Multifunctional fibers enable modulation of cortical and deep brain activity during cognitive behavior in macaques.

Recording and modulating neural activity in vivo enables investigations of the neurophysiology underlying behavior and disease. However, there is a dearth of translational tools for simultaneous recording and localized receptor-specific modulation. We address this limitation by translating multifunctional fiber neurotechnology previously only available for rodent studies to enable cortical and subcortical neural recording and modulation in macaques. We record single-neuron and broader oscillatory activity during intracranial GABA infusions in the premotor cortex and putamen. By applying state-space models to characterize changes in electrophysiology, we uncover that neural activity evoked by a working memory task is reshaped by even a modest local inhibition. The recordings provide detailed insight into the electrophysiological effect of neurotransmitter receptor modulation in both cortical and subcortical structures in an awake macaque. Our results demonstrate a first-time application of multifunctional fibers for causal studies of neuronal activity in behaving nonhuman primates and pave the way for clinical translation of fiber-based neurotechnology.

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. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers.SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system.

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. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease.

Sensitivity to biomechanical limitations during postural decision-making depends on the integrity of posterior superior parietal cortex.

Most object-directed limb movements can be carried out with a comfortable grasp posture. However, the orientation of an object relative to our bodies can sometimes lead us to select an uncomfortable or awkward grasp posture due to limitations imposed by the biomechanics of the arm. In a series of experiments, we identified a network of cortical areas that are engaged during the selection of movement strategies. Neurologically intact participants and two brain-damaged patients with overlapping lesions in the right posterior superior parietal lobule (pSPL) performed a grasp posture selection task in which biomechanical constraints were the primary consideration for selecting an action. The task induced states of bistable actions whereby the same stimulus gave rise to categorically different grasp postures. In a behavioral experiment, the two patients displayed a large range of manual bistability with the contralesional hand, resulting in a higher incidence of awkward grasping postures. In neurologically intact participants, a separate functional magnetic resonance imaging (fMRI) experiment revealed activation of a parieto-frontal network, which included the posterior intraparietal sulcus (pIPS) along the banks of the pSPL that was parametrically modulated by the degree of bistability in grasp posture selection. Superimposing this activation over the patients' structural MRIs revealed that the pIPS/pSPL activation in the neurologically intact participants overlapped with lesioned cortical tissue in both patients; all other areas of activation overlapped with intact cortical tissue in the patients. These results provide converging evidence that the posterior parietal cortex plays a critical role in selecting biomechanically appropriate postures during reach-to-grasp behaviors.

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

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. Although muscarinic receptors have been implicated in executive performance and gating of synaptic signals, their effect on local primate DLPFC neuronal activity in vivo during cognitive tasks remains poorly understood. Here, we examined the effects of muscarinic receptor blockade on rule-related activity in the macaque prefrontal cortex by combining iontophoretic application of the general muscarinic receptor antagonist scopolamine with single-cell recordings while monkeys performed a mnemonic rule-guided saccade task. We found that scopolamine reduced overall neuronal firing rate and impaired rule discriminability of task-selective cells. Saccade and visual direction selectivity measures were also reduced by muscarinic antagonism. These results demonstrate that blockade of muscarinic receptors in DLPFC creates deficits in working memory representation of rules in primates. SIGNIFICANCE STATEMENT: Acetylcholine plays a pivotal role in higher-order cognitive functions, including planning, reasoning, impulse-control, and making decisions based on contingencies or rules. Disruption of acetylcholine function is central to many psychiatric disorders manifesting cognitive impairments, including Alzheimer's disease. Although much is known about the involvement of acetylcholine and its receptors in arousal and attention, its involvement in working memory, an essential short-term memory component of cognition dependent on the integrity of prefrontal cortex, remains poorly understood. Herein, we explored the impact of suppressing acetylcholine signaling on neurons encoding memorized rules while macaque monkeys made responses based on those rules. Our findings provide insights into the neural mechanisms by which a disruption in acetylcholine function impairs working memory in the prefrontal cortex.