Early Pup Removal Leads to Social Dysfunction and Dopamine Deficit in Late Postpartum Rats: Prevention by Social Support

Abstract

Offspring interaction is among the most highly motivated behaviors in maternal mammals and is mediated by mesolimbic dopamine (DA) system activation. Disruption or loss of significant social relationships is among the strongest individual predictors of affective dysregulation and depression onset in humans. However, little is known regarding the effects of disrupted mother–infant attachment (pup removal) in rat dams. Here, we tested the effects of permanent pup removal in rat dams, which were assigned to one of three groups on postpartum day (PD) 1: pups; pups removed, single-housed; or pups removed, co-housed with another dam who also had pups removed; and underwent a behavioral test battery during PD 21–23. In vivo electrophysiological recordings of ventral tegmental area (VTA) DA neurons were performed on PD 22 and 23 in a subset of animals. Pup removal did not impact sucrose consumption or anxiety-like behavior, but increased passive forced swim test (FST) coping responses. Pup-removal effects on social behavior and VTA activity were sensitive to social buffering: only single-housed dams exhibited reduced social motivation and decreased numbers of active DA neurons. Dams that had pups removed and were co-housed did not exhibit changes in social behavior or VTA function. Moreover, no changes in social behavior, FST coping, or VTA activity were found in socially isolated adult virgin females, indicating that effects observed in dams are specific to pup loss. This study showed that deprivation of species-expected social relationships (pups) during the postpartum precipitates an enduring negative affect state (enhanced passive coping, blunted social motivation) and attenuated VTA DA function in the dam, and that a subset of these effects is partially ameliorated through social buffering.

Social Determinants of Inter-Individual Variability and Vulnerability: The Role of Dopamine

“…Recent studies indicate that postpartum rats show transient changes in dopaminergic activity which are linked with the expression of depressive-like behaviors ( Rincón-Cortés and Grace, 2019 ). The unique social stressor of pup removal further alters dopaminergic activity in postpartum dams, resulting in a decrease of spontaneously active dopamine neurons, which can be rescued by paring housing two pup-separated dams together ( Rincón-Cortés and Grace, 2021 ). These results suggest provide initial evidence that social support may attenuate the effect of stressors by restoring dopamine neuron activity.…”

Dopamine downregulation in novel rodent models useful for the study of postpartum depression

“…The second model consists of manipulating the dam’s physical environment by reducing the amount of bedding material within the dam’s home cage (i.e., resource scarcity; Ivy et al, 2008 ). We have recently shown that both models converge in disrupting a variety of behaviors in the dam, including maternal and depression-relevant behaviors, and attenuating mesolimbic DA system function (Rincón-Cortés and Grace, 2021 , 2022 ).…”

“…Because we cannot measure grief in rodents, we focus on the increased depression-related phenotypes resulting from permanent pup removal. Permanent pup removal increases passive FST coping responses (i.e., immobility) and reduces social motivation during the late postpartum period in rat dams (Pawluski et al, 2009 ; Rincón-Cortés and Grace, 2021 ). These behavioral effects overlap with those observed in female rodent models relevant to depression, including stress-based, pharmacologically-induced and genetic models (Iniguez et al, 2018 ; Newman et al, 2019 ; Lima et al, 2022 ), as well as in PPD rodent models employed during the postpartum (Perani and Slattery, 2014 ; Li and Chou, 2016 ; Qiu et al, 2020 ; Mir et al, 2022 ).…”

“…In terms of mesolimbic DA function, permanent pup removal results in a long-lasting attenuation of VTA DA neuron activity, as indexed by a reduction in the number of active DA neurons ~3 weeks after pup removal (Rincón-Cortés and Grace, 2021 ). Moreover, this reduction in VTA DA neuron activity was correlated with reduced social sniff time in dams that had pups removed.…”

“…Within this context, a decrease in VTA DA neuron activity would be expected to diminish stimulus-driven DA neuron responses, leading to attenuated mesolimbic DA system activation and blunted reward-related responses, including a reduced social approach (Grace, 2016 ). Importantly, the enduring effects of permanent pup removal are specific to pup loss from postpartum days (PD) 1–21, as a 3-week social isolation window did not impact social approach, FST immobility, or DA function in adult virgin females (Rincón-Cortés and Grace, 2021 ). In sum, the presence of pups during the postpartum period appears to be important for establishing adequate levels of maternal affect and mesolimbic DA system activity, whereas the lack of pup presence can trigger a long-lasting negative affect (i.e., depressive-like) state associated with mesolimbic DA downregulation.…”