Brain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development ...produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior.
Display omitted
•Microglia are more phagocytic in the male amygdala during neonatal development•Androgen-induced endocannabinoids increase phagocytosis in males•Microglia engulf viable newborn astrocytes in a complement-dependent manner•Developmental phagocytosis produces a sex difference in juvenile social play
VanRyzin et al. demonstrate that microglia in the developing amygdala engulf and kill otherwise viable newborn astrocytes, establishing sex differences in social circuits. This process, which depends on gonadal hormones and endocannabinoid signaling, promotes juvenile play by males.
Microglia, the innate immune cells of the brain, have recently been removed from the position of mere sentinels and promoted to the role of active sculptors of developing circuits and cells. ...Alongside their functions in normal brain development, microglia coordinate sexual differentiation of the brain, a set of processes which vary by region and endpoint like that of microglia function itself. In this review, we highlight the ways microglia are both targets and drivers of brain sexual differentiation. We examine the factors that may drive sex differences in microglia, with a special focus on how changing microenvironments in the developing brain dictate microglia phenotypes and discuss how their diverse functions sculpt lasting sex‐specific changes in the brain. Finally, we consider how sex‐specific early life environments contribute to epigenetic programming and lasting sex differences in microglia identity.
Main Points
The process of sexual differentiation generates sex‐specific microenvironments in brain development. Microenvironmental signals drive sex‐specific microglia functions to sculpt brain development and behavior. Sex differences in microglia drive sex‐specific changes in neuronal and astrocytic functions that endure throughout the lifespan.
Social play is a dynamic and rewarding behavior abundantly expressed by most mammals during the juvenile period. While its exact function is debated, various rodent studies on the effects of juvenile ...social isolation suggest that participating in play is essential to appropriate behavior and reproductive success in adulthood. However, the vast majority of these studies were conducted in one sex only, a critical concern given the fact that there are known sex differences in play's expression: across nearly all species that play, males play more frequently and intensely than females, and there are qualitative sex differences in play patterns. Further limiting our understanding of the importance of play is the use of total isolation to prevent interactions with other juveniles. Here, we employed a novel cage design to specifically prevent play in rats while allowing for other forms of social interaction. We find that play deprivation during the juvenile period results in enduring sex-specific effects on later-life behavior, primarily in males. Males prevented from playing as juveniles exhibited decreased sexual behavior, hypersociability, and increased aggressiveness in adulthood, with no effects on these measures in females. Importantly, play deprivation had no effect on anxiety-like behavior, object memory, sex preference, or social recognition in either sex, showing the specificity of the identified impairments, though there were overall sex differences in many of these measures. Additionally, acute play deprivation impaired performance on a test of prosocial behavior in both sexes, indicating a difference in the motivation and/or ability to acquire this empathy-driven task. Together, these findings provide novel insight into the importance and function of juvenile social play and how this differs in males and females.
The sexually dimorphic nucleus of the preoptic area (SDN-POA) is the oldest and most robust sex difference reported in mammalian brain and is singular for its presence across a wide range of species ...from rodents to ungulates to man. This small collection of Nissl-dense neurons is reliably larger in volume in males. Despite its notoriety and intense interrogation, both the mechanism establishing the sex difference and the functional role of the SDN have remained elusive. Convergent evidence from rodent studies led to the conclusion that testicular androgens aromatized to estrogens are neuroprotective in males and that higher apoptosis (naturally occurring cell death) in females determines their smaller SDN. In several species, including humans, a smaller SDN correlates with a preference for mating with males. We report here that this volume difference is dependent upon a participatory role of phagocytic microglia which engulf more neurons in the female SDN and assure their destruction. Selectively blocking microglia phagocytosis temporarily spared neurons from apoptotic death and increased SDN volume in females without hormone treatment. Increasing the number of neurons in the SDN in neonatal females resulted in loss of preference for male odors in adulthood, an effect paralleled by dampened excitation of SDN neurons as evidenced by reduced immediate early gene (IEG) expression when exposed to male urine. Thus, the mechanism establishing a sex difference in SDN volume includes an essential role for microglia, and SDN function as a regulator of sexual partner preference is confirmed.
Glutamatergic projections of the thalamic rostral intralaminar nuclei of the thalamus (rILN) innervate the dorsal striatum (DS) and are implicated in dopamine (DA)-dependent incubation of drug ...seeking. However, the mechanism by which rILN signaling modulates reward seeking and striatal DA release is unknown. We find that activation of rILN inputs to the DS drives cholinergic interneuron burst-firing behavior and DA D2 receptor-dependent post-burst pauses in cholinergic interneuron firing. In vivo, optogenetic activation of this pathway drives reinforcement in a DA D1 receptor-dependent manner, and chemogenetic suppression of the rILN reduces dopaminergic nigrostriatal terminal activity as measured by fiber photometry. Altogether, these data provide evidence that the rILN activates striatal cholinergic interneurons to enhance the pursuit of reward through local striatal DA release and introduce an additional level of complexity in our understanding of striatal DA signaling.
Display omitted
•The rostral intralaminar nuclei of the thalamus (rILN) project to the dorsal striatum•Glutamatergic rILN projections induce local dopamine release in the dorsal striatum•rILN activity suppression correlates with reduced nigrostriatal activity and movement•rILN terminal activation supports behavioral reinforcement
Cover et al. identify a glutamatergic thalamostriatal pathway that locally elicits striatal dopamine release to drive reward-related behavior in mice.
Atmospheric rivers (ARs) are long, narrow synoptic scale weather features important for Earth’s hydrological cycle typically transporting water vapor poleward, delivering precipitation important for ...local climates. Understanding ARs in a warming climate is problematic because the AR response to climate change is tied to how the feature is defined. The Atmospheric River Tracking Method Intercomparison Project (ARTMIP) provides insights into this problem by comparing 16 atmospheric river detection tools (ARDTs) to a common data set consisting of high resolution climate change simulations from a global atmospheric general circulation model. ARDTs mostly show increases in frequency and intensity, but the scale of the response is largely dependent on algorithmic criteria. Across ARDTs, bulk characteristics suggest intensity and spatial footprint are inversely correlated, and most focus regions experience increases in precipitation volume coming from extreme ARs. The spread of the AR precipitation response under climate change is large and dependent on ARDT selection.
Plain Language Summary
Atmospheric rivers (ARs) are long and narrow weather features often referred to as “rivers in the sky.” They often transport water from lower latitudes to higher latitudes typically across climate zones and produce precipitation necessary for local climates. Understanding ARs in a warming climate is challenging because of the variety of ways an AR can be defined on gridded data sets. Unlike weather features such as tropical cyclones where identification methodologies are similar, algorithms that determine the characteristics of ARs vary depending on the science question posed. Because there is no real consensus on AR identification methodology, we aim to quantify the algorithmic uncertainty in AR metrics and precipitation. We compare 16 different ways of defining an AR on gridded data sets and present the range of possibilities in which an AR could change under global warming. Generally, ARs are projected to increase but the amount of that increase is a function of the algorithm. Across all algorithms and focus regions, AR precipitation is projected to become more extreme.
Key Points
High‐resolution historical and future simulations are used to evaluate atmospheric river detection tools (ARDT) uncertainty
ARDTs mostly show increases in frequency and intensity of future atmospheric rivers (ARs) but the scale of response is dependent on algorithmic restrictiveness
Most regions experience an increase in precipitation volume coming from extreme ARs
Cannabis use during pregnancy has increased over the past few decades, with recent data indicating that, in youth and young adults especially, up to 22% of people report using cannabis during ...pregnancy. Animal models provide the ability to study prenatal cannabis exposure (PCE) with control over timing and dosage; however, these studies utilize both injection and inhalation approaches. While it is known that Δ9‐tetrahydrocannabinol (THC; primary psychoactive component of cannabis) can cross the placenta, examination of the transmission and concentration of THC and its metabolites from maternal blood into the placenta and fetal brain remains relatively unknown, and the influence of route of administration has never been examined. Pregnant female rats were exposed to either vaporized THC‐dominant cannabis extract for pulmonary consumption or subcutaneous injection of THC repeatedly during the gestational period. Maternal blood, placenta, and fetal brains were collected following the final administration of THC for analysis of THC and its metabolites, as well as endocannabinoid concentrations, through mass spectrometry. Both routes of administration resulted in the transmission of THC and its metabolites in placenta and fetal brain. Repeated exposure to inhaled THC vapor resulted in fetal brain THC concentrations that were about 30% of those seen in maternal blood, whereas repeated injections resulted in roughly equivalent concentrations of THC in maternal blood and fetal brain. Neither inhalation nor injection of THC during pregnancy altered fetal brain endocannabinoid concentrations. Our data provide the first characterization of maternal‐fetal transmission of THC and its metabolites following both vaporized delivery and injection routes of administration. These data are important to establish the maternal‐fetal transmission in preclinical injection and inhalation models of PCE and may provide insight into predicting fetal exposure in human studies.
Animal models provide the ability to study prenatal cannabis exposure with control over timing and dosage but employ both injection and inhalation approaches; however, the degree of transmission of THC through placenta to fetal brain within these models is unknown. Here we show differences in THC and metabolite distribution following injection versus inhalation.
Play is a complex social behavior that is highly conserved across mammals. In most species, males engage in more frequent and vigorous play as juveniles than females, which reflects subtle yet ...impactful sex differences in brain circuitry and development. In this protocol, we describe a behavioral testing paradigm to assess social play in male and female juvenile rats. We highlight the behavior scoring criteria for distinguishing rough-and-tumble play from other play-related social behaviors. By analyzing both sexes, play behavior can be leveraged as a powerful tool to understand the sex-specific development and expression of social behavior.
Social play consists of reciprocal physical interactions between conspecifics with many features conserved across species, including the propensity for males to engage in play more frequently and ...with higher physical intensity. Animal models, such as the laboratory rat, reveal that the underlying neural circuitry of play is subject to sexual differentiation during a critical period early in life. In this review, we discuss the developmental processes that produce distinct neural nodes which modulate both shared and sex-specific aspects of play with a focus on the medial amygdala, lateral septum, and prefrontal cortex. While the cellular mechanisms determining sex differences in play are beginning to be uncovered, the ultimate advantages of play continue to be debated.
PDF
