Cholinergic modulation of working memory activity in primate prefrontal cortex

Abstract

DT, Constantinidis C. Cholinergic modulation of working memory activity in primate prefrontal cortex. J Neurophysiol 106: 2180-2188. First published July 27, 2011 doi:10.1152/jn.00148.2011The prefrontal cortex, a cortical area essential for working memory and higher cognitive functions, is modulated by a number of neurotransmitter systems, including acetylcholine; however, the impact of cholinergic transmission on prefrontal activity is not well understood. We relied on systemic administration of a muscarinic receptor antagonist, scopolamine, to investigate the role of acetylcholine on primate prefrontal neuronal activity during execution of working memory tasks and recorded neuronal activity with chronic electrode arrays and single electrodes. Our results indicated a dose-dependent decrease in behavioral performance after scopolamine administration in all the working memory tasks we tested. The effect could not be accounted for by deficits in visual processing, eye movement responses, or attention, because the animals performed a visually guided saccade task virtually error free, and errors to distracting stimuli were not increased. Performance degradation under scopolamine was accompanied by decreased firing rate of the same cortical sites during the delay period of the task and decreased selectivity for the spatial location of the stimuli. These results demonstrate that muscarinic blockade impairs performance in working memory tasks and prefrontal activity mediating working memory.

Muscarinic Attenuation of Mnemonic Rule Representation in Macaque Dorsolateral Prefrontal Cortex during a Pro- and Anti-Saccade Task

“…This difference could be due to differential expression of M1Rs between DLPFC and V1; M1R expression in the latter is higher in parvalbumin-positive interneurons (Disney and Aoki, 2008). Scopolamine-induced reduction in rule selectivity found in this study is consistent with results from Zhou et al (2011), wherein rule selectivity of DLPFC neurons was degraded during the delay epoch of spatial WM and delayed match-to-sample tasks. They also found scopolamineinduced delay-dependent deficits in behavioral performance, which were interestingly unaffected by distractor load.…”

“…In agreement with this, a human imaging study found scopolamine-induced degradation in parahippocampal persistent activity (Schon et al, 2005). The observed scopolamine-induced neuronal suppression herein is in accord with activity in DLPFC after systemic scopolamine administration (Zhou et al, 2011) and V1 after iontophoretic scopolamine application . However, Miller and Desimone (1993) found paradoxical increases in stimulusresponsive activity of macaque inferotemporal neurons after systemic scopolamine administration during delayed matchto-sample performance, although spontaneous activity remained unchanged, suggesting that scopolamine-induced suppression is not universal.…”

“…They also found scopolamineinduced delay-dependent deficits in behavioral performance, which were interestingly unaffected by distractor load. In contrast to rule selectivity, stimulus selectivity of DLPFC neurons was found to be unaffected by scopolamine (Zhou et al, 2011). Here, we found that peripheral stimulus selectivity was also reduced.…”

“…However, Miller and Desimone (1993) found paradoxical increases in stimulusresponsive activity of macaque inferotemporal neurons after systemic scopolamine administration during delayed matchto-sample performance, although spontaneous activity remained unchanged, suggesting that scopolamine-induced suppression is not universal. Indeed, our results suggest that suppression due to systemic muscarinic blockade (Zhou et al, 2011) can be a direct consequence of PFC muscarinic antagonism and not due to indirect network-effects on activity in other brain areas with PFC connectivity.…”

“…Zhou et al (2011) reported marked suppression of DLPFC neurons in the memory period with concomitant behavioral degradation upon systemic scopolamine administration. However, because scopolamine was systemically administered, it is unclear whether the DLPFC neuronal suppression involved local muscarinic modulation or was a consequence of dysregulation of inputs to DLPFC circuitry.…”