Challenge Hypothesis". Here we put forth an integration of the mechanisms through which testosterone controls territorial behavior and consider how reproductive experience may alter these mechanisms. The emphasis is placed on the function of socially induced increases in testosterone (T) pulses, which occur in response to social interactions, as elegantly developed by Wingfield and colleagues. We focus on findings from the monogamous California mouse, as data from this species shows that reproductive status is a key factor influencing social interactions, site fidelity, and vigilance for offspring defense. Specifically, we examine differences in T pulses in sexually naïve versus sexually experienced pair bonded males. Testosterone pulses influence processes such as social decision making, the winner-challenge effect, and location preferences through rewarding effects of T. We also consider how social and predatory vigilance contribute to T pulses and how these interactions contribute to a territory centered around maximizing reproduction. Possible underlying mechanisms for these effects include the nucleus accumbens (rewarding effects of testosterone), hippocampus (spatial memories for territories), and the bed nucleus of the stria terminalis (social vigilance). The development of the challenge effect has provided an ideal framework for understanding the complex network of behavioral, environmental, physiological and neural mechanisms that ultimately relates to competition and territoriality across taxa. The opportunity to merge research on the challenge effect using both laboratory and field research to understand social behavior is unparalleled.
      Cover page: The challenge hypothesis revisited: Focus on reproductive experience and neural mechanisms
      • Thesis
      • Peer Reviewed
      UC Davis Electronic Theses and Dissertations (2023)

      Social Anxiety Disorder (SAD) is one of the most prevalent and debilitating stress-related affective disorders across nations. Despite its high prevalence, current treatments, such as selective serotonin reuptake inhibitor and cognitive behavioral therapy, only work in about half of the patients. Thus, there is a strong need for novel therapeutics that address the underlying biological mechanisms of SAD. This dissertation explores the roles of neuropeptides oxytocin and hypocretin in social behaviors and stress responses, highlighting their potential as treatment targets for SAD.Chapter 1 examines the anxiogenic effects of oxytocin receptor (OTR) signaling. We find that OTR-Gq signaling in the bed nucleus of the stria terminalis (BNST) promotes social avoidance and social vigilance behaviors in female and male California mice. Chapter 1 also provides analyses of published BNST and nucleus accumbens (NAc) single cell RNA-seq data and reveals a diverse expression pattern of OTRs across numerous cell types. Chapter 2 broadens the scope to include the hypocretin (Hcrt) system, typically associated with arousal and wakefulness, but also implicated in stress responses. This chapter presents a comprehensive review of how Hcrt may contribute to individual differences in stress coping strategies, especially in response to social stress. We propose that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and cell types. Chapter 3 focuses on understanding sex differences in SAD since women are twice as likely to be diagnosed with an anxiety disorder. Experimental findings from the study of California mice demonstrate that the effects of Hcrt on social behaviors are anatomically and sex specific. In female but not male mice, the Hcrt receptor signaling regulates social approach and vigilance in the NAcshell but not anterodorsalBNST.

        Cover page: Exploring Neuropeptides Implicated in Social Anxiety-related Behaviors
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2017)
        Women are nearly twice as likely as men to be diagnosed with major depressive disorder, yet the use of female animal models in studying the biological basis of depression lags behind that of males. The social defeat model uses social stress to generate depression-like symptoms in order to study the neurobiological mechanisms. In general, social defeat is difficult to apply in female rodents. However, male and female California mice (Peromyscus californicus) are territorial. This allows defeat to be studied in both sexes. Males exposed to defeat tend to exhibit proactive coping mechanisms and demonstrate aggression and reduced cognitive flexibility. Females exposed to defeat engage more in reactive coping mechanisms which is highlighted by social avoidance and low aggression. Importantly, effects of defeat on social interaction behavior in females is independent of adult gonadal steroids. These behavioral phenotypes are associated with sex-specific changes in arginine vasopressin (AVP) and oxytocin (OT), closely related peptides that regulate social behavior and stress reactivity. In brain regions associated with stress responses and social behavior, defeat induced long term decreases in AVP activity and increases in OT activity in males and females respectively. Intranasal OT administration was shown to mimic the effects of defeat-induced increases in endogenous OT activity, causing social withdrawal in undefeated females. This suggests that inhibition of OT activity could reduce the impact of stress on behavior in females. These results highlight the value of maintaining diverse rodent models in the search for sex-specific pharmacological approaches to treating mood disorders.
          Cover page: Sex differences in the effects of social defeat on brain and behavior in the California mouse: Insights from a monogamous rodent
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2022)
          Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral "building blocks" such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced "single-variable" readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal "big behavior" data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.
            Cover page: Quantifying Sex Differences in Behavior in the Era of "Big" Data.
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2018)
            A roadblock to successful treatment for anxiety and depression is the high proportion of individuals that do not respond to existing treatments. Different underlying neurobiological mechanisms may drive similar symptoms, so a more personalized approach to treatment could be more successful. There is increasing evidence that sex is an important biological variable modulating efficacy of antidepressants and anxiolytics. We review evidence for sex-specific effects of traditional monoamine based antidepressants and newer pharmaceuticals targeting kappa opioid receptors (KOR), oxytocin receptors (OTR), and N-methyl-D-aspartate receptors (ketamine). In some cases, similar behavioral effects are observed in both sexes while in other cases strong sex-specific effects are observed. Most intriguing are cases such as ketamine which has similar behavioral effects in males and females, perhaps through sex-specific neurobiological mechanisms. These results show how essential it is to include both males and females in both clinical and preclinical evaluations of novel antidepressants and anxiolytics.
              Cover page: The impact of sex as a biological variable in the search for novel antidepressants
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2020)
              Social vigilance is a behavioral strategy commonly used in adverse or changing social environments. In animals, a combination of avoidance and vigilance allows an individual to evade potentially dangerous confrontations while monitoring the social environment to identify favorable changes. However, prolonged use of this behavioral strategy in humans is associated with increased risk of anxiety disorders, a major burden for human health. Elucidating the mechanisms of social vigilance in animals could provide important clues for new treatment strategies for social anxiety. Importantly, during adolescence the prevalence of social anxiety increases significantly. We hypothesize that many of the actions typically characterized as anxiety behaviors begin to emerge during this time as strategies for navigating more complex social structures. Here, we consider how the social environment and the pubertal transition shape neural circuits that modulate social vigilance, focusing on the bed nucleus of the stria terminalis and prefrontal cortex. The emergence of gonadal hormone secretion during adolescence has important effects on the function and structure of these circuits, and may play a role in the emergence of a notable sex difference in anxiety rates across adolescence. However, the significance of these changes in the context of anxiety is still uncertain, as not enough studies are sufficiently powered to evaluate sex as a biological variable. We conclude that greater integration between human and animal models will aid the development of more effective strategies for treating social anxiety.
                Cover page: Anxious to see you: Neuroendocrine mechanisms of social vigilance and anxiety during adolescence.
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2017)
                Stress is a major risk factor for development of psychiatric disorders such as depression and development of substance use disorder. Although there are important sex differences in the prevalence of these disorders, most preclinical models used to study stress-induced disorders have used males only. Social defeat stress is a commonly used method to induce stress in an ethologically relevant way but has only recently begun to be used in female rodents. Using these new female models, recent studies have examined how social defeat stress affects males and females differently at the behavioral, circuit, and molecular levels. This Mini-Review discusses sex differences in the effects of social defeat stress on social behavior and drug-seeking behavior as well as its impact on the mesolimbic dopamine system and the highly connected region of the bed nucleus of the stria terminalis. © 2016 Wiley Periodicals, Inc.
                  Cover page: Stress, sex, and motivated behaviors
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2014)
                  Mounting evidence suggests that environmental factors-in particular, those that we are exposed to during perinatal life-can dramatically shape the organism's risk for later diseases, including neurobehavioral disorders. However, depending on the environmental insult, one sex may demonstrate greater vulnerability than the other sex. Herein, we focus on two well-defined extrinsic environmental factors that lead to sexually dimorphic behavioral differences in animal models and linkage in human epidemiological studies. These include maternal or psychosocial stress (such as social stress) and exposure to endocrine-disrupting compounds (such as one of the most prevalent, bisphenol A [BPA]). In general, the evidence suggests that early environmental exposures, such as BPA and stress, lead to more pronounced behavioral deficits in males than in females, whereas female neurobehavioral patterns are more vulnerable to later in life stress. These findings highlight the importance of considering sex differences and developmental timing when examining the effects of environmental factors on later neurobehavioral outcomes.
                    Cover page: Environmental Health Factors and Sexually Dimorphic Differences in Behavioral Disruptions
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2021)
                    Social stressors are known to have strong negative impacts on mental health. There is a long history of preclinical social defeat stress studies in rodents focusing on males that has produced important insights into the neural mechanisms that modulate depression- and anxiety-related behavior. Despite these impressive results, a historical weakness of rodent social stress models has been an under-representation of studies in females. This is problematic because rates of depression and anxiety are higher in women versus men. Recently there has been a surge of interest in adapting social stress methods for female rodents. Here we review new rodent models that have investigated numerous facets of social stress in females. The different models have different strengths and weaknesses, with some model systems having stronger ethological validity with other models having better access to molecular tools to manipulate neural circuits. Continued use and refinement of these complementary models will be critical for addressing gaps in understanding the function of neural circuits modulating depression- and anxiety-related behavior in females.
                      Cover page: Mean Girls: Social Stress Models for Female Rodents
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