Serotonin-specific lesions of the dorsal raphe disrupt maternal aggression and caregiving in postpartum rats

Abstract

The behavioral modifications associated with early motherhood, which include high aggression, caring for the young, and low anxiety, are all affected by acute pharmacological manipulation of serotonin signaling. However, the effects on all these behaviors of permanently disrupting serotonin signaling from one of its primary sources, the dorsal raphe nucleus (DR), have not been examined in detail. To address this, serotonin-specific lesions centered on the dorsomedial DR (DRdm; DR subregion strongly implicated in emotional behaviors) were induced at mid-pregnancy (day 15) or early postpartum (day 2) in rats using a saporin-conjugated neurotoxin targeting the serotonin transporter (Anti-SERT-SAP). Prepartum or postpartum Anti-SERT-SAP reduced DRdm serotonin immunoreactivity by ∼40-65%, and postpartum Anti-SERT-SAP also reduced it in the ventromedial and lateral wings of the DR, as well as in the median raphe. Serotonin-immunoreactive fibers were significantly reduced in the anterior hypothalamus, but not medial preoptic area, of lesioned dams. Pre- or postpartum lesions both greatly reduced maternal aggression, but while prepartum lesions did not affect later undisturbed maternal caregiving, the larger postpartum lesions prevented the postpartum decline in kyphotic nursing and reduced pup licking. Serotonin lesions did not affect pup retrieval, but the prepartum lesions temporarily increased maternal hovering over and licking the pups observed immediately after the disruptive retrieval tests. Dams' anxiety-like behaviors and litter weight gains were unaffected by the lesions. These findings suggest that DRdm serotonin projecting to the AH is particularly critical for maternal aggression, but that more widespread disruption of midbrain raphe serotonin is necessary to greatly impair maternal caregiving. Postpartum anxiety may rely more on other neurochemical systems or different midbrain serotonergic cell populations.

Dorsal raphe oxytocin receptors regulate the neurobehavioral consequences of social touch

“…Our OTR knockdown also produced a >3-fold increase in the number of maternal attacks against male intruders and a >6-fold increase in the time that mothers spent attacking (Figs 3K-M). This pro-aggressive effect of OTR knockdown is consistent with studies showing that impairing DR serotonin cell function with selective lesions decreases maternal aggression 50 , that serotonin is positively associated with aggression in females 51 , and that destroying the PAGvl/DRlw doubles the frequency of maternal attacks on an intruder 35 .…”

“…On postpartum day 7, following undisturbed maternal behavior observations, dams were brought in their homecage to a nearby behavior testing room and a male intruder was placed in their cage as previously described 50 . Following the 10-min test, males were removed from the cage and sacrificed by CO 2 asphyxiation.…”

“…Immunohistochemistry was conducted using methods previously described 50 . The number of serotonin-ir cells in the DR (complete visual area) was counted on each section by naive experimenters under 100X magnification.…”

Extensive juvenile “babysitting” facilitates later adult maternal responsiveness, decreases anxiety, and increases dorsal raphe tryptophan hydroxylase‐2 expression in female laboratory rats

“…That is, the typical age‐related decline in serotonin functioning seemed to be prevented by early experience with pups, which we propose resulted in some behavioral similarities between alloparentally experienced females and postpartum rats. This link between high maternal responsiveness and elevated serotonin is supported by the disrupted mothering in female mice with knockout of the TPH2 gene (Angoa‐Pérez et al, ), in rats with lesions of the raphe nuclei (Barofsky et al, ; Holschbach, Vitale, & Lonstein, ), and in rats treated with 5HT receptor modulators (Chen et al, ). Work by Olazábal et al (2004) also supports this idea, in that they found that juveniles have higher tissue content of serotonin and its metabolite compared to nulliparous adult female rats in brain regions involved in maternal behavior including the medial preoptic area (mPOA).…”

Psychological and neurobiological mechanisms underlying the decline of maternal behavior

“…This region is well known for its a central role in top-down control of many higher-order functions, such as working memory, attention, emotion regulation, inhibitory control, and cognitive flexibility (Anastasio et al, 2015;Moghaddam and Homayoun, 2008;Puig and Gulledge, 2011;Puig et al, 2015). It is densely interconnected with numerous cortical and subcortical structures, including the MPOA, VTA, NAc and dorsal raphe (DR) (Holschbach et al, 2018), part of the excitatory maternal neural circuit. The robust anatomical and functional interconnections between the mPFC and the excitatory neural circuit suggest that the mPFC could play a role in maternal behavior through different behavioral mechanisms, including the executive control and organization of maternal activities and the regulation of dopamine-mediated maternal motivation (Afonso et al, 2007;Hansen, 1994;Li, 2015;Li and Fleming, 2003;Olazabal et al, 2013;Pereira and Ferreira, 2006;Pereira et al, 2005;Stern and Keer, 1999;Zhao and Li, 2009).…”