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1. Three daily intraperitoneal injections of sub‐anesthetic ketamine ameliorate activity‐based anorexia vulnerability of adult female mice

   https://doi.org/10.1002/eat.24036  

   Goodwin‐Groen, Sebastian ; Dong, Yiru ; Aoki, Chiye ( August 2023 , International Journal of Eating Disorders)

   To identify ketamine's dosing schedule that ameliorates voluntary food restriction, hyperactivity and body weight loss of adult mice undergoing activity‐based anorexia (ABA), an animal model of anorexia nervosa.

   Female and male C57BL6 mice underwent three cycles of ABA, starting from mid‐adolescence. ABA vulnerability was compared within and across two groups of animals: those injected intraperitoneally with 30 mg/kg ketamine for three consecutive days (30mgKetx3) during the second ABA in late adolescence (ABA2) or with vehicle only (Vx3).

   Vx3 females and males exhibited individual differences in wheel running and weight retention during first ABA in mid‐adolescence (ABA1), ABA2, and third ABA in adulthood (ABA3). Their wheel running correlated with anxiety‐like behavior. During ABA1 and ABA3, weight gain of Vx3 females (but not males) after food consumption correlated negatively with food‐anticipatory activity (FAA) preceding the feeding hours, indicating that females with higher levels of running restrict feeding more and persistently. This paradoxical relationship confirms earlier findings of ABA females without ketamine treatment, capturing the maladaptive behaviors exhibited by individuals diagnosed with anorexia nervosa. By contrast, 30mgKetx3 had an effect on both sexes of reducing hyperactivity during the feeding hours acutely and reducing anxiety‐like behavior's contribution to running. For females, only, 30mgKetx3 acutely improved the extent of compensatory food consumption relative to FAA and improved weight retention during ABA3, 12 days post ketamine in adulthood.

   Sub‐anesthetic ketamine evokes behavior‐specific ameliorative effects for adult mice re‐experiencing ABA, supporting the notion that multiple doses of ketamine may be helpful in reducing relapse among adults with anorexia nervosa.

   This study examined whether ketamine reduces anorexia‐like behaviors in adult mice. Three daily sub‐anesthetic ketamine injections suppress wheel running during and leading up to the hours of food availability and enable animals to compensate better for weight loss associated with excessive exercise by eating more. These findings suggest that ketamine may help adult females diagnosed with anorexia nervosa but also point to sex‐ and age‐related differences in the action of ketamine.

    

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2. 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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3. 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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4. 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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5. Human‐like adrenal development in wild chimpanzees: A longitudinal study of urinary dehydroepiandrosterone‐sulfate and cortisol

   https://doi.org/10.1002/ajp.23064  

   Sabbi, Kris H. ; Muller, Martin N. ; Machanda, Zarin P. ; Otali, Emily ; Fox, Stephanie A. ; Wrangham, Richard W. ; Emery Thompson, Melissa ( November 2019 , American Journal of Primatology)

   The development of the adrenal cortex varies considerably across primates, being most conspicuous in humans, where a functional zona reticularis–the site of dehydroepiandrosterone‐sulfate (DHEA/S) production–does not develop until middle childhood (5–8 years). Prior reports suggest that a human‐like adrenarche, associated with a sharp prepubertal increase in DHEA/S, may only occur in the genusPan. However, the timing and variability in adrenarche in chimpanzees remain poorly described, owing to the lack of longitudinal data, or data from wild populations. Here, we use urine samples from East African chimpanzees (Pan troglodytes schweinfurthii)collected over 20 years at Kanyawara in Kibale National Park, Uganda, to trace the developmental trajectories of DHEAS (n = 1,385 samples, 53 individuals) and cortisol (n = 12,726 samples, 68 individuals). We used generalized additive models (GAM) to investigate the relationship between age, sex, and hormone levels. Adrenarche began earlier in chimpanzees (~2–3 years) compared with what has been reported in humans (6–8 years) and, unlike humans, male and female chimpanzees did not differ significantly in the timing of adrenarche nor in DHEAS concentrations overall. Similar to what has been reported in humans, cortisol production decreased through early life, reaching a nadir around puberty (8–11 years), and a sex difference emerged with males exhibiting higher urinary cortisol levels compared with females by early adulthood (15–16 years). Our study establishes that wild chimpanzees exhibit a human‐like pattern of cortisol production during development and corroborates prior reports from captive chimpanzees of a human‐like adrenarche, accompanied by significant developmental increases in DHEAS. While the role of these developmental hormone shifts are as yet unclear, they have been implicated in stages of rapid behavioral development once thought unique to humans, especially in regard to explaining the divergence of female and male social behavior before pubertal increases in gonadal hormones.

    

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