The timing of neuronal loss across adolescence in the medial prefrontal cortex of male and female rats

Abstract

Adolescence is a critical period for brain maturation characterized by the reorganization of interacting neural networks. In particular the prefrontal cortex, a region involved in executive function, undergoes synaptic and neuronal pruning during this time in both humans and rats. Our laboratory has previously shown that rats lose neurons in the medial prefrontal cortex (mPFC) and there is an increase in white matter under the frontal cortex between adolescence and adulthood. Female rats lose more neurons during this period, and ovarian hormones may play a role as ovariectomy before adolescence prevents neuronal loss. However, little is known regarding the timing of neuroanatomical changes that occur between early adolescence and adulthood. In the present study, we quantified the number of neurons and glia in the male and female mPFC at multiple time points from preadolescence through adulthood (postnatal days 25, 35, 45, 60 and 90). Females, but not males, lost a significant number of neurons in the mPFC between days 35 and 45, coinciding with the onset of puberty. Counts of GABA immunoreactive cell bodies indicated that the neurons lost were not primarily GABAergic. These results suggest that in females, pubertal hormones may exert temporally specific changes in PFC anatomy. As expected, both males and females gained white matter under the prefrontal cortex throughout adolescence, though these gains in females were diminished after day 35, but not in males. The differences in cell loss in males and females may lead to differential vulnerability to external influences and dysfunctions of the prefrontal cortex that manifest in adolescence.

Neonatal Stress Has a Long-Lasting Sex-Dependent Effect on Anxiety-Like Behavior and Neuronal Morphology in the Prefrontal Cortex and Hippocampus

“…Considerable evidence indicates that the medial prefrontal cortex exhibits age-dependent sexual dimorphism [38-40]. For example, there is a loss of volume during adolescence, which is at least partially attributable to a loss of neurons, which is more significant in females [41].…”

Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making

“…Substantial neuroanatomical changes, including pruning of neurons (Markham, Morris, & Juraska, 2007;Willing & Juraska, 2015) and synapses (Drzewiecki, Willing & Juraska, 2015), have been reported to occur at pubertal onset in the medial PFC in rats of both sexes. These neuroanatomical changes may underlie adult-like performance in set-shifts in the postpubertal adolescent rats in the present study and the previous literature discussed above (Newman & McGaughy, 2011).…”

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes

“…Similar developmentally regulated changes have been observed in rodents during their adolescent period, which has been argued to range from as early as postnatal day (P) 28 to at least P60 based on social, cognitive, hormonal, and neurophysiological changes that parallel markers of human adolescence (Tirelli et al 2003;Spear 2011). For example, during rodent adolescence there are significant increases in connectivity between the basolateral amygdala and medial prefrontal cortex (Cunningham et al 2002(Cunningham et al , 2008, changes in the density of monoamine transporters (Moll et al 2000;Bradshaw et al 2016), increases in prefrontal cortex dopamine innervation (Kalsbeek et al 1988), decreases in medial prefrontal cortex neuron number (Markham et al 2007;Willing and Juraska 2015), and reorganization of the amygdala (Rubinow and Juraska 2009;Koss et al 2014). …”