Cholinergic modulation of working memory activity in primate prefrontal cortex.

The 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.

Comparison of neural activity related to working memory in primate dorsolateral prefrontal and posterior parietal cortex.

Neurons in a distributed network of cortical and subcortical areas continue to discharge after the presentation and disappearance of stimuli, providing a neural correlate for working memory. While it is thought that the prefrontal cortex plays a central role in this network, the relative contributions of other brain areas are not as well understood. In order to compare the contributions of the dorsolateral prefrontal and posterior parietal cortex, we recorded neurophysiological activity in monkeys trained to perform two different visuo-spatial working memory tasks: a Match/Nonmatch task, and a Spatial Delayed-Match-to-Sample Task. Neurons in both areas exhibited discharges in the delay periods of the tasks that could be classified in two forms. Sustained discharges persisted after the presentation of a stimulus in the receptive field with a constant or declining rate. Anticipatory responses increased in rate during the delay period, often appearing after presentation of a stimulus out of the receptive field. Despite similarities, we uncovered distinct differences between patterns of delay period in each brain area. Only in the prefrontal cortex sustained responses related to the original stimulus survived presentation of a second stimulus, in the context of the Match/Nonmatch task. Our results provide insights on the nature of processing in two areas active during working memory, and on the unique role of the prefrontal cortex in memory maintenance.

Sprouting of substance P-expressing primary afferent central terminals and spinal micturition reflex NK1 receptor dependence after spinal cord injury.

The primary afferent neurotransmitter triggering the spinal micturition reflex after complete spinal cord injury (SCI) in the rat is unknown. Substance P detected immunohistochemically in the sacral parasympathetic nucleus was significantly higher in 12 SCI rats than in 12 spinally intact rats (P = 0.008), suggesting substance P as a plausible candidate for the primary afferent neurotransmitter. The effects of the tachykinin NK1 receptor antagonist L-733060 on the spinal micturition reflex were then determined by performing conscious cystometry in an additional 14 intact rats and 14 SCI rats with L-733060 (0.1-100 microg) administered intrathecally at L6-S1. L-733060 was without effect in intact rats, but blocked the spinal micturition reflex in 10 of 14 SCI rats and increased the intermicturition interval in 2 of 4 others at doses ranging from 10 to 100 microg. Both phasic and nonphasic voiding contractions, differentiated according to the presence of phasic external urethral sphincter (EUS) activity, were present in most SCI rats. Both types of contractions were blocked by high doses of L-733060. Interestingly, there was a relative decline in phasic voiding contractions at high doses as well as a decline in contraction amplitude in nonphasic voiding contractions. In other respects, cystometric variables were largely unaffected in either spinally intact or SCI rats. L-733060 did not affect tonic EUS activity at any dose except when the spinal micturition reflex was blocked and tonic activity was consequently lost. These experiments show that tachykinin action at spinal NK1 receptors plays a major role in the spinal micturition reflex in SCI rats.