Estrogen-cholinergic interactions: Implications for cognitive aging

Abstract

This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects.

Keywords: Acetylcholine; Attention; Brain imaging; Cognitive performance; Estradiol; Memory.

Figure 1. Choice Reaction Task

Median motor reaction time difference scores (in milliseconds) following 3 months of 1 mg oral estradiol or placebo treatment and after exposure to anti-cholinergic challenge. Paired bars represent reaction time difference from placebo challenge following each drug challenge by long-term treatment (estradiol or placebo). Positive difference score indicates a slowing of RT (impaired performance) after drug compared to placebo challenge. SCOP = scopolamine; MECA = mecamylamine. Doses are μg/kg for intravenous scopolamine and oral milligram dosage for mecamylamine. F(1,12) = 7.71, p < .05 for main effect of estradiol treatment. Reproduced with permission from (Dumas et al., 2006).

Figure 2. Continuous Performance Task

Hit reaction time difference scores (in milliseconds) following 3 months of 1 mg oral estradiol or placebo treatment and after exposure to anti-cholinergic challenge. Paired bars represent reaction time difference from placebo challenge following each drug challenge by long-term treatment (estradiol or placebo). Positive difference score indicates a slowing of RT (impaired performance) after drug compared to placebo challenge. SCOP = scopolamine; MECA = mecamylamine. Doses are μg/kg for intravenous scopolamine and oral milligram dosage for mecamylamine. F(1,14) = 7.69, p < .05 for main effect of estradiol treatment during scopolamine challenge and F(1,14) = 9.71, p < .01 for main effect of estradiol treatment during mecamylamine challenge. Reproduced with permission from (Dumas et al., 2006).

Figure 3. Selective Reminding Task

Recall failure difference scores following 3 months of 1 mg oral estradiol or placebo treatment and after exposure to anti-cholinergic challenge. Paired bars represent total recall failure difference from placebo challenge following each drug challenge by long-term treatment (estradiol or placebo). Greater impairment indicated by greater positive difference score. SCOP = scopolamine; MECA = mecamylamine. Doses are μg/kg for intravenous scopolamine and oral milligram dosage for mecamylamine. F(1,14) = 4.82, p < .05 for treatment by mecamylamine challenge dosage interaction. Reproduced with permission from (Dumas et al., 2006).

Figure 4. Selective Reminding Task

Total recall difference scores following 3 months of 2 mg oral estradiol or placebo treatment and after exposure to anticholinergic (scopolamine) challenge vs placebo (greater impairment indicated by greater negative score). Paired bars represent 8-trial total recall difference from placebo challenge following scopolamine challenge by age group (Young = 50–60; Old = 70+). F(1,20) = 10.73, p = .004 for age group by estradiol treatment interaction. Reproduced with permission from (Dumas et al., 2008a).

Figure 5. Selective Reminding Task

Delayed recall difference scores following 3 months of 10 mg daily oral tamoxifen or placebo treatment and after exposure to anticholinergic (scopolamine and mecamylamine) challenge vs placebo (greater impairment indicated by greater negative score). Paired bars represent delayed word recall difference from placebo challenge following each drug challenge by long-term treatment tamoxifen (TMX) or placebo (PLC).. SCOP = scopolamine; MECA = mecamylamine. Doses are μg/kg for intravenous scopolamine and oral milligram dosage for mecamylamine. F(1,17) = 5.0, p=.03 for main effect of tamoxifen treatment (Newhouse et al., 2013).

Figure 6. Virtual Morris Water Maze

(modified from Newhouse et al., 2013): A. Platform latency during learning trials after mecamylamine 10 mg challenge. Filled triangle represents long-term placebo treatment. Filled squares represent long-term tamoxifen 10 mg treatment. F(1,14) = 6.6, p=.024 for main effect of tamoxifen treatment. B. Time spent in correct quadrant during the probe trial; difference from placebo challenge during mecamylamine challenge (10 mg). Crosshatch bar represents placebo long-term treatment and dark bar represents tamoxifen 10 mg oral long-term treatment. F(1,67) = 6.28, p<.01 for main effect of tamoxifen treatment.

Figure 7. N-Back Working Memory Task

(Reproduced with permission from Dumas et al., 2012): A. Activation map for estradiol treatment minus placebo treatment for the 3-back minus 0-back conditions of the N-back task for subjects on the scopolamine challenge day (p < .05). Blue colors represent activation that is greater for the placebo treatment group relative to the estradiol treatment group. B. Activation map for estradiol treatment minus placebo treatment for the 3-back minus 0-back conditions of the N-back task for subjects on the mecamylamine challenge day (p < .05). Orange colors represent activation that is greater for the estradiol treatment group relative to the placebo treatment group.

Figure 8. Cholinergic functional compensation model of age-related cognitive dysfunction with the proposed role of estrogen

The functional compensation model illustrating the effects of aging and cholinergic dysfunction on the focus of attention (FOA). Dotted and grayed lines indicate impairments. When younger adults (left panel) perform attention and memory tasks they show cholinergic modulation of the FOA. Normal cognitive aging (middle panel) may degrade the control processes of the focus of attention thereby affecting working memory and long-term memory. Functional compensation will recruit further activity of the cholinergic system and associated cortical areas to maintain adequate performance on a task. Estradiol (estradiol) treatment during the critical window may help maintain a middle-aged configuration of cognitive performance by maintaining cholinergic basal forebrain functioning. By contrast, estradiol treatment of dementia patients is ineffective because the basal forebrain cholinergic system is severely damaged and does not respond positively to estradiol treatment. Modified from Dumas and Newhouse, 2011.