The role of microglia in 67NR mammary tumor-induced suppression of brain responses to immune challenges in female mice.

It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1ß injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.

Sex-dependent effects of paternal deprivation and chronic variable stress on novel object recognition in adult California mice (Peromyscus californicus).

Early-life stress exposure can confer vulnerability for development of psychiatric illnesses and impaired cognition in adulthood. It is well-known that early-life stress can dysregulate the hypothalamic-pituitary-adrenal (HPA) axis in a sex-dependent manner. Specifically, uniparental rodent models of prolonged disrupted mother-offspring relationships (e.g., maternal separation) have demonstrated greater alterations in stress responsivity in adult males, compared to females. Also, chronic early-life stressors (e.g., limited bedding model) impair cognitive function in males more than females. However, the sex-dependent effects of early-life stress and later-life chronic HPA axis activation on cognition have not been well-characterized. Here, we utilized the biparental California mouse (Peromyscus californicus) to model the early-life adversity of paternal deprivation (PD). Fathers either remained in the nest (biparental care) or were permanently removed (PD) on postnatal day (PND) 1. Adult offspring were exposed to daily handling (control) or chronic variable stress (CVS; three stressors for seven days). Twenty-four hours after the final stressor, the novel object recognition (NOR) task commenced, followed by serum collection for corticosterone (CORT) analysis. Independent of sex or rearing, CVS increased CORT. Exploration during acquisition for the NOR task was increased as a result of CVS and PD. During NOR testing, non-stressed females exhibited greater difference scores (i.e., increased recognition memory), compared to non-stressed males. However, the addition of CVS diminished difference scores in females - an effect not observed in CVS-exposed males. Overall, these data suggest that neonatal paternal experience, sex, and chronic stress contribute to exploratory behavior, cognition, and stress hormone concentrations in a biparental species.

More than just mothers: The neurobiological and neuroendocrine underpinnings of allomaternal caregiving.

In a minority of mammalian species, mothers depend on others to help raise their offspring. New research is investigating the neuroendocrine mechanisms supporting this allomaternal behavior. Several hormones have been implicated in allomaternal caregiving; however, the role of specific hormones is variable across species, perhaps because allomothering independently evolved multiple times. Brain regions involved in maternal behavior in non-human animals, such as the medial preoptic area, are also critically involved in allomaternal behavior. Allomaternal experience modulates hormonal systems, neural plasticity, and behavioral reactivity. In humans, fatherhood-induced decreases in testosterone and increases in oxytocin may support sensitive caregiving. Fathers and mothers activate similar neural systems when exposed to child stimuli, and this can be considered a global "parental caregiving" network. Finally, early work on caregiving by non-kin (e.g., foster parents) suggests reliance on similar mechanisms as biologically-related parents. This article is part of the 'Parental Brain and Behavior' Special Issue.

Neurogenesis and anxiety-like behavior in male California mice during the mate's postpartum period.

Our understanding of postpartum anxiety (PPA) in fathers is limited, despite the negative consequences of anxiety on the father and child. Offspring contact reduces PPA in mothers; however, parallel investigations in fathers has gone unaddressed. Adult neurogenesis in the dentate gyrus (DG) contributes to anxiety regulation and is altered during the postpartum period, yet the effects of fatherhood on the production, or survival, of newborn cells in the DG, and the role of adult neurogenesis in PPA regulation, have not been examined. Using the biparental California mouse (Peromyscus californicus), we examined the relationships among postnatal day, anxiety-like behavior and adult neurogenesis in fathers. We hypothesized that attenuated anxiety-like behavior and enhanced adult neurogenesis would be observed when father-offspring contact was increased. We observed a reduction in anxiety-like behavior on the elevated plus-maze, but only at PND 16, a time of peak pup retrieval. Fatherhood reduced 1-week survival of newborn cells; however, surviving cells were maintained until 2 weeks postpartum. In contrast, non-fathers experienced a significant reduction in the survival of newborn cells between 1 and 2 weeks postpartum. Fatherhood also increased the numbers of newborn cells that expressed a neuronal phenotype. Collectively, these findings suggest that offspring interaction contributes to reductions in anxiety-like behavior and the maintenance of newborn neurons in the DG of fathers. These data contribute to our knowledge of the postpartum affective state in fathers, findings that may contribute to improved health of both the father and offspring.