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.

Autism spectrum disorder (ASD) impacts an individual's ability to socialize, communicate, and interact with, and adapt to, the environment. Over the last two decades, research has focused on early identification of ASD with significant progress being made in understanding the early behavioral and biological markers that precede a diagnosis, providing a catalyst for pre-symptomatic identification and intervention. Evidence from preclinical trials suggest that intervention prior to the onset of ASD symptoms may yield more improved developmental outcomes, and clinical studies suggest that the earlier intervention is administered, the better the outcomes. This article brings together a multidisciplinary group of experts to develop a conceptual framework for behavioral intervention, during the pre-symptomatic period prior to the consolidation of symptoms into diagnosis, in infants at very-high-likelihood for developing ASD (VHL-ASD). The overarching goals of this paper are to promote the development of new intervention approaches, empirical research, and policy efforts aimed at VHL-ASD infants during the pre-symptomatic period (i.e., prior to the consolidation of the defining features of ASD).

The immediate and long-term effects of exposure to early life stress (ELS) have been documented in humans and animal models. Even relatively brief periods of stress during the first 10 days of life in rodents can impact later behavioral regulation and the vulnerability to develop adult pathologies, in particular an impairment of cognitive functions and neurogenesis, but also modified social, emotional, and conditioned fear responses. The development of preclinical models of ELS exposure allows the examination of mechanisms and testing of therapeutic approaches that are not possible in humans. Here, we describe limited bedding and nesting (LBN) procedures, with models that produce altered maternal behavior ranging from fragmentation of care to maltreatment of infants. The purpose of this paper is to discuss important issues related to the implementation of this chronic ELS procedure and to describe some of the most prominent endpoints and consequences, focusing on areas of convergence between laboratories. Effects on the hypothalamic-pituitary adrenal (HPA) axis, gut axis and metabolism are presented in addition to changes in cognitive and emotional functions. Interestingly, recent data have suggested a strong sex difference in some of the reported consequences of the LBN paradigm, with females being more resilient in general than males. As both the chronic and intermittent variants of the LBN procedure have profound consequences on the offspring with minimal external intervention from the investigator, this model is advantageous ecologically and has a large translational potential. In addition to the direct effect of ELS on neurodevelopmental outcomes, exposure to adverse early environments can also have intergenerational impacts on mental health and function in subsequent generation offspring. Thus, advancing our understanding of the effect of ELS on brain and behavioral development is of critical concern for the health and wellbeing of both the current population, and for generations to come.

Many symptoms of neurologic or psychiatric illness--such as cognitive impairment, depression, anxiety, attention deficits, and migraine--occur more frequently in people with epilepsy than in the general population. These diverse comorbidities present an underappreciated problem for people with epilepsy and their caregivers because they decrease quality of life, complicate treatment, and increase mortality. In fact, it has been suggested that comorbidities can have a greater effect on quality of life in people with epilepsy than the seizures themselves. There is increasing recognition of the frequency and impact of cognitive and behavioral comorbidities of epilepsy, highlighted in the 2012 Institute of Medicine report on epilepsy. Comorbidities have also been acknowledged, as a National Institutes of Health (NIH) Benchmark area for research in epilepsy. However, relatively little progress has been made in developing new therapies directed specifically at comorbidities. On the other hand, there have been many advances in understanding underlying mechanisms. These advances have made it possible to identify novel targets for therapy and prevention. As part of the International League Against Epilepsy/American Epilepsy Society workshop on preclinical therapy development for epilepsy, our working group considered the current state of understanding related to terminology, models, and strategies for therapy development for the comorbidities of epilepsy. Herein we summarize our findings and suggest ways to accelerate development of new therapies. We also consider important issues to improve research including those related to methodology, nonpharmacologic therapies, biomarkers, and infrastructure.