# Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk? > **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $691,218 ## Abstract Project Summary: A robust autoresuscitatory reflex (AR) is critical to newborn survival from birth. The transition to independent breathing and accommodation of breathing interruptions, apneas, that are common in neonates and infants, requires a coordinated cardiorespiratory response for recovery. 5-hydroxytryptamine (5- HT, serotonin) and the brainstem raphe cells that produce it, referred to as Pet1 neurons, organize and drive successful AR in newborn animals and humans. Unsuccessful AR is understood to be a major contributor to the sudden infant death syndrome (SIDS), where alterations in the brain 5-HTergic system have been described in ~half of human SIDS cases, including increased number of 5-HT neurons of differing morphology (smaller, simpler, perhaps immature), deficiencies in autoreceptor 5-HT1A binding, and decreased levels of 5- HT and tryptophan hydroxylase 2 (TPH2, the rate-limiting biosynthetic enzyme for 5-HT). We propose investigations to reveal in mice how aspects of this SIDS brain 5-HTergic phenotype develop prenatally. Our approach is informed by two recent findings. First, Pet1+ neurons in the raphe expressing high levels of 5-HT identity genes (e.g. Ddc, Vmat2, Gata3, Pet1) have been identified, smaller in size, with modest levels of autoreceptor 5-HT1A yet remarkably expressing little or no TPH2 and 5-HT. We call these novel cells para-5- HTergic neurons, signifying their partially shared molecular phenotype, shared location, and developmental emergence with 5-HT neurons. Second is the discovery of neurotransmitter switching, a noncanonical form of neuronal plasticity that occurs in response to stressors. Recent data support its role in shaping the 5-HTergic neuronal system, where stressors may drive some para-5-HT neurons to produce 5-HT as an adaptive response. Preliminary findings reveal that para-5-HT neurons derived from rhombomere (r) 4 densely and selectively innervate respiratory and arousal centers, and that gestational exposure to intermittent hypoxia results in an increased number of TPH2+ cells postnatally with as yet uncertain 5-HT levels. We propose that para-5-HT neurons are a pliant population that may be transformed when challenged prenatally by hypoxia to produce 5-HT in newborns as a compensatory mechanism to support AR. We hypothesize that in response to the major SIDS risk factor of prenatal hypoxia, certain para-5-HT neurons adaptively transform to produce 5-HT to rectify a 5-HTergic signaling imbalance that hinders the AR and, alternatively, that an insufficient transformation plays a critical role in SIDS. We will test this by exposing mice to intermittent hypoxia or normoxia during gestation, characterizing cellular and molecular phenotypes and querying neurotransmitter transformation (Aim 1); further, we will determine the effect of acute activation or inhibition of these r4-para-5-HT neurons on the AR in these mice (Aim 2), and we will examine phenotypic markers of para-5-HT neurons in human SIDS... ## Key facts - **NIH application ID:** 10049280 - **Project number:** 1R01HD100823-01A1 - **Recipient organization:** HARVARD MEDICAL SCHOOL - **Principal Investigator:** Susan M. Dymecki - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $691,218 - **Award type:** 1 - **Project period:** 2020-09-04 → 2025-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10049280 ## Citation > US National Institutes of Health, RePORTER application 10049280, Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk? (1R01HD100823-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049280. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*