Objectives: Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the central nervous system (CNS). Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Methods: Human autopsied CNS tissues (male and female), human cell cultures and cuprizone-mediated demyelination mice (female) were examined by RT-PCR, western blotting and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. Results: White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared to non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-α-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human ...

How do we come to sense that a hand in view belongs to our own body or not? Previous studies have suggested that the integration of vision and somatosensation in the frontoparietal areas plays a critical role in the sense of body ownership, i.e., the multisensory perception of limbs and body parts as our own. However, little is known about how these areas implement the multisensory integration process at the computational level and whether activity predicts illusion elicitation in individual participants on a trial-by-trial basis. To address these questions, we used functional magnetic resonance imaging and a rubber hand illusion-detection task and fitted the registered neural responses to a Bayesian causal inference model of body ownership. Thirty healthy human participants (male and female) performed 12-second trials with varying degrees of asynchronously delivered visual and tactile stimuli of a rubber hand (in view) and a (hidden) real hand. After the 12-second period, participants had to judge whether...

In severely affected stroke survivors, cortico-muscular control is disturbed and volitional upper limb movements often absent. Mental rehearsal of the impaired movement in conjunction with sensory feedback provision are suggested as promising rehabilitation exercises. Knowledge about the underlying neural processes, however, remains vague. In male and female chronic stroke patients with hand paralysis, a brain-computer interface controlled a robotic orthosis and turned sensorimotor beta-band desynchronization during motor imagery (MI) of finger extension into contingent hand opening. Healthy control subjects performed the same task and received the same proprioceptive feedback with a robotic orthosis or visual feedback only. Only when proprioceptive feedback was provided, cortico-muscular coherence (CMC) increased with a predominant information flow from the sensorimotor cortex to the finger extensors. This effect (i) was specific to the beta frequency-band, (ii) transferred to a motor task, (iii) was prop...

Although previous studies point to qualitative similarities between working memory (WM) and attention, the degree to which these two constructs rely on shared neural mechanisms remains unknown. Focusing on one such potentially shared mechanism, we tested the hypothesis that selecting an item within WM utilizes similar neural mechanisms as selecting a visible item via a shift of attention. We used fMRI and machine learning to decode both the selection among items visually available and the selection among items stored in WM in human subjects (both sexes). Patterns of activity in visual, parietal, and to a lesser extent frontal cortex predicted the locations of the selected items. Critically, these patterns were strikingly interchangeable; classifiers trained on data during attentional selection predicted selection from WM, and classifiers trained on data during selection from memory predicted attentional selection. Using models of voxel receptive fields, we visualized topographic population activity that re...

The spatial-frequency (SF) tuning of neurons in the early visual cortex is adjusted for stimulus contrast. As the contrast increases, SF tuning is modulated so that the transmission of fine features is facilitated. A variety of mechanisms are involved in shaping SF tunings, but those responsible for the contrast-dependent modulations are unclear. To address this, we measured the time course of SF tunings of area 17 neurons in male cats under different contrasts with a reverse correlation. After response onset, the optimal SF continuously shifted to a higher SF over time, with a larger shift for higher contrast. At high contrast, whereas neurons with a large shift of optimal SF exhibited a large bandwidth decrease, those with a negligible shift increased the bandwidth over time. Between these two extremes, the degree of SF shift and bandwidth change continuously varied. At low contrast, bandwidth generally decreased over time. These dynamic effects enhanced the processing of high-frequency range under a hig...

The entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr) constitute the output nuclei of the basal ganglia, but studies on the EPN are limited compared with those on the SNr. Both nuclei receive projections from the striatum with axons containing substance P (SP) and cannabinoid type-1 receptor (CB1R), and immunoreactivities for these substances show complementary patterns in the striatum and SNr. In this study we revealed a similar complementarity in the mouse EPN, combined it with region-specific neuronal distributions, and defined subregions of the EPN. First, the EPN was divided into two areas, one showing low SP and high CB1R (lSP/hCB1R) immunoreactivities and the other showing opposite immunoreactivities (hSP/lCB1R). The former received inputs from the dorsolateral striatum that is innervated by sensorimotor cortices, whereas the latter received inputs from the medial striatum innervated by limbic/association cortices. Then, the lSP/hCB1R area was further divided into the dorsolate...

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer’s disease. In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of Alzheimer’s disease-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of beta (20-30 Hz) oscillations (beta bursts) which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of beta bursts. Additionally, theta-alpha/beta cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was signific...

Before visual information from the retina reaches primary visual cortex, it is dynamically filtered by the lateral geniculate nucleus (LGN) of the thalamus, the first location within the visual hierarchy at which non-retinal structures can significantly influence visual processing. To explore the form and dynamics of geniculate filtering we used data from monosynpatically connected pairs of retinal ganglion cells (RGCs) and LGN relay cells in the cat that, under anesthetized conditions, were stimulated with binary white noise and/or drifting sine-wave gratings to train models of increasing complexity to predict which RGC spikes were relayed to cortex, what we call “relay status”. In addition, we analyze and compare a smaller data set recorded in the awake state to assess how anesthesia might influence our results. Consistent with previous work, we find that the preceding retinal inter-spike interval is the primary determinate of relay status with only modest contributions from longer patterns of retinal sp...

We tested the hypothesis that the pallidum contributes to the control of both posture and movement. We recorded neuronal activity from the pallidum in a task in which male cats reached forward from a standing posture to depress a lever. In agreement with previous studies, we found that a majority of pallidal cells (91/116, 78%), including neurons in both the entopeduncular nucleus and the globus pallidus, showed significant modulation of their activity during reaching with the contralateral limb. Mostly different populations of cells were active during the transport (flexion) and lever press (extension) phase of the task. Most cells showed dynamic patterns of activity related to the movement. However, a modest proportion of modulated cells (18/91, 20%) showed properties consistent with a contribution to the control of anticipatory postural responses, whereas a further 10% showed activity consistent with a contribution to postural support during the movement. Although some cells that showed modified activit...

Experiences of physical exertion guide our assessments of effort. While these assessments critically influence our decisions to engage in daily activities, little is known about how they are generated. We had female and male human participants exert grip force and assess how effortful these exertions felt; and used magnetic resonance spectroscopy to measure their brain GABA concentration. We found that variability in exertion (i.e., the coefficient of variation in their force exertion profile) was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA levels in the sensorimotor cortex (SM1) moderated the influence of exertion variability on overassessments of effort. In individuals with higher sensorimotor GABA, exertion variability had a diminished influence on overassessments of effort. Essentially, sensorimotor GABA had a protective effect on the influence of exertion variability on inflations of effort assessment. Our findings provide a neurobiologica...