Type of early life adversity confers differential, sex-dependent effects on early maturational milestones in mice.

Early life adversity (ELA) increases risk for negative health outcomes, with sex disparities in prevalence and form of ELA experienced and risk for neuropsychiatric pathology. ELA comes in many forms (e.g. parental neglect/loss, limited access to resources) but whether disparate forms of ELA have common effects on outcomes, and if males and females are equally affected, remains unknown. Epidemiological studies often fail to accurately account for differences in type, timing, and duration of adversity experienced. Rodent models allow precise control of many of these variables. However, differences in the form of ELA, species, strain, housing, and testing paradigms used may contribute to differences in outcomes leading to questions of whether differences are the result of the form of ELA or these other variables. Here, we directly compared two mouse models of ELA, maternal separation (MS) and limited bedding (LB) in males and females on development of the body, motor and visual milestones, stress physiology, and anxiety-like behavior. LB affected timing of early milestones, somatic growth, and stress physiology in both sexes, yet only females showed later anxiety-like behaviors. MS rearing affected males and females similarly in early milestone development, yet only males showed changes in stress physiology and anxiety-like outcomes. These studies provide a platform to directly compare MS and LB models within one lab. The current work advances our understanding of the unique features of ELA that shape early neurodevelopmental events and risk for later pathology, increasing the translational relevance of these ELA models.

Elevated risk for psychiatric outcomes in pediatric patients with Multisystem Inflammatory Syndrome (MIS-C): A review of neuroinflammatory and psychosocial stressors.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a secondary immune manifestation of COVID-19 involving multiple organ systems in the body, resulting in fever, skin rash, abdominal pain, nausea, shock, and cardiac dysfunction that often lead to hospitalization. Although many of these symptoms resolve following anti-inflammatory treatment, the long-term neurological and psychiatric sequelae of MIS-C are unknown. In this review, we will summarize two domains of the MIS-C disease course, 1) Neuroinflammation in the MIS-C brain and 2) Psychosocial disruptions resulting from stress and hospitalization. In both domains, we present existing clinical findings and hypothesize potential connections to psychiatric outcomes. This is the first review to conceptualize a holistic framework of psychiatric risk in MIS-C patients that includes neuroinflammatory and psychosocial risk factors. As cases of severe COVID-19 and MIS-C subside, it is important for clinicians to monitor outcomes in this vulnerable patient population.

Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior.

Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor-mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that Gi-mediated inhibition of the indirect pathway (IP) during postnatal days 8-15 led to long-lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of outcome-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long-lasting impacts on neuronal function and behavior.

Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala.

Early life adversity (ELA) is a major risk factor for the development of pathology, including anxiety disorders. Neurodevelopmental and behavioral outcomes following ELA are multifaceted and are influenced heavily by the type of adversity experienced and sex of the individual experiencing ELA. It remains unclear what properties of ELA portend differential neurobiological risk and the basis of sex-differences for negative outcomes. Predictability of the postnatal environment has emerged as being a core feature supporting development, with the most salient signals deriving from parental care. Predictability of parental care may be a distinguishing feature of different forms of ELA, and the degree of predictability afforded by these manipulations may contribute to the diversity of outcomes observed across models. Further, questions remain as to whether differing levels of predictability may contribute to differential effects on neurodevelopment and expression of genes associated with risk for pathology. Here, we tested the hypothesis that changes in maternal behavior in mice would be contingent on the type of ELA experienced, directly comparing predictability of care in the limited bedding and nesting (LBN) and maternal separation (MS) paradigms. We then tested whether the predictability of the ELA environment altered the expression of corticotropin-releasing hormone (Crh), a sexually-dimorphic neuropeptide that regulates threat-related learning, in the amygdala of male and female mice. The LBN manipulation reliably increased the entropy of maternal care, a measure that indicates lower predictability between sequences of dam behavior. LBN and MS rearing similarly increased the frequency of nest sorties and licking of pups but had mixed effects on other aspects of dam-, pup-, and nest-related behaviors. Increased expression of Crh-related genes was observed in pups that experienced ELA, with gene expression measures showing a significant interaction with sex and type of ELA manipulation. Specifically, MS was associated with increased expression of Crh-related genes in males, but not females, and LBN primarily increased expression of these genes in females, but not males. The present study provides evidence for predictability as a distinguishing feature of models of ELA and demonstrates robust consequences of these differing experience on sex-differences in gene expression critically associated with stress responding and sex differences in risk for pathology.

Early life stress leads to sex differences in development of depressive-like outcomes in a mouse model.

Childhood trauma and neglect influence emotional development and increase the risk for and severity of mental illness. Women have a heightened susceptibility to the effects of early life stress (ELS) and are twice as likely as men to develop debilitating, stress-associated disorders later in life, such as major depressive disorder (MDD). Until now, mouse models of depression have been largely unsuccessful at replicating the diverse symptomatology of this disease and the sex bias in vulnerability. From P4 to P11, a limited bedding model that leads to fragmented maternal care, was used to induce ELS. Early adolescent and young adult mice were tested on an array of assays to test for depressive-like behavior. This included our newly developed automated home cage behavioral recognition system, where the home cage behavior of ELS and control mice could be monitored over a continuous 5-10 day span. ELS females, but not males, exhibited depressive-like behaviors on traditional assays. These effects emerged during adolescence and became more severe in adulthood. Using the novel home cage video monitoring method, we identified robust and continuous markers of depressive-like pathology in ELS females that phenocopy many of the behavioral characteristics of depression in humans. ELS effects on home cage behavior were rapidly rescued by ketamine, a fast-acting antidepressant. Together, these findings highlight that limited bedding ELS (1) produces an early emerging, female-specific depressive phenotype that responds to a fast-acting antidepressant and (2) this model has the potential to inform sex-selective risk for the development of stress-induced mental illness.

Early Life Stress Delays Sexual Maturation in Female Mice.

In humans, some forms of early life stress (ELS) have been linked with precocious puberty, altered brain maturation, and increased risk for a variety of forms of pathology. Interestingly, not all forms of ELS have been found to equally impact these metrics of maturation. In recent work, we have found that ELS in the form of limited bedding (LB) from P4 to P11, was associated with precocious hippocampus maturation in males and increased risk for depressive-like pathology and attentional disturbance in female mice. Here, we sought to test whether ELS in the form of LB also impacted the timing of sexual maturation in female mice. To establish rate of somatic and sexual development, distinct cohorts of mice were tested for weight gain, timing of vaginal opening, and development of estrous cycling. ELS animals weighed significantly less than controls at every timepoint measured. Onset of vaginal opening was tracked from P21 to 40, and ELS was found to significantly delay the onset of vaginal opening. To test the impact of ELS on estrous cycle duration and regularity, vaginal cytology was assessed in independent groups of animals using either a continuous sampling (daily from P40 to P57) or random sampling approach (single swab at P35, P50, or P75). ELS did impact measures of estrous cycling, but these effects were dependent upon the sampling method used. We also tested the impact of ELS on anxiety-like behaviors over development and across the estrous cycle. We observed a developmental increase in anxiety-like behavior in control but not ELS mice. No effect of estrous cycle stage was found on anxiety-like behavior for either group of mice. Together these results provide evidence that ELS in the form of LB delays somatic and sexual development. Additional work will be required to determine the mechanism by which ELS impacts these measures, and if these effects are common to other models of ELS in rodents.

Limited Bedding and Nesting Induces Maternal Behavior Resembling Both Hypervigilance and Abuse.

Early life adversity (ELA) is associated with altered neural development and increased risk for the development of psychopathology across the lifespan. Rodent models of ELA are an important tool for investigating the possible mechanistic underpinnings of pathology development. We used a limited bedding and nesting model (LBN) to induce stress in the dam and alter dam-pup interactions during a sensitive period in early postnatal development. The primary characteristics previously identified in this model include fragmented and unpredictable maternal care and possibly neglect. However, previous studies have not considered the effects of this manipulation over the full circadian cycle and the evolution of changes of maternal behavior throughout the duration of the manipulation. In the current study, we leverage a novel continuous video monitoring setup to unobtrusively observe and subsequently analyze maternal behaviors. Through this more in-depth analysis, we discovered that LBN dams spent more time than control dams on their nest, returned to their nest more frequently than control dams, and showed intact maternal care. Importantly, a subset of LBN dams (~40%) engaged in abusive-like kicking, a behavioral pattern not previously identified in this paradigm. Exposure to ELA and abusive-like kicking were associated with differences in risk-taking behavior in adulthood. The LBN model of ELA may drive a more complex constellation of effects on maternal behavior driving a pattern of increased dam-pup interactions and increased abuse-like kicking behavior, with unique consequences for pup outcomes.

Early life stress impairs contextual threat expression in female, but not male, mice.

Early life stress (ELS) is associated with altered processing of threat signals, and increased lifetime risk of anxiety and affective pathology, disorders that disproportionately affect females. We tested the impact of a limited bedding paradigm of ELS (from P4-11) on contextual threat learning, context memory, footshock sensitivity, and anxietylike behavior, in adult male and female mice. To examine contextual threat learning, mice conditioned by context/footshock association were tested 24 hr later for the context memory. To determine the effect of ELS on footshock sensitivity, a separate cohort of mice were exposed to footshocks of increasing intensity (0.06 to 0.40 mA) and behavioral responses (jump and audible vocalization) were assessed by observers blind to treatment condition, sex, and cycle stage. ELS impaired context memory in female, but not male, mice. ELS increased footshock-induced threshold to vocalize, but not to jump, in both sexes. In female mice, this effect was most apparent during estrus. Decreased body weight, indicative of higher stress incurred by an individual mouse, correlated with increased threshold to jump in both sexes reared in ELS, and to audibly vocalize in ELS females. As ELS effects on shock sensitivity were present in both sexes, the contextual recall deficit in females was not likely driven by changes in the salience of aversive footshocks. No effects on anxietylike behavior, as measured in the elevated plus maze (EPM), were observed. More work is needed to better understand the impact of ELS on both somatic and gonadal development, and their potential contribution to threat learning. (PsycINFO Database Record

Early life stress leads to developmental and sex selective effects on performance in a novel object placement task.

Disruptions in early life care, including neglect, extreme poverty, and trauma, influence neural development and increase the risk for and severity of pathology. Significant sex disparities have been identified for affective pathology, with females having an increased risk of developing anxiety and depressive disorder. However, the effects of early life stress (ELS) on cognitive development have not been as well characterized, especially in reference to sex specific impacts of ELS on cognitive abilities over development. In mice, fragmented maternal care resulting from maternal bedding restriction, was used to induce ELS. The development of spatial abilities were tracked using a novel object placement (NOP) task at several different ages across early development (P21, P28, P38, P50, and P75). Male mice exposed to ELS showed significant impairments in the NOP task compared with control reared mice at all ages tested. In female mice, ELS led to impaired NOP performance immediately following weaning (P21) and during peri-adolescence (P38), but these effects did not persist into early adulthood. Prior work has implicated impaired hippocampus neurogenesis as a possible mediator of negative outcomes in ELS males. In the hippocampus of behaviorally naïve animals there was a significant decrease in expression of Ki-67 (proliferative marker) and doublecortin (DCX-immature cell marker) as mice aged, and a more rapid developmental decline in these markers in ELS reared mice. However, the effect of ELS dissipated by P28 and no main effect of sex were observed. Together these results indicate that ELS impacts the development of spatial abilities in both male and female mice and that these effects are more profound and lasting in males.