Viral-induced encephalitis initiates distinct and functional CD103+ CD11b+ brain dendritic cell populations within the olfactory bulb.

Dendritic cells (DC) are antigen-presenting cells found in both lymphoid and nonlymphoid organs, including the brain (bDC) of Cd11c/eyfp transgenic C57BL/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP(+) cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP(+) CD45(+) CD11b(+) populations, all but one being able to functionally promote both T lymphocyte proliferation and T(H)1 cytokine production. One population was shown to emanate from the brain and a second population was peripherally derived. The third population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP(+) population contained CD11b(+) CD103(+) subpopulations and could be distinguished in terms of CD115, Gr-1, and Ly-6C expression, highlighting mucosal and monocyte-derived DC lineages.

Serotonin-1A receptor, a psychiatric disease risk factor, influences offspring immunity via sex-dependent genetic nurture.

Serotonin-1A receptor (5HT1AR) is highly expressed in corticolimbic regions and its deficit is associated with anxiety and depression. A similar reduction in 5HT1AR heterozygous knockout (Het) mice results in anxiety-like and increased stress-reactivity phenotypes. Here we describe immunological abnormalities in Het females, characterized by an activated state of innate and adaptive immune cells. Het males showed only limited immune dysregulation. Similar immune abnormalities were present in the genetically WT female (F1) but not male offspring of Het mothers, indicating sex-specific immune system abnormalities that are dependent on the mother's 5HT1AR deficit, known as maternal genetic effect or "genetic nurture". Expression profiling of the maternal-fetal interface revealed reduced immune cell invasion to decidua and accelerated trophoblast migration. These data suggest that 5HT1AR deficit, by altering the maternal immune system and midgestational in utero environment, leads to sex-biased outcomes, predominantly immune dysregulation in the female and anxiety-like behavior in the male offspring.

Maternal Programming of Social Dominance via Milk Cytokines.

Regular physical activity improves physical and mental health. Here we found that the effect of physical activity extends to the next generation. Voluntary wheel running of dams, from postpartum day 2 to weaning, increased the social dominance and reproductive success, but not the physical/metabolic health, of their otherwise sedentary offspring. The individual's own physical activity did not improve dominance status. Maternal exercise did not disrupt maternal care or the maternal and offspring microbiota. Rather, the development of dominance behavior in the offspring of running mothers could be explained by the reduction of LIF, CXCL1, and CXCL2 cytokines in breast milk. These data reveal a cytokine-mediated lactocrine pathway that responds to the mother's postpartum physical activity and programs offspring social dominance. As dominance behaviors are highly relevant to the individual's survival and reproduction, lactocrine programming could be an evolutionary mechanism by which a mother promotes the social rank of her offspring.

Maternal Brain TNF-α Programs Innate Fear in the Offspring.

Tumor necrosis factor alpha (TNF-α) is a cytokine that not only coordinates local and systemic immune responses [1, 2] but also regulates neuronal functions. Most prominently, glia-derived TNF-α has been shown to regulate homeostatic synaptic scaling [3-6], but TNF-α-null mice exhibited no apparent cognitive or emotional abnormalities. Instead, we found a TNF-α-dependent intergenerational effect, as mothers with a deficit in TNF-α programmed their offspring to exhibit low innate fear. Cross-fostering and conditional knockout experiments indicated that a TNF-α deficit in the maternal brain, rather than in the hematopoietic system, and during gestation was responsible for the low-fear offspring phenotype. The level of innate fear governs the balance between exploration/foraging and avoidance of predators and is thus fundamentally important in adaptation, fitness, and survival [7]. Because maternal exercise and activity are known to reduce both brain TNF-α [8] and offspring innate fear [9], whereas maternal stress has been reported to increase brain TNF-α [10] and offspring fear and anxiety [11, 12], maternal brain TNF-α may report environmental conditions to promote offspring behavioral adaptation to their anticipated postnatal environment.

Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms.

Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.