Prenatal opioid exposure inhibits microglial sculpting of the dopamine system during adolescence

The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. However, little is know about the mechanisms by which prenatal opioid exposure leads to long term changes in reward circuit function and behavior. Microglia, the resident immune cells of the brain, are known to respond to perinatal opioid exposure and to sculpt neural circuits during development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors in the nucleus accumbens (NAc) is required for the natural development decline in NAc-D1R that occurs between adolescence and adulthood. Morever, this microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. Here, we show that maternal oxycodone self-administration during pregnancy leads to higher D1R density within the NAc in adult male, but not female, offspring in rats. Furthermore, adolescent microglial phagocytosis of D1R is reduced following prenatal oxycodone exposure. Ths work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to long-term changes in neural systems.

Is Play Sexually Dimorphic in the Polygamous Squirrel Monkey?

Play behavior is widespread in juvenile mammals and may be a mechanism for practicing skills needed in adulthood. In mammals characterized by strong adult male competition over females, juvenile males perform more social play than do females, and such play may assist in later mating competition. This study examined whether social play behavior is sexually dimorphic in a polygamous neotropical primate, the squirrel monkey (Saimiri collinsi), through a six-week field study of two groups of wild monkeys in Eastern Amazonia, Brazil. We hypothesized that males would conduct more rough-and-tumble play than females and that any sex-based play differences would be more evident in older juveniles. We video recorded juvenile play bouts and scored: age category (younger or older juvenile) and sex of players (male or female); and rough-and-tumble play behaviors (i.e., bite, grab, and wrestle). Juvenile males initiated more play bouts than did females. Most players were older juvenile males, while older juvenile females were the least represented. Older juvenile play bouts occurred mostly among males, while younger juvenile bouts consisted of a more even sex distribution. While younger juveniles did not significantly affect the number of rough-and-tumble behaviors in bouts, the number of behaviors was significantly affected by the sex of older individuals. These results indicate that social play is sexually dimorphic in juvenile S. collinsi; specifically, males play more than females and sex differences are more pronounced in older cohorts. KEYWORDS: Squirrel Monkeys; Mating System; Sexual Dimorphism; Juvenile Period; Development; Play Behavior; Social Behavior; Ethology

The Behavior and Postnatal Development in Infant and Juvenile Rats After Ultrasound-Induced Chronic Prenatal Stress

Fetal development is susceptible to environmental factors. One such factor is exposure to stress during pregnancy. The present study aimed to investigate the effects of chronic prenatal stress (PS) on the development and behavior of rat offspring during infancy and juvenile ages. Existing approaches to modeling prenatal stress on animals do not correlate with the main type of stress in pregnant women, namely psychological stress. We used a new stress paradigm in the experiment, namely, stress induced by exposure to variable frequency ultrasound (US), which acted on pregnant Wistar rats on gestational days 1–21. This type of stress in rodents can be comparable to psychological stress in humans. We assessed physical development, reflex maturation, motor ability development, anxious behavior, response to social novelty, and social play behavior in male and female offspring. Additionally, we investigated maternal behavior and the effect of neonatal handling (NH) on behavior. Prenatal stress did not affect postnatal developmental characteristics in rat pups, but prenatally stressed rats had higher body weight in early and adult age than controls. Prenatal exposure to a stressor increased anxiety in the open-field test (OF), changed social preferences in the social novelty test (SN), and impaired social play behavior in males. Neonatal handling reduced anxiety and restored social behavior, but evoked hyperactive behavior in rat pups. Maternal behavior did not change. Our study demonstrated for the first time that exposure to variable frequency ultrasound during pregnancy influences offspring development and impairs behavior, correlating with the effects of other types of stress during pregnancy in rodents. This supports the idea of using this exposure to model prenatal stress.

Structural and functional sex differences in the ventral pallidal vasopressin system are associated with the sex-specific regulation of juvenile social play behavior in rats

The ventral pallidum (VP) has been implicated in the regulation of rewarding adult social behaviors, such as pair-bonding and sociosexual motivation. However, the role of the VP in regulating rewarding juvenile social behaviors, such as social play, is unknown. Social play is predominantly displayed by juveniles of many mammalian species and engagement in social play helps develop social competence. In this study, we determined whether the VP is involved in regulating social play in juvenile rats by temporarily inactivating the VP via bilateral infusions of muscimol, the GABAA receptor agonist. Muscimol treatment decreased social play duration in males and females compared to the same-sex control groups. We then focused on the vasopressin (AVP) system in the VP as one potential modulator of social play. We examined the organization of the AVP system in the VP in juvenile rats and found robust sex differences, with denser AVP-immunoreacive fibers and denser vasopressin 1a receptor (V1aR) binding in males compared to females, but a greater number of V1aR-expressing cells in females compared to males. Next, we determined whether exposure to social play changed the activation of V1aR-expressing VP cells in male and female juvenile rats. We found that exposure to social play enhanced the number of V1aR-expressing VP cells co-expressing fos, a marker of neuronal activation, in males only. Finally, we determined the causal involvement of AVP signaling in the VP in social play behavior by infusion of a specific V1aR antagonist into the VP prior to social play exposure. We found that V1aR blockade in the VP increased social play duration in juvenile male rats but decreased social play duration in juvenile female rats compared to same-sex control groups. These findings reveal structural and functional sex differences in the AVP system in the VP that are associated with the sex-specific regulation of juvenile social play behavior.

Methamphetamine exposure during the first, but not the second half of prenatal development, affects social play behavior

Methamphetamine (MA), as a psychostimulant drug that crosses the placental barrier, may disrupt the development of social play. The present study aims to examine the effect of prenatal MA (5 mg/kg) exposure during the first (gestational day (GD) 1-11) or second (GD 12–22) halves of prenatal development of rats on social play behavior. To investigate an acute effect of MA on social play in adulthood, juvenile rats were exposed to a dose of 1 mg/kg MA or saline on the test day and tested for social play for 15 min. Prenatal exposure to MA during GD 1–11 increased social play behavior during 5-10 min interval of the test in males but not females. Prenatal MA during GD 12–22 did not influence social play in males nor females. However, social play occurred to a greater extent in GD 12–22 groups compared with GD 1–11. Acute exposure to MA eliminated playful behavior in all groups and decreased social exploration in GD 1–11. Our results suggest that manipulation of prenatal development during the first half of the gestational period has a greater impact on social play behavior than during the second half.