Spike frequency adaptation in primate lateral prefrontal cortex neurons results from interplay between intrinsic properties and circuit dynamics.

Cortical neurons in brain slices display intrinsic spike frequency adaptation (I-SFA) to constant current inputs, while extracellular recordings show extrinsic SFA (E-SFA) during sustained visual stimulation. Inferring how I-SFA contributes to E-SFA during behavior is challenging due to the isolated nature of slice recordings. To address this, we recorded macaque lateral prefrontal cortex (LPFC) neurons in vivo during a visually guided saccade task and in vitro in brain slices.

Neuromodulation of Persistent Activity and Working Memory Circuitry in Primate Prefrontal Cortex by Muscarinic Receptors.

Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks.

Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity for Rules in Primate Prefrontal Cortex.

Acetylcholine release in the prefrontal cortex (PFC), acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer's disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses.

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control.

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders.

Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex.

Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes.

Dopamine D1 and D2 Receptors Make Dissociable Contributions to Dorsolateral Prefrontal Cortical Regulation of Rule-Guided Oculomotor Behavior.

Studies of neuromodulation of spatial short-term memory have shown that dopamine D1 receptor (D1R) stimulation in dorsolateral prefrontal cortex (DLPFC) dose-dependently modulates memory activity, whereas D2 receptors (D2Rs) selectively modulate activity related to eye movements hypothesized to encode movement feedback. We examined localized stimulation of D1Rs and D2Rs on DLPFC neurons engaged in a task involving rule representation in memory to guide appropriate eye movements toward or away from a visual stimulus. We found dissociable effects of D1R and D2R on DLPFC physiology.

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

Unlabelled: Maintenance of context is necessary for execution of appropriate responses to diverse environmental stimuli. The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in executive function, including working memory and representation of abstract rules. DLPFC activity is modulated by the ascending cholinergic system through nicotinic and muscarinic receptors.

Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels.

Background: Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing.

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position.

Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory.

Dopamine (DA) D1 receptor (D1R) stimulation in prefrontal cortex (PFC) produces an 'inverted-U' dose-response, whereby either too little or too much D1R stimulation impairs spatial working memory. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. The cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms.

Selective D2 receptor actions on the functional circuitry of working memory.

Prefrontal neurons engaged by working memory tasks express a sequence of phasic and tonic activations linked to a train of sensory, mnemonic, and response-related events. Here, we report that the dopamine D2 receptor selectively modulates the neural activities associated with memory-guided saccades in oculomotor delayed-response tasks yet has little or no effect on the persistent mnemonic-related activity, which is instead modulated by D1 receptors. This associates the D2 receptor with a specific component of working memory circuitry and fractionates the modulatory effects of D1 and D2 receptors on the neural machinery of a cognitive process.