Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats

Abstract

Behavioral flexibility, the ability to modify responses due to changing task demands, is detrimentally affected by aging with a shift towards increased cognitive rigidity. The neurobiological basis of this cognitive deficit is not clear although striatal cholinergic neurotransmission has been implicated. To investigate the possible association between striatal acetylcholine signaling with age-related changes in behavioral flexibility, young, middle-aged, and aged F344 X Brown Norway F1 rats were assessed using an attentional set-shifting task that includes two tests of behavioral flexibility: reversal learning and an extra-dimensional shift. Rats were also assessed in the Morris water maze to compare potential fronto-striatal-dependent deficits with hippocampal-dependent deficits. Behaviorally characterized rats were then assessed for acetylcholine muscarinic signaling within the striatum using oxotremorine-M-stimulated [35S]GTPγS binding and [3H]AFDX-384 receptor binding autoradiography. The results showed that by old age, cognitive deficits were pronounced across cognitive domains, suggesting deterioration of both hippocampal and fronto-striatal regions. A significant decline in oxotremorine-M-stimulated [35S]GTPγS binding was limited to the dorsomedial striatum of aged rats when compared to young and middle-aged rats. There was no effect of age on striatal [3H]AFDX-384 receptor binding. These results suggest that a decrease in M2/M4 muscarinic receptor coupling is involved in the age-associated decline in behavioral flexibility.

Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats

“…This age difference could not be accounted for by general discrimination learning deficits, as aged rats performed comparably to young on the initial discrimination rule. These results are in agreement with previously reported results using a multidimensional set-shifting paradigm in aged FBN rats (Nieves-Martinez et al, 2012) and are comparable with studies shown previously in aged rats of other strains, as well as aged monkeys and humans (Alexander et al, 2012; Barense et al, 2002; Beas et al, 2017, 2013; Berg, 1948; Moore et al, 2003). Together, these findings suggest that deficits in cognitive flexibility are a common feature of aging.…”

Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats

“…Studies in rodents, non-human primates, and humans show that performance on set shifting tasks is impaired in aged compared to young subjects (Barense et al, 2002; Bizon et al, 2012; Nieves-Martinez et al, 2012; Beas et al, 2013). Uniformly, such age-associated deficits are evident only when subjects are expected to adapt behavior following a rule shift but not during simple discrimination learning that does not require such flexibility (Robbins et al, 1998; Volkow et al, 1998; Barense et al, 2002; Moore et al, 2003, 2006; Ashendorf and McCaffrey, 2008; Nieves-Martinez et al, 2012; Beas et al, 2013).…”

“…Uniformly, such age-associated deficits are evident only when subjects are expected to adapt behavior following a rule shift but not during simple discrimination learning that does not require such flexibility (Robbins et al, 1998; Volkow et al, 1998; Barense et al, 2002; Moore et al, 2003, 2006; Ashendorf and McCaffrey, 2008; Nieves-Martinez et al, 2012; Beas et al, 2013). The present findings are consistent with this prior body of work, in that aged rats performed no differently than young on an initial (visual cue) discrimination, but were impaired in their acquisition of a subsequent left/right discrimination that required a shift in behavioral strategy.…”

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

“…Thus, it can be suggested that the positive effect of enriched environment on water maze learning may also be related to the environmental impact on the survival of striatal cholinergic neurons. Along this line, it is noteworthy that aging-dependent alterations of cholinergic pharmacodynamics in the striatum were correlated with levels of water maze performance ) and that the M 2 /M 4 muscarinic receptor coupling in the striatum of cognitively impaired aged rats is reduced (Nieves-Martinez et al 2012).…”