Hyperactivation of cyclin-dependent kinase 5 (Cdk5) by p25, contributes to neuroinflammation causing neurodegeneration in Parkinson’s disease (PD) and Alzheimer’s disease. However, the mechanism by which Cdk5 induces neuroinflammation in the PD brain is largely unexplored. Here, we show that Cdk5 phosphorylates cytosolic phospholipase A2 (cPLA2) at Thr-268 and Ser-505 sites lead to its activation and generation of eicosanoid products. Mutational studies using site-directed mutagenesis and molecular simulations show that the architecture of the protein changes on each single-point mutation. Interestingly, double mutations also led to a severe decline in the activity of cPLA2 and to the disruption of its translocation to the plasma membrane. Further, the brain lysates of transgenic PD mouse models show hyperactivation of Cdk5, resulting in enhanced phosphorylation of Thr-268 and Ser-505 of cPLA2 and its heightened activity, confirming the findings observed in the cell culture model of PD. These phosphorylati...

Visual accuracy is consistently shown to be modulated around the time of the action execution. The neural underpinning of this motor-induced modulation of visual perception is still unclear. Here, we investigate with EEG whether it is related to the readiness potential, an event-related potential (ERP) linked to motor preparation. Across 18 human participants, the magnitude of visual modulation following a voluntary button press was found to correlate with the readiness potential amplitude measured during visual discrimination. Participants’ amplitude of the readiness potential in a purely motor-task was also found to correlate with the extent of the motor-induced modulation of visual perception in the visuomotor task. These results provide strong evidence that perceptual changes close to action execution are associated with motor preparation processes and that this mechanism is independent of task contingencies. Further, our findings suggest that the readiness potential provides a fingerprint of individua...

The ability of humans to coordinate stereotyped, alternating movements between the two legs during bipedal walking is a complex motor behavior that requires precisely timed activities across multiple nodes of the supraspinal network. Understanding of the neural network dynamics that underlie natural walking in humans is limited. We investigated cortical and subthalamic neural activities during overground walking and evaluated spectral biomarkers to decode the gait cycle in three patients with Parkinson’s disease without gait disturbances. Patients were implanted with chronic bilateral deep brain stimulation (DBS) leads in the subthalamic nucleus (STN) and electrocorticography paddles overlaying the primary motor and somatosensory cortices. Local field potentials were recorded from these areas while the participants performed overground walking and synchronized to external gait kinematic sensors. We found that the STN displays increased low-frequency (4–12 Hz) spectral power during the period before contral...

Absence of presynaptic protein MUNC18-1 (gene: Stxbp1 ) leads to neuronal cell death at an immature stage before synapse formation. Here, we performed transcriptomic and proteomic profiling of immature Stxbp1 knock-out (KO) cells to discover which cellular processes depend on MUNC18-1. Hippocampi of Stxbp1 KO mice showed cell type-specific dysregulation of 2123 transcripts primarily related to synaptic transmission and immune response. To further investigate direct, neuron-specific effects of MUNC18-1 depletion, a proteomic screen was performed on murine neuronal cultures at two developmental timepoints before onset of neuron degeneration. 399 proteins were differentially expressed, which were primarily involved in synaptic function (especially synaptic vesicle exocytosis) and neuron development. We further show that many of the downregulated proteins on loss of MUNC18-1 are normally upregulated during this developmental stage. Thus, absence of MUNC18-1 extensively dysregulates the transcriptome and proteo...

Successful retrieval of a specific item from visual working memory (VWM) depends on the binding of that item to its unique context. Recent functional magnetic resonance imaging studies of VWM manipulating memory set homogeneity have identified an important role for the intraparietal sulcus in context binding, independent of any role in representing stimulus identity. The current study explored whether the contralateral delay activity (CDA), which is an event-related potential (ERP) component derived from posterior electrodes that tracks the amount of information held in VWM, might also be sensitive to context-binding demands. In experiment 1, human participants performed lateralized delayed recognition with memory sets containing one, three, or five items that were drawn from the same category (orientations: “homogeneous”) or from different categories (orientation, color, and luminance: “heterogeneous”). Because the location and identity of the memory probe indicated the item to be retrieved, homogeneous t...

When looking around a visual scene, humans make saccadic eye movements to fixate objects of interest. While the extraocular muscles can execute saccades in any direction, not all saccade directions are equally likely: saccades in horizontal and vertical directions are most prevalent. Here, we asked whether head orientation plays a role in determining saccade direction biases. Study participants ( n  = 14) viewed natural scenes and abstract fractals (radially symmetric patterns) through a virtual reality headset equipped with eye tracking. Participants’ heads were stabilized and tilted at −30°, 0°, or 30° while viewing the images, which could also be tilted by −30°, 0°, and 30° relative to the head. To determine whether the biases in saccade direction changed with head tilt, we calculated polar histograms of saccade directions and cross-correlated pairs of histograms to find the angular displacement resulting in the maximum correlation. During free viewing of fractals, saccade biases largely followed the or...

Oligodendrocytes, the myelinating cells of the CNS, promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known whether neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from postnatal day 40 (P40) to P70. This mechanism of nodal...

Place code representation is ubiquitous in circuits that encode spatial parameters. For visually guided eye movements, neurons in many brain regions emit spikes when a stimulus is presented in their receptive fields and/or when a movement is directed into their movement fields. Crucially, individual neurons respond for a broad range of directions or eccentricities away from the optimal vector, making it difficult to decode the stimulus location or the saccade vector from each cell’s activity. We investigated whether it is possible to decode the spatial parameter with a population-level analysis, even when the optimal vectors are similar across neurons. Spiking activity and local field potentials (LFPs) in the superior colliculus (SC) were recorded with a laminar probe as monkeys performed a delayed saccade task to one of eight targets radially equidistant in direction. A classifier was applied offline to decode the spatial configuration as the trial progresses from sensation to action. For spiking activity...

Adaptive control is the online adjustment of behavior to guide and optimize responses after errors or conflict. The neural circuits involved in monitoring and adapting behavioral performance following error are poorly understood. The prefrontal cortex (PFC) plays a critical role in this form of control. However, these brain areas are densely connected with many other regions, and it is unknown which projections are critical for adaptive behavior. Here, we tested the involvement of four distinct dorsal and ventral prefrontal cortical projections to striatal and thalamic target areas in adaptive control. We re-analyzed data from published experiments, using trial-by-trial analyses of behavior in an operant task for attention and impulsivity. We find that male rats slow their responses and perform worse following errors. Moreover, by combining retrograde labeling and chemogenetic silencing, we find that dorsomedial prefrontal pyramidal neurons that project to the lateral nucleus of the mediodorsal thalamus (M...

A significant proportion of the human neurotypical population exhibits some degree of sensory eye dominance (SED), referring to the brain’s preferential processing of one eye’s input versus another. The neural substrates underlying this functional imbalance are not well known. Here, we investigated the relationship between visual white matter tract properties and SED in the human neurotypical population. Observers’ performance on two commonly used dichoptic tasks were used to index SED, along with performance on a third task to address a functional implication of binocular imbalance: stereovision. We show that diffusivity metrics of the optic radiations (ORs) well predict behavioral SED metrics. We found no relationship between SED and stereosensitivity. Our data suggest that SED is not simply reflected by gray matter structural and functional alterations, as often suggested, but relates, at least in part to the microstructural properties of thalamocortical white matter.