Intracortical microstimulation in human primary somatosensory cortex has been used to successfully evoke naturalistic sensations. However, the neurophysiological mechanisms underlying the evoked sensations remain unknown. To understand how specific stimulation parameters elicit certain sensations we must first understand the representation of those sensations in the brain. In this study we record from intracortical microelectrode arrays implanted in primary somatosensory cortex, pre-motor cortex and posterior parietal cortex of a male human participant performing a somatosensory imagery task. The sensations imagined were those previously elicited by intracortical microstimulation of primary somatosensory cortex, in the same array of the same participant. In both spike and local field potential recordings, features of the neural signal can be used to classify different imagined sensations. These features are shown to be stable over time. The sensorimotor cortices only encode the imagined sensation during th...

The acquisition of neuronal polarity is a complex molecular process that depends on changes in cytoskeletal dynamics and directed membrane traffic, regulated by the Rho and Rab families of small GTPases, respectively. However, during axon specification, a molecular link that couples these protein families has yet to be identified. In this paper, we describe a new positive feedback loop between Rab8a and Cdc42, coupled by Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), that ensures a single axon generation in rodent hippocampal neurons from embryos of either sex. Accordingly, Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Although Rab8 and Tuba do not interact physically, the activity of Rab8 is essential to generate a proximal to distal axonal gradient of Tuba in cultured neurons. Tuba- and Rab8a-associated polarity defects ...

Transient Receptor Potential Melastatin 3 (TRPM3) is a heat-activated ion channel in primary sensory neurons of the dorsal root ganglia (DRG). Pharmacological and genetic studies implicated TRPM3 in various pain modalities, but TRPM3 inhibitors were not validated in TRPM3-/- mice. Here we tested two inhibitors of TRPM3 in male and female wild type and TRPM3-/- mice in nerve injury-induced neuropathic pain. We found that intraperitoneal injection of either isosakuranetin, or primidone reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve, in wild type, but not in TRPM3-/- mice. Primidone was also effective when injected locally in the hind paw, or intrathecally. Consistently, intrathecal injection of the TRPM3 agonist CIM0216 reduced paw withdrawal latency to radiant heat in wild type, but not in TRPM3-/- mice. Intraperitoneal injection of 2 mg/kg, but not 0.5 mg/kg isosakuranetin, inhibited cold and mechanical hypersensitivity in CCI, both in wild-type and TRPM3-/-...

Increased level of kynurenic acid is thought to contribute to the development of cognitive deficits in schizophrenia through an α7nAChR-mediated mechanism in the prefrontal cortex (PFC). Yet, it remains unclear to what extent disruption of PFC α7nAChR signaling impacts afferent transmission and its modulation of behavior. Here we found that PFC infusion of methyllycaconitine (MLA, α7nAChR antagonist) shifts ventral hippocampal-induced local field potential (LFP) suppression to LFP facilitation, an effect only observed in adult male rats. Hippocampal stimulation can also elicit a GluN2B-mediated LFP potentiation (when PFC GABAAR is blocked) that is insensitive to MLA. Conversely, PFC infusion of MLA diminished the gain of amygdalar transmission, which is already enabled by postnatal day 30. Behaviorally, the impact of prefrontal MLA on trace fear-conditioning and extinction was also age-related. While freezing behavior during conditioning was reduced by MLA only in adults, it elicited opposite effects in ad...

Spinocerebellar ataxias (SCAs) are diseases characterized by cerebellar atrophy and loss of Purkinje neurons caused by mutations in diverse genes. In SCA14, the disease is caused by point mutations or small deletions in protein kinase C gamma (PKCγ), a crucial signaling protein in Purkinje cells. It is still unclear whether increased or decreased PKCγ activity may be involved in the SCA14 pathogenesis. In this study we present a new knock-in mouse model related to SCA14 with a point mutation in the pseudosubstrate domain, PKCγ-A24E, known to induce a constitutive PKCγ activation. In this protein conformation, the kinase domain of PKCγ is activated, but at the same time the protein is subject to dephosphorylation and protein degradation. As a result, we find a dramatic reduction of PKCγ protein expression in PKCγ-A24E mice of either sex. Despite this reduction there is clear evidence for an increased PKC activity in Purkinje cells from PKCγ-A24E mice. Purkinje cells derived from PKCγ-A24E have short thicke...

Seizures invite seizures. At the initial stage of epilepsy, seizures intensify with each episode; however, the mechanisms underlying this exacerbation remain to be solved. Astrocytes have a strong control over neuronal excitability and the mode of information processing. This control is accomplished by adjusting the levels of various ions in the extracellular space. The network of astrocytes connected via gap junctions allows a wider or more confined distribution of these ions depending on the open probability of the gap junctions. K+ clearance relies on the K+ uptake by astrocytes and the subsequent diffusion of K+ through the astrocyte network. When astrocytes become uncoupled, K+ clearance becomes hindered. Accumulation of extracellular K+ leads to hyperexcitability of neurons. Here, using acute hippocampal slices from mice, we uncovered that brief periods of epileptiform activity result in gap junction uncoupling. In slices that experienced short-term epileptiform activity, extracellular K+ transients ...

Understanding the relationship between neuroanatomy and function in portions of cortex that perform functions largely specific to humans such as lateral prefrontal cortex (LPFC) is of major interest in systems and cognitive neuroscience. When considering neuroanatomical-functional relationships in LPFC, shallow indentations in cortex known as tertiary sulci have been largely unexplored. Here, by implementing a multi-modal approach and manually defining 936 neuroanatomical structures in 72 hemispheres (in both males and females), we show that a subset of these overlooked tertiary sulci serve as a meso-scale link between microstructural (myelin content) and functional (network connectivity) properties of human LPFC in individual participants. For example, the posterior middle frontal sulcus ( pmfs ) is a tertiary sulcus with three components that differ in their myelin content, resting state connectivity profiles, and engagement across meta-analyses of 83 cognitive tasks. Further, generating microstructural ...

The actin cytoskeleton is crucial for oligodendrocyte differentiation and myelination. Here we show that p21-activated kinase1 (PAK1), a well-known actin regulator, promotes oligodendrocyte morphological change and myelin production in the central nervous system. A combination of in vitro and in vivo models demonstrated that PAK1 is expressed throughout the oligodendrocyte lineage with highest expression in differentiated oligodendrocytes. Inhibiting PAK1 early in oligodendrocyte development decreased oligodendrocyte morphological complexity and altered F-actin spreading at the tips of oligodendrocyte progenitor cell processes. Constitutively activating AKT in oligodendrocytes in male and female mice, which leads to excessive myelin wrapping, increased PAK1 expression, suggesting an impact of PAK1 during active myelin wrapping. Furthermore, constitutively activating PAK1 in oligodendrocytes in zebrafish led to an increase in myelin internode length while inhibiting PAK1 during active myelination decreased ...

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathological quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFN γ R1 ( Ifngr1 ) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IF...

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.