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 [(35)S]GTPγS binding and [(3)H]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 [(35)S]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 [(3)H]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.

Figure 1. Effects of aging on spatial learning in the water maze in young, middle-aged and aged rats

Aged and middle-aged rats performed poorly when compared to young on the acquisition of the platform location during training trials (A) and have a less accurate search for the platform during probe trials (B). Sensorimotor ability testing demonstrated that aging did not affect visual acuity, (C) but impaired swim speed. Old rats swam significantly slower than middle-age and young rats (D). * Aged vs. young, p < .05.

Figure 2. Effects of aging on reversal learning and set shifting ability

Aged rats performed poorly when compared to young and middle-aged rats in the reversal learning (IDS-R) and set shifting phases of the attentional-set shifting tasks *^, ** Aged vs. young and Aged vs. MA, p <.05.

Figure 3. Effect of aging on muscarinic receptor signaling and receptor level in the striatum

A) Schematic illustration of the anatomical areas sampled for optical density (shaded gray). B) Typical oxotremorine-M-stimulated [³⁵S]GTPγS and [³H]AFDX-384 autoradiograms C) and D) show the densitometric analysis of oxotremorine-M-stimulated [³⁵S]GTPγS. E) and F) show the densitometric analysis of [³H]AFDX-384 binding. *, p < .05.