The forebrain cholinergic system and age-related decline in and compensation of attentional capacities.

摘要

Aging is characterized by an increase in inter-individual variability in cognitive capacity. Slight decrements in learning and memory emerge; however, age-related shifts in attentional function remain controversial. In pathological aging, however, attentional dysfunction is prominent and the circuitry critical to signal detection and thus attention as a whole, the corticopetal cholinergic system, exhibits substantial disruption and deterioration. One contributing factor to cholinergic dysfunction is the loss of neurotrophic support, specifically nerve growth factor's high-affinity receptor tropomyosin-related kinase A (trkA). Previous cross-sectional studies demonstrated that reduced trkA receptor levels selectively impaired attentional capacity in aged rats. However, it remains unclear if reduced trkA receptors in the basal forebrain (BF) interact with aging to elicit these attentional deficits. Thus developmental suppression of trkA receptors on attentional capacity and BF cholinergic markers was examined, with the expectation that attentional deficits would emerge earlier in trkA-suppressed rats and cholinergic integrity would be altered. Despite persistent trkA suppression and reduced cholinergic cell size in 6-week-old rats, aged rats that were maintained on a cognitive task throughout life exhibited comparable attentional capacity and stable cholinergic markers compared to controls. Thus, activation of a compensatory mechanism may have stabilized the attentional network. Due to continuous performance on the attentional task, lifelong cognitive engagement may have served to bolster cholinergic integrity and stabilize attentional function.;To examine the role of compensatory mechanisms in aging and their interactions with the attentional network, a consistently observed neural activation pattern in aging, termed the anterior-to-posterior shift in aging (PASA), was evaluated. PASA is characterized by enhanced frontal and reduced visual neural activity. Thus, the necessity of cholinergic afferents to the maintenance of PASA was investigated, as well as the role of PASA in stabilizing cognitive function in aging. If cholinergic afferents, specifically those innervating the prefrontal and posterior parietal cortices (PFC; PC), were crucial to PASA then partial cholinergic pruning of the PFC was expected to disrupt PASA and produce attentional deficits. Prefrontal infusion produced attentional deficits in aged rats regardless of infusion type, and elicited a corresponding age-related shift in neural activity, with decreases in visual and increases in parietal cortical activation in aged rats. Partial parietal cholinergic deafferentation impaired performance in both young and aged rats and altered prefrontal cortical recruitment, which was correlated with attentional performance in young rats. Increased recruitment of the attentional network was associated with worse performance in aged rats. Thus, prefrontal and parietal cholinergic afferents are not critical to PASA and increased activation may be representative of reduced neural efficiency rather than compensation. Moreover, aged rats rely heavily on the prefrontal cortex for attentional function, and aberrant prefrontal activity, via generalized damage or disruption of parietal cholinergic inputs, is associated with attentional impairments. Together these findings suggest that enhanced vulnerability of attentional capacity due to prefrontal disruption arises in aging; however, activation of compensatory mechanisms, such as lifelong cognitive activity, may bolster cholinergic integrity and stabilize cognitive function in aging.