The Contribution of AMPA and NMDA Receptors to Persistent Firing in the Dorsolateral Prefrontal Cortex in Working Memory.

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks.SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.

The threshold for conscious report: Signal loss and response bias in visual and frontal cortex.

Why are some visual stimuli consciously detected, whereas others remain subliminal? We investigated the fate of weak visual stimuli in the visual and frontal cortex of awake monkeys trained to report stimulus presence. Reported stimuli were associated with strong sustained activity in the frontal cortex, and frontal activity was weaker and quickly decayed for unreported stimuli. Information about weak stimuli could be lost at successive stages en route from the visual to the frontal cortex, and these propagation failures were confirmed through microstimulation of area V1. Fluctuations in response bias and sensitivity during perception of identical stimuli were traced back to prestimulus brain-state markers. A model in which stimuli become consciously reportable when they elicit a nonlinear ignition process in higher cortical areas explained our results.

The influence of attention and reward on the learning of stimulus-response associations.

We can learn new tasks by listening to a teacher, but we can also learn by trial-and-error. Here, we investigate the factors that determine how participants learn new stimulus-response mappings by trial-and-error. Does learning in human observers comply with reinforcement learning theories, which describe how subjects learn from rewards and punishments? If yes, what is the influence of selective attention in the learning process? We developed a novel redundant-relevant learning paradigm to examine the conjoint influence of attention and reward feedback. We found that subjects only learned stimulus-response mappings for attended shapes, even when unattended shapes were equally informative. Reward magnitude also influenced learning, an effect that was stronger for attended than for non-attended shapes and that carried over to a subsequent visual search task. Our results provide insights into how attention and reward jointly determine how we learn. They support the powerful learning rules that capitalize on the conjoint influence of these two factors on neuronal plasticity.

Nicotine facilitates memory consolidation in perceptual learning.

Perceptual learning is a special type of non-declarative learning that involves experience-dependent plasticity in sensory cortices. The cholinergic system is known to modulate declarative learning. In particular, reduced levels or efficacy of the neurotransmitter acetylcholine were found to facilitate declarative memory consolidation. However, little is known about the role of the cholinergic system in memory consolidation of non-declarative learning. Here we compared two groups of non-smoking men who learned a visual texture discrimination task (TDT). One group received chewing tobacco containing nicotine for 1 h directly following the TDT training. The other group received a similar tasting control substance without nicotine. Electroencephalographic recordings during substance consumption showed reduced alpha activity and P300 latencies in the nicotine group compared to the control group. When re-tested on the TDT the following day, both groups responded more accurately and more rapidly than during training. These improvements were specific to the retinal location and orientation of the texture elements of the TDT suggesting that learning involved early visual cortex. A group comparison showed that learning effects were more pronounced in the nicotine group than in the control group. These findings suggest that oral consumption of nicotine enhances the efficacy of nicotinic acetylcholine receptors. Our findings further suggest that enhanced efficacy of the cholinergic system facilitates memory consolidation in perceptual learning (and possibly other types of non-declarative learning). In that regard acetylcholine seems to affect consolidation processes in perceptual learning in a different manner than in declarative learning. Alternatively, our findings might reflect dose-dependent cholinergic modulation of memory consolidation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Luminance contrast has little influence on the spread of object-based attention.

We direct our attention to those visual stimuli that are relevant to our behavioral goals. Some of the visual stimuli that surround us are represented more strongly, because they have a higher luminance contrast. However, selective attention also boosts the representation of visual stimuli. It is not yet well understood how attention and contrast interact. Some previous theories proposed that attentional effects are strongest at low contrast, others that they are strongest at high contrast and yet others that the effects of selective attention are largely independent of contrast. In the present study, we investigated the interaction between selective attention and luminance contrast with a contour-grouping task that provides a sensitive measure of the spread of object-based attention, with delays of several hundreds of milliseconds. We find that the spread of object-based attention is largely independent of contrast, and that subjects experience little difficulty in grouping low-contrast contour elements in the presence of other contour elements with a much higher contrast. The results imply that object-based attention and contrast have largely independent effects on visual processing.