Early‐life stress increases the survival of midbrain neurons during postnatal development and enhances reward‐related and anxiolytic‐like behaviors in a sex‐dependent fashion

Abstract

Clinical studies have suggested that early-life stress (ELS) increases the risk of psychopathologies that are strongly associated with dysfunction of dopaminergic neurotransmission. Thus, ELS may interfere with the development and maturation of the dopaminergic system; however, the mechanisms involved in such interference are poorly understood. In the present study, we investigated the effect of ELS on the survival of specific populations of neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) during postnatal development. First, we injected bromodeoxyuridine (BrdU) into pregnant rat dams on embryonic days 12, 13 and 14 to permanently label midbrain neurons. Then, after birth, the dams and litters were subjected to a maternal separation (MS) procedure to model ELS conditions. The number of BrdU+ neurons and the total number of neurons (cresyl violet+, CV+) were estimated in both male and female juvenile, adolescent, and adult rats. Moreover, sucrose preference and anxiety-like behaviors were studied during adulthood. We found that MS permanently increased the number of BrdU+ and CV+ neurons in the VTA of males. In the SNc, a temporary increase in the number of BrdU+ neurons was observed in juvenile MS males; however, only adult MS males displayed an increase in the number of CV+ neurons. Immunofluorescence analysis implied that MS affected the fate of non-dopaminergic neurons. MS males displayed anxiolytic-like behavior and an increase in sucrose preference. These results suggest that ELS induces distinct dysregulation in the midbrain circuitry of males, which may lead to sex-specific psychopathology of the reward system.

The effects of early‐life stress on dopamine system function in adolescent female rats

“…For instance, ELS-triggered disturbances in GCs concentrations may interfere with the process of sex-specific organizational differentiation of dopamine systems during early postnatal period (Gillies and McArthur, 2010). We have recently discussed in detail the ground for sex differences in the response of dopamine system to MS (Chocyk et al, 2015).…”

Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle?

“…The effects of maternal separation are more pronounced in male animals than female indicating that males are more susceptible to postnatal adverse situations, particularly associated with the mother-infant interaction (Chocyk et al, 2015). Yet, early life stress in females may moderate the beneficial effects of suitable interventions (Pusceddu et al, 2015).…”

Stereological analyses of reward system nuclei in maternally deprived/separated alcohol drinking rats

“…A similar study found no changes in total neurons in the VTA in juveniles even as Ki67, a marker of neuronal proliferation was reduced (Chocyk et al, 2011). Recently, this same group used BrdU dating and Nissl stain to demonstrate that total neurons of the VTA were increased in adults, but that these increases were due to non-dopamine neuron proliferation (Monroy et al, 2010, Chocyk et al, 2015). Together, these studies indicate that MS could change the balance of cell types in the VTA.…”