Habituation, as described in the landmark paper by Thompson and Spencer (1966), is a form of simple, nonassociative learning in which the magnitude of the response to a specific stimulus decreases with repeated exposure to that stimulus. A variety of neuronal and behavioral responses have been shown to be subject to habituation based on the criteria presented in that paper. It has been known for several decades that the magnitude of hypothalamic-pituitary-adrenal (HPA) activation occurring in response to a stressor declines with repeated exposure to that same stressor. For some time this decline has been referred to as “habituation” in the stress neurobiology literature. However, how this usage compares to the definition proposed by Thompson and Spencer has not been systematically addressed. For this special issue, we review the stress neurobiology literature and examine the support available for considering declines in HPA response to repeated stress to be response habituation in the sense defined by Thompson and Spencer. We conclude that habituation of HPA activity meets many, but not all, important criteria for response habituation, supporting the use of this term within the context of repeated stress. However, we also propose that response habituation can, at best, only partially explain the phenomenon of HPA habituation which also involves well-known negative feedback mechanisms, activation of broad stress-related neural circuitry and potentially more complex associative learning mechanisms.

The executive functions allow for purposeful, deliberate, and intentional interactions with the world-attention and focus, impulse control, decision making, and working memory. These measures have been correlated with academic outcomes and quality of life, and are impacted by deleterious environmental events throughout the life span, including gestational and early life insults. This review will address the topic of sex differences in executive function including a discussion of differences arising in response to developmental programming. Work on gender differences in human studies and sex differences in animal research will be reviewed. Overall, we find little support for significant gender or sex differences in executive function. An important variable that factors into the interpretation of potential sex differences include differing developmental trajectories. We conclude by discussing future directions for the field and a brief discussion of biological mechanisms.

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

The size of an infant at birth, a measure of gestational growth, has been recognized for many years as a biomarker of future risk of morbidity. Both being born small for gestational age (SGA) and being born large for gestational age (LGA), are associated with increased rates of obesity and metabolic disorder, as well as a number of mental disorders including attention deficit/hyperactivity disorder, autism, anxiety, and depression. The common risks raise the question of what neurobiological mechanisms are altered in SGA and LGA offspring. Here we review recent findings allowing for direct comparison of neurobiological outcomes of SGA and LGA in human and animal models. We also present new data highlighting similarities and differences in behavior and neurobiology in our mouse models of SGA and LGA. Overall, there is significant data to support aberrant epigenetic mechanisms, particularly related to DNA methylation, in the brains of SGA and LGA offspring, leading to disruptions in the cell cycle in development and gene expression in adulthood.

Poor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), d-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function.

Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.

Exposure to inflammation during pregnancy has been linked to adverse neurodevelopmental consequences for the offspring. One common route through which a developing fetus is exposed to inflammation is with intrauterine inflammation. To that end, we utilized an animal model of intrauterine inflammation (IUI; intrauterine lipopolysaccharide (LPS) administration, 50µg, E15) to assess placental and fetal brain inflammatory responses, white matter integrity, anxiety-related behaviors (elevated zero maze, light dark box, open field), microglial counts, and the CNS cytokine response to an acute injection of LPS in both males and females. These studies revealed that for multiple endpoints (fetal brain cytokine levels, cytokine response to adult LPS challenge) male IUI offspring were uniquely affected by intrauterine inflammation, while for other endpoints (behavior, microglial number) both sexes were similarly affected. These data advance our understanding of sex-specific effects of early life exposure to inflammation in a translationally- relevant model.

Restraint elicits a number of physiological stress responses that can be increased or decreased in magnitude based on prior stress history. For instance, repeated exposure to restraint leads to habituation of hypothalamic-pituitary-adrenal (HPA) activation to restraint. In contrast, acute restraint after a different repeated stressor leads to facilitation of HPA activity to the novel stress. Acute restraint also elicits a variety of behaviors including struggling, but the effect of prior stress in regulating behavioral responses to restraint is not clear. The goal of the present studies was to assess struggling during restraint with or without a prior history of repeated stress. Using automated behavioral analysis software (EthoVision), we quantified struggling during restraint. We found that acutely restrained rats exhibit vigorous struggling behavior that declines during a single restraint period. Repeated restraint lead to habituated struggling behavior, whereas acute restraint after repeated swim elicited facilitated struggling behavior. These effects on struggling were found alongside expected differences in HPA activity. Removing stress-induced increases in corticosterone via adrenalectomy did not significantly affect struggling responses to restraint. Overall, restraintinduced struggling appears to be regulated in a manner similar to HPA responses to restraint, but is not dictated by adrenal hormones.