Interaction of the pre- and postnatal environment in the maternal immune activation model.

Adverse influences during pregnancy are associated with a range of unfavorable outcomes for the developing offspring. Maternal psychosocial stress, exposure to infections and nutritional imbalances are known risk factors for neurodevelopmental derangements and according psychiatric and neurological manifestations later in offspring life. In this context, the maternal immune activation (MIA) model has been extensively used in preclinical research to study how stimulation of the maternal immune system during gestation derails the tightly coordinated sequence of fetal neurodevelopment. The ensuing consequence of MIA for offspring brain structure and function are majorly manifested in behavioral and cognitive abnormalities, phenotypically presenting during the periods of adolescence and adulthood. These observations have been interpreted within the framework of the "double-hit-hypothesis" suggesting that an elevated risk for neurodevelopmental disorders results from an individual being subjected to two adverse environmental influences at distinct periods of life, jointly leading to the emergence of pathology. The early postnatal period, during which the caregiving parent is the major determinant of the newborn´s environment, constitutes a window of vulnerability to external stimuli. Considering that MIA not only affects the developing fetus, but also impinges on the mother´s brain, which is in a state of heightened malleability during pregnancy, the impact of MIA on maternal brain function and behavior postpartum may importantly contribute to the detrimental consequences for her progeny. Here we review current information on the interaction between the prenatal and postnatal maternal environments in the modulation of offspring development and their relevance for the pathophysiology of the MIA model.

Zygotic genome activation by the totipotency pioneer factor Nr5a2.

Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA). Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. On the basis of de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse two-cell embryos. Nr5a2 is required for progression beyond the two-cell stage. It binds to its motif within SINE B1/Alu retrotransposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear receptors. Nr5a2 promotes chromatin accessibility during ZGA and binds nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that regulates ZGA.

The metabolic regulator USF-1 is involved in the control of affective behaviour in mice.

Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood. Here, we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF-1) knock-out (KO) mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits and found a reduction of depression-like and anxiety-like behaviours associated with USF-1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF-1 KO mice. Further, the absence of USF-1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNA-seq analysis characterised the molecular signature of USF-1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. The transcriptional changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity in USF-1 KO mice. Collectively these data suggest that the metabolic regulator USF-1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF-1-dependent BAT activation, but reflected in structural changes in the brain.

An accessory prefrontal cortex-thalamus circuit sculpts maternal behavior in virgin female mice.

The ability to care for the young is innate and readily displayed by postpartum females after delivery to ensure offspring survival. Upon pup exposure, rodent virgin (nulliparous) females also develop parental behavior that over time becomes displayed at levels equivalent to parenting mothers. Although maternal behavior in postpartum females and the associated neurocircuits are well characterized, the neural mechanisms underlying the acquisition of maternal behavior without prior experience remain poorly understood. Here, we show that the development of maternal care behavior in response to first-time pup exposure in virgin females is initiated by the activation of the anterior cingulate cortex (ACC). ACC activity is dependent on feedback excitation by Vglut2+ /Galanin+ neurons of the centrolateral nucleus of the thalamus (CL), with their activity sufficient to display parenting behaviors. Accordingly, acute bidirectional chemogenetic manipulation of neuronal activity in the ACC facilitates or impairs the attainment of maternal behavior, exclusively in virgin females. These results reveal an ACC-CL neurocircuit as an accessory loop in virgin females for the initiation of maternal care upon first-time exposure to pups.