Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study

Abstract

Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer’s disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability. An adeno-associated viral vector expressing trkA shRNA (AAV-trkA) was utilized to knockdown trkA receptors in postnatal rats at an ontogenetic time point when cortical cholinergic inputs mature, and the impact of this manipulation on performance was assessed in animals maintained on an operant attention task throughout adulthood and until old (24 months) age. A within-subject comparison across different time points illustrated a gradual age-related decline in attentional capacities. However, the performance under baseline and distracted conditions did not differ between the AAV-trkA-infused and animals infused with a vector expressing shRNA against the control protein luciferase at any time point. Additional analysis of cholinergic measures conducted at 24 months showed that the capacity of cholinergic terminals to release acetylcholine following a depolarizing stimulus, cortical cholinergic fiber density and BF cholinergic cell size remained comparable between the two groups. Contrary to our predictions, these data indicate that developmental BF trkA disruption does not impact age-related changes in attentional functions. It is possible that life-long engagement in cognitive activity might have potentially rescued the developmental insults on the cholinergic system, thus preserving attentional capacities in advanced age.

Role of Cholinergic Signaling in Alzheimer’s Disease

“…Memory formation increases BDNF and p-CREB/CREB in PFC, the hippocampus and amygdala [ 30 ]. Dysfunction or degeneration of BFCNs can lead to cholinergic atrophy and cognitive decline, and affect normal function of the hippocampus; it may be associated with the development of neuroinflammatory components of diseases such as AD [ 31 ]. The nucleus basalis of Meynert (NBM) is a key brain region that is mainly cholinergic.…”

“…Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD [ 31 ]. Glutamate and cholinergic dysfunction are known features of AD [ 51 ].…”

Chemogenetic inhibition of prefrontal projection neurons constrains top–down control of attention in young but not aged rats

“…Water-regulated young and aged rats were trained in an operant-based sustained attention task (SAT) as previously described ( Demeter et al, 2008 ; McGaughy & Sarter, 1995 ; St Peters et al, 2011 ; Yegla & Parikh, 2017 ). Animals were initially autoshaped using an FR-1 reinforcement schedule to attain the lever press response and succeeding water reward (0.02 mL).…”

“…Each session was analyzed in terms of the proportion of hits (h = h/[h+m]*100) for each signal length, proportion of correct rejections (cr = cr/[cr+fa]*100), and proportion of omissions ([omitted trials/total trials]*100. The overall measure of attentional performance was calculated as a performance score (SAT/dSAT score) using the formula: (h − fa)/[2(h + fa) − (h + fa) 2 ] as described previously ( Demeter et al, 2008 ; McGaughy & Sarter, 1995 ; St Peters et al, 2011 ; Yegla & Parikh, 2017 ). SAT/dSAT scores vary from +1.0 to −1.0; a score of +1.0 indicated that all responses on signal and non-signal trials were correct, 0 indicated the inability to discern signal from non-signal events, and −1.0 indicated that all responses were misses/false alarms.…”

“…For these experiments, a separate cohort of naïve young (N = 6) and aged (N = 5) rats underwent stereotaxic surgeries for bilateral infusions of Gi-DREADD vector as explained above. Approximately 4–5 weeks following vector infusions, animals were prepared for amperometric recordings of cholinergic transmission based on procedures described earlier ( Howe et al, 2010 ; Parikh et al, 2014 ; Parikh et al, 2010 ; Yegla & Parikh, 2017 ). In brief, ceramic-based microelectrode arrays (Quanteon, Nicholasville, KY, USA) consisting of four rectangular platinum recording sites linearly arranged in pairs were coated with choline oxidase (Sigma-Aldrich, St. Louis, MO, USA).…”