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1. Neural systems underlying reward cue processing in early adolescence: The role of puberty and pubertal hormones

   https://doi.org/doi: 10.1016/j.psyneuen.2018.12.016.  

   Ladouceur CD, Kerestes R (April 2019, Psychoneuroendocrinology)

   Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10-13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence. 

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2. Sexual differentiation of neural mechanisms of stress sensitivity during puberty

   https://doi.org/10.1073/pnas.2306475120  

   Wright, Emily C.; Luo, Pei X.; Zakharenkov, Hannah C.; Serna Godoy, Alexandra; Lake, Alyssa A.; Prince, Zhana D.; Sekar, Shwetha; Culkin, Hannah I.; Ramirez, Alison V.; Dwyer, Tjien; et al (October 2023, Proceedings of the National Academy of Sciences)

   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. 

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3. Hypocretin in the nucleus accumbens shell modulates social approach in female but not male California mice

   https://doi.org/10.1038/s41386-024-01937-9  

   Luo, Pei_X; Serna_Godoy, Alexandra; Zakharenkov, Hannah_Cortez; Vang, Nou; Wright, Emily_C; Balantac, Taylor_A; Archdeacon, Sinéad_C; Black, Alexis_M; Lake, Alyssa_A; Ramirez, Alison_V; et al (August 2024, Neuropsychopharmacology)

   Abstract The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice andMus musculusNAc showed thatHcrtr2was more abundant thanHcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance. 

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4. Sex differences in head‐fixed voluntary running behavior in C57BL/6J mice

   https://doi.org/10.1111/ejn.14654  

   Warner, Emily J.; Padmanabhan, Krishnan (December 2019, European Journal of Neuroscience)

   Abstract Sex differences in running behaviors between female and male mice occur naturally in the wild. Recent experiments using head‐fixed mice on a voluntary running wheel have exploited analogous locomotor activity to gain insight into the neural underpinnings of a number of behaviors ranging from spatial navigation to decision‐making. It is however largely unknown if sex differences exist between females and males in a head‐fixed experimental paradigm. To address this, we characterized locomotor activity in head‐fixed female and male C57BL/6J mice on a voluntary running wheel. First, we found that over the initial 7‐day period, on average, animals increased both the velocity and the time spent running. Furthermore, we found that female mice habituated to running forward over the initial 2 days of encountering the wheel, while male mice took up to 4 days to habituate to running forward. Taken together, we characterized features of a sexually divergent behavior in head‐fixed running that should be considered in experiments employing female and male mice. 

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5. Acute intranasal oxytocin dose enhances social preference for parents over peers in male but not female peri-adolescent California mice (Peromyscus californicus)

   https://doi.org/10.1016/j.ygcen.2023.114230  

   Guoynes, Caleigh D.; Marler, Catherine A. (May 2023, General and Comparative Endocrinology)

   Peri-adolescence is a critical developmental stage marked by profound changes in the valence of social interactions with parents and peers. We hypothesized that the oxytocin (OXT) and vasopressin (AVP) systems, known for influencing social behavior, would be involved in the maintenance and breaking of bonding behavior expressed by very early peri-adolescent males and females. In rodents, OXT is associated with mother–pup bonding and may promote social attachment to members of the natal territory. AVP, on the other hand, can act in contrasting ways to OXT and has been associated with aggression and territoriality. Specifically, we predicted that in peri-adolescent male and female juveniles of the biparental and territorial California mouse (Peromyscus californicus), a) OXT would increase the social preferences for the parents over unfamiliar age-matched peers (one male and one female), and b) AVP would break the parent-offspring bond and either increase time in the neutral chamber and/or approach to their unfamiliar and novel peers. We examined anxiety and exploratory behavior using an elevated plus maze and a novel object task as a control. Peri-adolescent mice were administered an acute intranasal (IN) treatment of 0.5 IU/kg IN AVP, 0.5 IU/kg IN OXT, or saline control; five minutes later, the behavioral tests were conducted. As predicted, we found that IN OXT enhanced social preference for parents; however, this was only in male and not female peri-adolescent mice. IN AVP did not influence social preference in either sex. These effects appear specific to social behavior and not anxiety, as neither IN OXT nor AVP influenced behavior during the elevated plus maze or novel object tasks. To our knowledge, this is the first evidence indicating that OXT may play a role in promoting peri-adolescent social preferences for parents and delaying weaning in males. 

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