Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

Abstract

The adult brain shows remarkable neuroplasticity in response to hormones and the socioemotional modifications that they influence. In females with reproductive and maternal experience, this neuroplasticity includes the birth and death of new and existing cells in several forebrain regions involved in maternal caregiving and postpartum affective state. Such plasticity in midbrain sites critical for these processes has never been examined, though. Visualizing bromodeoxyuridine (BrdU) to label mitotic cells, l NeuroD for neuronal precursors, and TUNEL to identify dying cells, we found that the midbrain dorsal raphe nucleus (DR, the source of most ascending serotoninergic projections) exhibited significant neuroplasticity in response to motherhood. Specifically, BrdU analyses revealed that DR newborn cell survival (but not proliferation) was regulated by reproductive state, such that cells born early postpartum were less likely to survive compared to cells born during late pregnancy. Many of the surviving cells in the DR were NeuN immunoreactive, suggesting a neuronal phenotype. Similarly, late postpartum rats had fewer NeuroD-immunoreactive DR cells than early postpartum rats. Maternal experience contributed to the late postpartum reduction in DR newborn cell survival because removing the litter at parturition increased cell survival and reduced cell death. Unlike cytogenesis in the maternal hippocampus, which is reduced by circulating glucocorticoids, DR newborn cell survival was unaffected by postpartum adrenalectomy. These effects of reproductive state and motherhood on DR plasticity were associated with concurrent changes in DR levels of serotonin's precursor, 5-HTP, and its metabolite, 5-HIAA. Our results demonstrate for the first time that cytogenesis occurs in the midbrain DR of any adult mammal, that DR plasticity is influenced by female reproductive state and maternal experience, and that this plasticity is accompanied by changes in DR serotonergic function. Because serotonin is critical for postpartum caregiving behaviors and maternal affective state, neuroplastic changes in the DR may contribute to the neurochemical changes necessary for successful motherhood.

Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome

“…This suggests that serotonin metabolism is altered in brain regions critical for mediating parental behaviors. Some of these neurochemical changes are only apparent during the early postpartum period; early postpartum dams have higher 5-hydroxytryptophan (5-HTP) and 5hydroxyindoleacetic acid (5-HIAA), both critical metabolites involved in serotonin synthesis, in the dorsal raphe compared to virgin and late postpartum rats (Holschbach and Lonstein, 2016).…”

“…Recent work also shows significant changes in neuroplasticity in response to motherhood in the midbrain dorsal raphe nucleus, the source of most ascending serotoninergic projections (Holschbach and Lonstein, 2017), and in other regions of the maternal brain; SSRIs increase R e v i s e d m a n u s c r i p t 9 neurogenesis in the maternal hippocampus (Pawluski et al, 2017;Pawluski et al, 2012b) and alter plasticity in the PFC and amygdala (Haim et al, 2015;Haim et al, 2014). Postpartum fluoxetine treatment also decreases both global measures of methylation in the dentate gyrus and serotonin metabolism in the hippocampus, but not the prefrontal cortex (PFC), of the mother (Gemmel et al, 2016).…”

Maternal experience and adult neurogenesis in mammals: Implications for maternal care, cognition, and mental health

“…These data suggest fewer DR neurons survive when generated during the early postpartum period compared to when they are generated during late pregnancy (Holschbach & Lonstein, ). BrdU‐ir cell number in the DR was not significantly altered in adrenalectomized postpartum rats, suggesting that CORT concentrations do not alter cell survival in the DR (Holschbach & Lonstein, ). However, permanent offspring removal within 1 hr of parturition increased cell survival and cell death in late postpartum rats, suggesting that offspring exposure suppressed neurogenesis in the DR (Holschbach & Lonstein, ).…”

“…BrdU‐ir cell number in the DR was not significantly altered in adrenalectomized postpartum rats, suggesting that CORT concentrations do not alter cell survival in the DR (Holschbach & Lonstein, ). However, permanent offspring removal within 1 hr of parturition increased cell survival and cell death in late postpartum rats, suggesting that offspring exposure suppressed neurogenesis in the DR (Holschbach & Lonstein, ). It is unclear how offspring removal disinhibited neurogenesis in the DR. Lower concentrations of ovarian hormones (estradiol and progesterone) during lactation could suppress cell survival in the DR.…”

“…Suppressed DR neurogenesis might facilitate the cessation of postpartum maternal care. Serotonin synthesis and metabolism decline through the postpartum period: early postpartum rats (PD 8) have higher concentrations of 5‐hydroxytryptamine (5‐HTP; the precursor for serotonin), and 5‐hydroxyindole acetic acid (5‐HIAA; a metabolite of serotonin) than late postpartum rats (PD 19) (Holschbach & Lonstein, ). The expression of maternal behavior depends on high serotonin turnover in the MPOA and bed nucleus of the stria terminalis (BNST; Lonstein, Dominguez, Putnam, De Vries, & Hull, ; Smith, Piasecki, Weera, Olszewicz, & Lonstein, ).…”