Allelic contribution of Nrxn1α to autism-relevant behavioral phenotypes in mice.

Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1α transcription, one carrying exon 9 deletion disrupting Nrxn1α protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1α expression. We found that homozygous loss of Nrxn1α resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1α affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1α gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism.

Lactation is not required for maintaining maternal care and active coping responses in chronically stressed postpartum rats: Interactions between nursing demand and chronic variable stress.

Women who do not breastfeed or discontinue breastfeeding early are more likely to develop postpartum depression (PPD) and stress is a significant risk factor for depression, including PPD. Using a rat model, we investigated whether the absence of nursing would increase the susceptibility to chronic stress-related behavioral and neural changes during the postpartum period. Adult female rats underwent thelectomy (thel; removal of teats), sham surgery, or no surgery (control) and were paired with males for breeding. All litters were rotated twice daily until postpartum day (PD) 26. Sham rats served as surrogates for thel litters, yielding a higher nursing demand for sham rats. Concurrently, rats received either no stress or chronic variable stress until PD 25. Rats were observed for maternal behaviors and tested in a series of tasks including open field, sucrose preference, and forced swim. We used immunohistochemistry (IHC) for doublecortin (DCX; to label immature neurons) or for mineralocorticoid receptor (MR). Contrary to our expectations, non-nursing thel rats were resistant to the effects of stress in all dependent measures. Our data indicate that even in chronic adverse conditions, nursing is not required for maintaining stable care to offspring or active coping responses in an acutely stressful task. We discuss the possible role of offspring contact and consider future directions for biomedical and clinical research. In rats with high nursing demand, however, chronic stress increased immobility, hippocampal neurogenesis, and MR expression (largely in opposition to the effects of stress in rats with typical nursing demand). We discuss these patterns in the context of energetics and allostatic load. This research highlights the complexity in relationships between stress, nursing, and neurobehavioral outcomes in the postpartum period and underscores the need for additional biomedical and clinical research geared toward optimizing treatments and interventions for women with PPD, regardless of breastfeeding status. SIGNIFICANCE STATEMENT: The goal of this research was to determine how the absence of nursing and higher nursing demand impact stress-coping behaviors and neural changes associated with chronic stress in order to disentangle the complex interplay of factors that contribute to psychological illness during the postpartum period.

Maternal experience and adult neurogenesis in mammals: Implications for maternal care, cognition, and mental health.

The transition to motherhood encompasses physiological and behavioral adaptations essential for the initiation and maintenance of offspring care and feeding and includes widespread changes throughout the brain. The growth of new neurons occurs across the lifespan in distinct regions of mammalian brains and changes dynamically across reproductive events in female mammals. The subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus undergo high rates of neurogenesis in adulthood and are sensitive to hormonal fluctuations. Pregnancy and the postpartum period are associated with increased cell proliferation in the SVZ and interneuron survival in the olfactory bulb. In mice, peripartum prolactin signaling mediates SVZ neurogenesis and is important for enhanced olfactory recognition of offspring and maternal care. In contrast, cell proliferation and immature neuron survival decrease in the DG during the postpartum period. High baseline glucocorticoid concentrations suppress hippocampal neurogenesis, potentially representing an energetic trade-off accompanying a reduced need for spatial navigation early postpartum. In women, hippocampal volume decline during pregnancy and partial recovery during the postpartum period could contribute to the risk of psychiatric illness. New evidence indicates that the dorsal raphe nucleus (DR) is an additional site for adult neurogenesis sensitive to reproductive experience and offspring contact. In this review, we discuss the initial and lasting impact of maternal experience on adult neurogenesis. Because neurogenesis has been implicated in a variety of psychiatric and neurodegenerative illnesses, understanding how reproductive experience alters new neuron production in maternal mammals has far-reaching implications for women's health and wellness across the lifespan.

Rotated nursing environment with underfeeding: A form of early-life adversity with sex- and age-dependent effects on coping behavior and hippocampal neurogenesis.

We investigated how a unique form of early-life adversity (ELA), caused by rotated nursing environment to induce underfeeding, alters anxiety-like and stress-coping behaviors in male and female Sprague Dawley rats in adolescence and adulthood. Adult female rats underwent either thelectomy (thel; surgical removal of teats), sham surgery, or no surgery (control) before mating. Following parturition, litters were rotated between sham and thel rats every 12 h to generate a group of rats that experienced ELA (rotated housing, rotated mother, and 50% food restriction) from postnatal day 0 to 26. Control litters remained with their natal, nursing dams. Regardless of age and sex, ELA reduced activity in the periphery of the open field. ELA increased immobility in the forced swim test, particularly in adults. We used doublecortin immunohistochemistry to identify immature neurons in the hippocampus. ELA increased the number and density of immature neurons in the dentate gyrus of adolescent males (but not females) and reduced the density of immature neurons in adult males (but not females). This research indicates that a unique form of ELA alters stress-related passive coping and hippocampal neurogenesis in an age- and sex-dependent manner.