The Role of Corticolimbic Circuits in Maternal Behavior - PROJECT ABSTRACT/SUMMARY The transition to motherhood brings dramatic changes in physiology and brain function, including plasticity within neural circuits regulating maternal care, threat and stress responses, which are essential for the survival and well-being of the offspring. Many human and animal studies highlight the importance of resilient threat and stress responses to efficient maternal care. Clinical work suggests that improving emotional states of the mother is critical for engaging more successfully with her progeny and creating sensitive parenting. Cortico- limbic circuits play a crucial role in threat and stress responses. However, little is known about the interactions between cortico-limbic circuitry and core maternal brain regions, making it challenging to relate threat and stress responses to maternal care. To address this gap in knowledge, we recently developed an approach to study how cortico-limbic brain regions regulate maternal care, threat and stress responses postpartum. We uncovered a distinct subpopulation of neurons within cortico-limbic circuits that regulate maternal care, threat and stress responses behavior in the postpartum state and showed the importance of plasticity to this process. Our research will yield new insights into how plasticity in cortico-limbic circuits regulate maternal care, threat and stress responses by defining the synaptic function and transcriptional mechanisms using a combination of genetic, neural-circuit dissection, synaptic electrophysiology, biochemical and transcriptional tools. This will allow a close examination of links between cell-signaling, synapses and the neuronal nucleus. In Aim 1 we identify cortico-limbic cell populations responsible for maternal care, threat and stress responses postpartum, using chemogenetics, optogenetics, cell-type specific gene promoters, novel knock-in mouse lines and viral vectors not previously tested in maternal behavior. In Aim 2 we define the synaptic mechanisms of maternal care, threat and stress responses postpartum. We will conduct a detailed analysis of key synaptic proteins, synaptic transmission and synaptic plasticity. Accomplishment of this aim will connect neural circuits (studied in Aim 1) with synaptic mechanisms that are part of a key intracellular signaling pathway that supports maternal care, threat and stress responses postpartum. In Aim 3 we make some of the first measurements of transcription in cortico-limbic circuits postpartum. We will examine expression of candidate genes in relevant brain regions of mothers of our newly developed transgenic mouse lines and compare these genes to synaptic molecules studied in Aim 2 and to gene databases of human mental disorders with similar neuronal mechanisms. Accomplishment of Aim 3 will provide a mechanistic foundation for connecting cortico-limbic circuits (studied in Aim 1), synaptic proteins and synaptic function (studied in Aim 2) with maternal care, threat and stress responses postpartum and will be a source of new gene targets to test this connection. The results of this work will guide neural circuit-based, gene-based and pharmacological strategies for improving mothers’ well-being and therefore their ability to take care of their offspring.
