Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood

Abstract

Background: Numerous psychiatric and behavioral disorders such as autism, attention deficit disorder and schizophrenia may involve disruptions in the development of the mesocortical dopamine pathway, consisting of dopaminergic projections from the midbrain ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC). Nuclear steroid hormone receptors are powerful transcription factors and can profoundly and permanently alter fundamental processes of neural development. Nuclear progesterone receptor (PR) is transiently expressed in both the VTA and the PFC of rodents during perinatal life, suggesting that PR may regulate the normal development of this important behavioral circuit. Methods and Results: Here, we demonstrate that virtually all PR-immunoreactive (PR-ir) cells in the VTA also express tyrosine hydroxylase immunoreactivity (TH-ir). In addition, retrograde tract tracing reveals that many PR-ir cells in the VTA project to the mPFC. Administration of a PR antagonist to rats during the neonatal period decreased TH-ir fiber density in the prelimbic mPFC of juveniles (postnatal day 25) and decreased levels of TH-ir in the VTA of adults. Neonatal treatment with a PR antagonist impaired adult performance on a passive inhibitory avoidance task and an attentional set-shifting task, measures of behavioral inhibition/impulsivity and cognitive flexibility, respectively. TH-ir levels in the VTA were reduced and cognitive flexibility was impaired in PR knockout mice as well. Conclusions: These findings provide novel insights into a potential role for PR in the developmental etiology of behavioral disorders that involve impairments in complex cognitive behaviors and have implications for the use of synthetic progestins in humans during critical neurodevelopmental periods.

Innervation of the medial prefrontal cortex by tyrosine hydroxylase immunoreactive fibers during adolescence in male and female rats

“…Developmental changes in cellular function and receptor expression could allow time-specific openings for steroid hormones to affect this system. While gonadal hormones have been shown to play a role in perinatal dopaminergic innervation of the mPFC (Kritzer, 1998;Willing & Wagner, 2016), results of the present study do not suggest a role for pubertal hormones in the increase in dopaminergic axon number after the juvenile period. However, they do not exclude a role for gonadal hormones in the maintenance of TH expression or activity within dopaminergic projections, which are acutely regulated by a complex feedback loop under the control of a variety of transcription factors (Tekin, Roskoski, Carkaci-Salli, & Vrana, 2014…”

“…Contrary to our hypothesis, the analysis of females at P35 and males at P45 suggested that the pubertal onset was not accompanied by changes in THir fiber volume in either sex. This would seemingly conflict with previous studies documenting both long and short-term effects of gonadal hormones on TH expression in the PFC during early development (King et al, 2000;Kritzer, 1998;Willing & Wagner, 2016), young adulthood (Kritzer & Kohama, 1998;Kritzer et al, 2007) and in aged rats (Chisholm et al, 2013;Chisholm, Packard, Koss, & Juraska, 2012). Depending upon the presence of specific receptors, steroid hormone actions could have different or even contrasting effects during different periods of development.…”

“…In contrast to the ontogeny of dopaminergic innervation, the expression of multiple dopamine receptor subtypes in the PFC is known to change in male rats throughout the adolescent period, with an increase until ∼P45, followed by a significant decrease thereafter (Andersen et al, 2000;Naneix et al, 2012), suggesting a different mechanism for regulation of PFC dopamine receptors. Both changes at the level of the synapse and more broad structural reorganization are fine-tuned throughout the adolescent period, and these changes in connectivity and function of the mesocortical dopaminergic pathway likely play a role in enhanced performance on select cognitive tasks that are influenced by dopamine activity, including cognitive flexibility (Chisholm et al, 2013;Mizoguchi, Shoji, Tanaka, Maruyama, & Tabira, 2009;Naneix et al, 2012;Stefani & Moghaddam, 2006;Willing & Wagner, 2016).…”

Pubertal onset as a critical transition for neural development and cognition

“…This indicates that ERβ may play a role in the mPFC during puberty. It also should be noted that progesterone receptors in the mPFC decrease after 10 days of age in rats and reach very low levels by P25 (Willing & Wagner, 2015). Thus while the information is incomplete, ERβ is the most likely candidate for mediating effects in the rodent mPFC.…”

“…(B) Unlike the females, males only showed a nonsignificant trend (p<.08) for age. From Willing and Juraska, 2015.…”