Effects of estrogen replacement therapy on cholinergic basal forebrain neurons and cortical cholinergic innervation in young and aged ovariectomized rhesus monkeys

Abstract

Estrogen modulates the function of cholinergic basal forebrain neurons in aged female rats. The present study tested the hypothesis that estrogen enhances the phenotype of cholinergic basal forebrain neurons and their cortical cholinergic innervation in young adult and aged ovariectomized rhesus monkeys. Sixteen monkeys (9 young and 7 aged) received two injections of estradiol cypionate or vehicle separated by 3 weeks. All monkeys were killed 1 day after the last injection. Quantitative immunofluorescence in the vertical limb of the diagonal band (VLDB) revealed enhanced optical density for choline acetyltransferase (ChAT) in both young and aged monkeys treated with estrogen. In contrast, optical density for low-affinity p75 neurotrophin receptor immunoreactivity in the VLDB did not change after estrogen treatment in either aged or young animals. Quantitative immunofluorescence for either ChAT or the low-affinity p75 neurotrophin receptor in the nucleus basalis Meynert failed to reveal differences between vehicle and estrogen treatment in either age group. Quantitative estimates of acetylcholinesterase (AChE) fiber density revealed that estrogen-treated aged monkeys but not their younger counterparts had decreased numbers of AChE-positive fibers in layer II of frontal, insular, and cingulate cortices. These data indicate that estrogen administered in a manner simulating natural hormonal cyclicity produces modest age-specific chemical phenotypic and regional changes in select neuronal subfields of the cholinergic basal forebrain and their cortical projection sites in nonhuman primates.

Liquiritigenin Attenuates Alzheimer’s-Like Neuropathology in an Amyloid Protein Precursor Transgenic Mouse Model and the Underlying Mechanisms

“…Estrogen treatment has been found to directly enhance the activity of the cholinergic system by some researchers (Kompoliti et al, 2004;Bora et al, 2005). In the present study, we found that the selective ER agonist liquiritigenin enhanced the activity of Chat and decreased AchE activity, thus enhancing cholinergic functioning.…”

Effect of Ovarian Hormone Therapy on Cognition in the Aged Female Rhesus Macaque

“…especially during middle and old age (Kompoliti et al, 2004;Hao et al, 2006;Browne et al, 2009), it is plausible that the effects of E treatment we observed on both tasks are related to mechanisms of hormonal action in this region.…”

“…The nonhuman primate (NHP) is an attractive and highly translational alternative model (Lacreuse et al, 2015), being a long-lived, close genetic relative, with a complex brain and cognitive ability (Kohama et al, 2012). Furthermore, the reproductive physiology of female NHPs is very similar to that of women, showing characteristic monthly menstrual cycles (Jewitt and Dukelow, 1972;Knobil, 1974;Goodman et al, 1977), cycle irregularity during perimenopause Downs and Urbanski, 2006), and cessation of cyclicity and ovarian estrogen production after menopause (Johnson and Kapsalis, 1995;Walker, 1995;Downs and Urbanski, 2006). Additionally, there are significant anatomical differences that exist between the frontal lobes of primates and rodents.…”

Estrogen Alters Spine Number and Morphology in Prefrontal Cortex of Aged Female Rhesus Monkeys

“…Virtually all layer III pyramidal neurons in area 46 participate in corticocortical circuitry and these neurons are vulnerable to aging (Hof and Morrison, 2004). Cholinergic and monoaminergic projections to monkey prefrontal cortex are also vulnerable to aging (Wenk et al, 1989;Arnsten, 1999) and responsive to estrogen, particularly in the supragranular layers Kohama, 1998, 1999;Kompoliti et al, 2004;Tinkler et al, 2004), the layers that contain most of the dendritic arbor of our target neurons. Thus, estrogen treatment in aged monkeys potentially impacts key corticocortically projecting neurons, as well as the cholinergic and monoaminergic circuits that modulate these circuits.…”