Corticocuneate projections are altered after spinal cord dorsal column lesions in New World monkeys.

Recovery of responses to cutaneous stimuli in the area 3b hand cortex of monkeys after dorsal column lesions (DCLs) in the cervical spinal cord relies on neural rewiring in the cuneate nucleus (Cu) over time. To examine whether the corticocuneate projections are modified during recoveries after the DCL, we injected cholera toxin subunit B into the hand representation in Cu to label the cortical neurons after various recovery times, and related results to the recovery of neural responses in the affected area 3b hand cortex. In normal New World monkeys, labeled neurons were predominately distributed in the hand regions of contralateral areas 3b, 3a, 1 and 2, parietal ventral (PV), secondary somatosensory cortex (S2), and primary motor cortex (M1), with similar distributions in the ipsilateral cortex in significantly smaller numbers. In monkeys with short-term recoveries, the area 3b hand neurons were unresponsive or responded weakly to touch on the hand, while the cortical labeling pattern was largely unchanged. After longer recoveries, the area 3b hand neurons remained unresponsive, or responded to touch on the hand or somatotopically abnormal parts, depending on the lesion extent. The distributions of cortical labeled neurons were much more widespread than the normal pattern in both hemispheres, especially when lesions were incomplete. The proportion of labeled neurons in the contralateral area 3b hand cortex was not correlated with the functional reactivation in the area 3b hand cortex. Overall, our findings indicated that corticocuneate inputs increase during the functional recovery, but their functional role is uncertain.

Endogenous Acetylcholine and Its Modulation of Cortical Microcircuits to Enhance Cognition.

Acetylcholine regulates the cerebral cortex to sharpen sensory perception and enhance attentional focus. The cellular and circuit mechanisms of this cholinergic modulation are under active investigation in sensory and prefrontal cortex, but the universality of these mechanisms across the cerebral cortex is not clear. Anatomical maps suggest that the sensory and prefrontal cortices receive distinct cholinergic projections and have subtle differences in the expression of cholinergic receptors and the metabolic enzyme acetylcholinesterase. First, we briefly review this anatomical literature and the recent progress in the field. Next, we discuss in detail the electrophysiological effects of cholinergic receptor subtypes and the cell and circuit consequences of their stimulation by endogenous acetylcholine as established by recent optogenetic work. Finally, we explore the behavioral ramifications of in vivo manipulations of endogenous acetylcholine. We find broader similarities than we expected between the cholinergic regulation of sensory and prefrontal cortex, but there are some differences and some gaps in knowledge. In visual, auditory, and somatosensory cortex, the cell and circuit mechanisms of cholinergic sharpening of sensory perception have been probed in vivo with calcium imaging and optogenetic experiments to simultaneously test mechanism and measure the consequences of manipulation. By contrast, ascertaining the links between attentional performance and cholinergic modulation of specific prefrontal microcircuits is more complicated due to the nature of the required tasks. However, ex vivo optogenetic manipulations point to differences in the cholinergic modulation of sensory and prefrontal cortex. Understanding how and where acetylcholine acts within the cerebral cortex to shape cognition is essential to pinpoint novel treatment targets for the perceptual and attention deficits found in multiple psychiatric and neurological disorders.

Serotonin Regulation of the Prefrontal Cortex: Cognitive Relevance and the Impact of Developmental Perturbation.

The prefrontal cortex is essential for both executive function and emotional regulation. The interrelationships among these behavioral domains are increasingly recognized, as well as their sensitivity to serotonin (5-hydroxytryptamine, 5-HT). Prefrontal cortex receives serotonergic inputs from the dorsal and median raphe nuclei and is modulated by multiple subtypes of 5-HT receptor across its layers and cell types. Extremes of serotonergic modulation alter mood regulation in vulnerable individuals, yet the impact of serotonin under more typical physiological parameters remains unclear. In this regard, new tools are permitting a closer examination of the behavioral impact of the serotonin system. Optogenetic and chemogenetic manipulations of dorsal raphe 5-HT neurons reveal that serotonin has a greater impact on executive function than previously appreciated. Domains that appear sensitive to fluctuations in 5-HT neuronal excitability include patience and cognitive flexibility. This work is broadly consistent with ex vivo research investigating how 5-HT regulates prefrontal cortex and its output projections. A growing literature suggests 5-HT modulation of these prefrontal circuits is unexpectedly flexible to alteration during development by genetic, behavioral, environmental or pharmacological manipulations, with lasting repercussions for cognition and emotional regulation. Here, we review the cellular and circuit mechanisms of prefrontal serotonergic modulation, investigate recent research into the cognitive consequences of the serotonergic system, and probe the lasting consequences of developmental perturbations. Understanding both the complexity of the prefrontal serotonin system and its sensitivity during development are essential to learn more about the vulnerabilities of this system in mood and anxiety disorders and the underappreciated cognitive consequences of these disorders and their treatment.