Males, but not females, lose tyrosine hydroxylase fibers in the medial prefrontal cortex and are impaired on a delayed alternation task during aging

Abstract

The structure of the prefrontal cortex (PFC) is particularly vulnerable to the effects of aging, and behaviors mediated by the PFC are impaired during aging in both humans and animals. In male rats, behavioral deficits have been correlated with a decrease in dopaminergic functioning. However, studies have found that anatomical changes associated with aging are sexually dimorphic, with males experiencing greater age-related loss than females. The present study investigated the effects of sex and aging on performance of a delayed alternation t-maze, a task mediated by the medial prefrontal cortex (mPFC), and on tyrosine hydroxylase (TH) immunoreactivity in this brain region using adult (7 months) and aged (21 months) male and female F344 rats. There was a sex by age interaction in performance of the delayed alternation task such that adult males performed better than aged males, but aged females were not different than adult females. Adult males performed better than adult females across all delays; however, this sex difference was reversed during aging and aged males performed worse than aged females. In addition, TH immunoreactivity decreased during aging in layers 2/3 in the male, but not female mPFC. Thus females were less sensitive to the effects of aging on the prefrontal dopaminergic system and on performance of a delayed alternation task. These effects may be due to decreases in testosterone in aging males, as well as the protective effects of ovarian hormones, which continue to be secreted after cessation of the estrous cycle in aging females.

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

“…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, ; Kritzer, ; Willing & Wagner, ), young adulthood (Kritzer & Kohama, ; Kritzer et al, ) and in aged rats (Chisholm et al, ; Chisholm, Packard, Koss, & Juraska, ). Depending upon the presence of specific receptors, steroid hormone actions could have different or even contrasting effects during different periods of development.…”

“…For each section, bilateral images were taken from layer 1, layers 2/3, and layers 5/6. Identification of these PFC subregions and cortical layers was made possible by their proximity to adjacent white matter under the frontal cortex and THir fiber orientation as was discussed in previous work from our laboratory (Chisholm, Kim, & Juraska, ). Briefly, layer 1 is comprised of a dense band of fibers with a dorsal/ventral orientation, fibers in layers 2/3 are arranged in a medial to lateral direction, while the fibers in 5/6 do not have a clear orientation (Figure ).…”

“…Before analysis, extraneous staining (blood vessels, cell bodies, diffuse background staining) was manually removed from the image by an experimenter blind to age and sex. Analysis was performed on both “binary” and “skeletonized” images (Chisholm et al, ). For binary images, the total number of saturated (ir) pixels was used in calculating TH fiber density, which includes both the length and thickness of fibers.…”

“…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).…”

Changes in sex differences in neuroanatomical structure and cognitive behavior across the life span

“…10 ). The same pattern of differences occurred in the density of tyrosine hydroxylase throughout the layers of the mPFC, so that males had more density as adults while females had a higher density during aging ( Chisholm et al 2013 ). Again, it should be noted that the aging females in all of these studies were secreting moderate to low levels of estrogen and progesterone.…”