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echnical innovation in neuroscience introduced powerful tools for measuring and manipulating neuronal activity via optical, chemogenetic, and calcium-imaging tools. These tools were initially tested primarily in male animals but are now increasingly being used in females as well. In this review, we consider how these tools may work differently in males and females. For example, we review sex differences in the metabolism of chemogenetic ligands and their downstream signaling effects. Optical tools more directly alter depolarization or hyperpolarization of neurons, but biological sex and gonadal hormones modulate synaptic inputs and intrinsic excitability. We review studies demonstrating that optogenetic manipulations are sometimes consistent across the rodent estrous cycle but within certain circuits; manipulations can vary across the ovarian cycle. Finally, calcium-imaging methods utilize genetically encoded calcium indicators to measure neuronal activity. Testosterone and estradiol can directly modulate calcium influx, and we consider these implications for interpreting the results of calcium-imaging studies. Together, our findings suggest that these neuroscientific tools may sometimes work differently in males and females and that users should be aware of these differences when applying these methods. 

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood. 

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n= 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research. 

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. 

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.