Effects of Maternal Deprivation on the Prefrontal Cortex of Male Rats: Cellular, Neurochemical, and Behavioral Outcomes.

Joko Poleksic,Milan Aksic,Slobodan Kapor,Branka Markovic,Vuk Djulejic,Marina Radovic,Tihomir Stojkovic,Antonios Stamatakis,Dubravka Aleksic

doi:10.3389/fnbeh.2021.666547

Abstract

Stressful events experienced during early life are associated with increased vulnerability of developing psychopathology in adulthood. In the present study, we exposed 9-day-old Wistar rats to 24 h maternal deprivation (MD) with the aim to investigate the impact of early life stress (ELS) on morphological, biochemical, and functional aspects of the prefrontal cortex (PFC), a brain region particularly sensitive to stress. We found that in the superficial medial orbital cortex (MO), young adult male rats had reduced density of GAD67 and CCK immunopositive cells, while the rostral part of the ventral lateral orbital cortex (roVLO) showed a decrease in the density of GAD67 immunopositive cells in both superficial and deep layers. In addition, the superficial rostral part of area 1 of the cingulate cortex (roCg1) and deep prelimbic cortex (PrL) was also affected by MD indicated by the reduction in PV immunopositive cellular density. Furthermore, MD induced upregulation of brain-derived neurotrophic factor (BDNF), while it did not affect the overall expression of Iba1 in neonatal or young adult PFC as measured by Western blot, however, microglial activation in young adult MD rats was detected immunohistochemically in deep layers of MO and infralimbic cortex (IL). Interestingly, when young adult male rats were subjected to a behavioral flexibility test in a T-maze, MD rats showed a subtle impairment in T-maze reversal learning indicating a mildly affected PFC function. Taken together, our findings demonstrated that MD reduced the density of interneurons and induced microglial activation, in particular, PFC areas at young adulthood, and could alter synaptic plasticity accompanied by PFC dysfunction.

Highlights

Adverse experiences during childhood such as parental death, neglect, physical or emotional abuse raise the susceptibility of developing mental illness in later life (Kessler et al, 2010)
The results of our study demonstrated a complex effect of acute early life stress on GAD67 +, PV +, and CCK + cell densities in various areas of the prefrontal cortex (PFC)
The observed structural and biochemical changes in the PFC were accompanied by a mild functional deficit in maternal deprivation (MD) rats when tested for cognitive flexibility

Summary

Introduction

Adverse experiences during childhood such as parental death, neglect, physical or emotional abuse raise the susceptibility of developing mental illness in later life (Kessler et al, 2010). An increasing amount of evidence suggests that stressful events during early life modulate the trajectory of normal brain development which precedes structural and functional vulnerability to psychopathology. Prolonged postnatal development highlights PFC as a cortical structure sensitive to early life stress (ELS) (Arnsten, 2009; Teicher et al, 2016). According to in vivo and post mortem human studies, ELS can be associated with functional and structural abnormalities such as impaired cognitive flexibility (Spann et al, 2012; Nikulina and Widom, 2013), increased impulsivity (Gondré-Lewis et al, 2016), and reduced PFC cortical density (Gorka et al, 2014; Underwood et al, 2019). CCK + neurons express serotonin type 3 (5-HT3) and cannabinoid type 1 (CB1) receptors (Katona et al, 1999; Freund and Katona, 2007; Vucurovic et al, 2010; Armstrong and Soltesz, 2012) and, as proposed by a recent study, CCK + neuronal activity is required for working memory retrieval as well as mood regulation, the exact function of these cells remains largely unclear (Whissell et al, 2015; Nguyen et al, 2020)

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Conclusion