Cellular and molecular signatures of motherhood in the adult and ageing rat brain

Abstract

Pregnancy is marked by robust changes, including brain changes to volume, structure, connectivity and neuroplasticity. Although some brain changes are restricted to pregnancy and the postpartum, others are long-lasting. Few studies have examined possible mechanisms of these changes or the effects of multiple pregnancies. We characterized various cellular and molecular signatures of parity (nulliparous, primiparous, biparous) in the rat hippocampus. We investigated density of neural stems cells (Sox2), microglia (Iba-1) and levels of a synaptic protein (PSD-95), cell signalling pathways, neuroinflammation, and the tryptophan–kynurenine (TRP–KYN) pathway, one week after weaning their pups from the last pregnancy (age of dam: seven months) and in middle-age (age of dam: 13 months). Parity increased PSD-95 levels in both age groups and prevented the age-related decrease in neural stem cell density observed in nulliparous rats. Biparity increased cell signalling phosphoproteins (pp70S6K, S6RP) and number of microglia in the dentate gyrus, regardless of age. Parity resulted in transient changes to the TRP–KYN system. Thus, previous parity has lasting effects on synaptic plasticity with fewer lasting effects on inflammation and cell signalling phosphoproteins in the whole hippocampus.

Pregnancy History and Estradiol Influence Spatial Memory, Hippocampal Plasticity, and Inflammation in Middle-aged Rats

“…Our results demonstrate not only that previous pregnancy, and the age of first pregnancy, can affect multiple brain parameters, but also that the effects of estradiol in middle age can vary with previous reproductive experience. This work converges with others to indicate that parity, and associated factors such as the number of pregnancies affect the trajectory of brain aging and health (Duarte-Guterman et al, 2019, 2023; Galea et al, 2018; Puri et al, 2023). With an aging global population, our work suggests that parity, and the age of first pregnancy should be taken into consideration when investigating the effects of estrogens in middle and older age.…”

“…These cytokines are 'antiinflammatory' and have very closely linked functions, and are secreted by Th2 type T-cells (KleinJan et al, 1999;Yssel & Groux, 2000). Although there are some previous studies that have investigated the effects of parity and inflammation and found no effect of parity on IL-13, IL-10, or TNF-α, they did not consider any hormonal treatment or age of first pregnancy, and also looked at circulating cytokines, whereas our study investigated cytokine levels in brain tissue (Duarte-Guterman et al, 2023;Eid et al, 2019).…”

“…Rodents experience similar changes with pregnancy, as primiparous rats (that have been pregnant and mothered once) show decreased hippocampal volume and reduced neurogenesis in the hippocampus during gestation and into the late postpartum (Eid et al, 2019; Galea et al, 2000). In middle age, however, reproductive experience is associated with less evident brain aging (as measured by grey matter volume) in humans, and increased hippocampal neurogenesis and the synaptic protein PSD-95 in rodents (Barha et al, 2015; de Lange et al, 2019, 2020; Duarte-Guterman et al, 2023; Eid et al, 2019; Galea et al, 2018; Puri et al, 2023). These findings show that the hippocampus displays dynamic plasticity from the short to the long term with reproductive experience.…”

“…Reproductive experience alters inflammation in the brain in both the short and long-term (Eid et al, 2019; Haim et al, 2017). In rats, maternal experience increases pro-inflammatory and decreases anti-inflammatory cytokine expression, and alters microglial morphology such that they become more ameboid in the early postpartum period (Duarte-Guterman et al, 2023; Eid et al, 2019; Haim et al, 2017). In middle age, primiparity increases the concentrations of IFN-γ and IL-4 but decreases the concentration of IL-1β peripherally in middle-aged rats (Eid et al, 2019).…”

Running to remember: The effects of exercise on perineuronal nets, microglia, and hippocampal angiogenesis in female and male mice

“…For each marker, counts were average from four dorsal and three ventral sections per individual. In addition, Iba-1 morphology was categorized into three groups: ameboid, stout/thick, and thick/thin, similar to previous work (Duarte-Guterman et al, 2023; Eid et al, 2019). Categorization was based on the branching of the processes, with an ameboid morphology having no processes, a stout/thick morphology having one to two processes close to the cell body, and a thick/thin morphology having several thin processes extending outwards from the cell body (Figure 1B-D).…”