The administration of synthetic progestins to pregnant women for the prevention of premature delivery has increased dramatically in recent years. Despite this increase, very little is known about the potential effects of synthetic progestins on the developing brain. Preliminary data from rodent models suggest that progestins may play a role in the development of frontal cortex and the mesocortical dopamine system, a neurochemical pathway implicated in Attention Deficit Hyperactivity Disorder (ADHD). The objective of this proposal is to examine the effects of exposure to the synthetic progestin, 17?-hydroxyprogesterone caproate in the development of the mesocortical dopamine pathway and subsequent complex cognitive behaviors using a rodent model.
Aim 1 will test the hypothesis that exposure to 17P during development will alter the number of dopaminergic cells in the midbrain ventral tegmental area and will alter the density of dopaminergic fibers within the medial prefrontal cortex.
Aim 2 will test the hypothesis exposure to 17P during postnatal life will alter working memory (Novel Object Recognition), behavioral inhibition/impulsivity (Inhibitory Avoidance Task) and cognitive flexibility (Set Shift Task). Results from these animal studies would vastly increase our knowledge about the potential effects of progestin exposure to generate specific hypotheses for future research regarding outcomes in children exposed in utero.
The incidence of premature birth is rising significantly in recent decades and the administration of the synthetic progestin, 17a-hydroxyprogesterone caproate (17P) to pregnant women in the second half of gestation to prevent preterm birth has increased dramatically in recent years. Despite this, very little is known about the role of progesterone in normal neural development or the potential effects of progestin exposure on the developing brain. This proposal investigates the effects of progestin activity on the development of the mesocortical dopamine system, a neural circuit implicated in Attention Deficit Hyperactivity Disorder (ADHD) and memory and cognitive behaviors in adulthood.
|Newell, Andrew J; Lalitsasivimol, Diana; Willing, Jari et al. (2018) Progesterone receptor expression in cajal-retzius cells of the developing rat dentate gyrus: Potential role in hippocampus-dependent memory. J Comp Neurol 526:2285-2300|
|Willing, Jari; Wagner, Christine K (2016) Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood. Neuroendocrinology 103:207-22|
|Willing, Jari; Wagner, Christine K (2016) Exposure to the Synthetic Progestin, 17?-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood. Endocrinology 157:77-82|