Early life stress and differential effects on the molecular maturation of specific subtypes of brain serotonin neurons

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Project Summary/Abstract Extreme adversity and stress in early life, affecting over one in three children, can perturb critical processes in brain development that may increase risk for mental illness throughout life. Possible underlying neurobiological pathways and temporal windows of particular sensitivity are explored in this R21 study in which we focus on a newly discovered organizational structure and maturation trajectory for the many different subtypes of brain serotonin (5-HT)-producing neurons across early postnatal life in mice. Rodent studies show neurobiological modifications in response to early life stress (ELS) that include brain 5-HTergic neurons, and clinical studies implicate diminished 5-HT-mediated neurotransmission. Thus, the ‘ground state’ of brain 5-HTergic neurons may change with ELS, and by adulthood, the causal pathway may no longer be present. Little is known about which of the many brain 5-HTergic neuron subtypes are vulnerable, what molecular mechanisms and timing underlie the ELS-sensitivity, and how this relates to long-term brain and behavioral dysfunction. This is now discoverable, through precision brain cell access tools in mice, advances in single-cell (sc) ‘omics,’ and recent discoveries – many from our group – that rewrite the organizational map for the brain 5-HTergic neuronal system. We now know that the adult brain 5-HTergic system in mice is organized into over twenty neuronal subtypes that, while sharing generic 5-HTergic features, are otherwise distinct molecularly, and in many cases also shown to be distinct functionally and hodologically. Mapping the embryonic 5-HTergic neuronal system has revealed fewer subgroups. Lacking have been studies across postnatal development at a resolution sufficient to identify 5-HTergic neuron subtypes and reveal potential molecular pathways and temporal sequences by which the mature subtype organization arises. We recently generated transcriptomic (scRNA- sequencing) data across postnatal development and discovered several novel features distinguishing the various 5-HTergic neuron subtypes that may be impacted by ELS. These findings provide a high-resolution developmental map of the emergence of brain 5-HTergic neuron subtypes and their differential windows of maximal maturational change as reflected in the state of their transcriptome and epigenome. Here we apply this new 5-HTergic system ‘lens’ to reveal short- and long-term cellular, molecular, and epigenetic effects of two well-documented early life [day 2(neonatal) through 15 (childhood)] exposures in mice: transient daily maternal separation (Aim 1), and chronic daily administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine (Aim 2). Discoveries will include neurobiological pathways sensitive to early life exposures and which may have relevance to human psychopathologies that originate early in life.