Effects of maternal experience on pup-induced activation of maternal neural circuits in virgin mice.

Maternal experience can promote a long-lasting increase in maternal motivation. This maintenance of caregiving behaviors, rather than avoidant or agnostic responses towards young, is advantageous for the survival of subsequent offspring. We have previously reported that maternal motivation is associated with differential immediate early gene expression in central motivation circuits and aversion circuits. Here we ask how these circuits come to differentially respond to infant cues. We used Targeted Recombination in Active Populations (TRAP) to identify cells that respond to pups in maternally hesitant TRAP2;Ai14 virgin female mice. Following an initial 60 min exposure to foster pups, virgin TRAP2;Ai14 mice were injected with 4-hydroxytamoxifen to induce recombination in c-Fos expressing cells and subsequent permanent expression of a red fluorescent reporter. We then examined whether the same cells that encode pup cues are reactivated during maternal memory retrieval two weeks later using c-Fos immunohistochemistry. Whereas initial pup exposure induced c-Fos activation exclusively in the medial preoptic area (MPOA), following repeated experience, c-Fos expression was significantly higher than baseline in multiple regions of maternal and central aversion circuits (e.g., ventral bed nucleus of the stria terminalis, nucleus accumbens, basolateral amygdala, prefrontal cortex, medial amygdala, and ventromedial nucleus of the hypothalamus). Further, cells in many of these sites were significantly reactivated during maternal memory retrieval. These data suggest that cells across both maternal motivation and central aversion circuits are stably responsive to pups and thus may form the cellular representation of maternal memory.

Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches.

Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain.

Hypothalamic interaction with the mesolimbic DA system in the control of the maternal and sexual behaviors in rats.

The medial preoptic area (MPOA) of the hypothalamus regulates maternal behavior, male sexual behavior, and female sexual behavior. Functional neuroanatomical evidence indicates that the appetitive aspects of maternal behavior are regulated through MPOA interactions with the mesolimbic dopamine (DA) system; a major focus of this review is to explore whether or not the MPOA participates in the appetitive aspects of sexual behavior via its interaction with the mesolimbic DA system. A second focus of this review is to examine the extent to which estradiol interactions with DA within this circuit regulate all three reproductive behaviors. One mechanism through which estradiol activates male sexual behavior is through the potentiation of DA activity in the MPOA. In the hypothalamus, estradiol has also been found to act in concert with DA, through the activation of similar intracellular signaling pathways, in order to stimulate female sexual behavior. Finally, recent evidence suggests that some effects of estradiol are mediated by direct action of estradiol on the mesolimbic DA system.