Sustained attention describes our ability to keep a constant focus on a given task. This ability is modulated by our physiological state of arousal. Although lapses of sustained attention have been linked with dysregulations of arousal, the underlying physiological mechanisms remain unclear. An emerging body of work proposes that the intrusion during wakefulness of sleep-like slow waves, a marker of the transition toward sleep, could mechanistically account for attentional lapses. This study aimed to expose, via pharmacological manipulations of the monoamine system, the relationship between the occurrence of sleep-like slow waves and the behavioural consequences of sustained attention failures. In a double-blind, randomised-control trial, 32 healthy human male participants received methylphenidate, atomoxetine, citalopram or placebo during four separate experimental sessions. During each session, electroencephalography (EEG) was used to measure neural activity whilst participants completed a visual task re...

This study assesses the involvement in human motor learning, of the ventrolateral prefrontal cortex (BA 9/46v), a somatic region in the middle frontal gyrus. The potential involvement of this cortical area in motor learning is suggested by studies in non-human primates which have found anatomical connections between this area and sensorimotor regions in frontal and parietal cortex, and also with basal ganglia output zones. It is likewise suggested by electrophysiological studies which have shown that activity in this region is implicated in somatic sensory memory and is also influenced by reward. We directly tested the hypothesis that area 9/46v is involved in reinforcement-based motor learning in humans. Participants performed reaching movements to a hidden target and received positive feedback when successful. Prior to the learning task, we applied continuous theta burst stimulation (cTBS) to disrupt activity in 9/46v in the left or right hemisphere. A control group received sham cTBS. The data showed th...

Environmental factors and life experiences impinge on brain circuits triggering adaptive changes. Epigenetic regulators contribute to this neuroadaptation by enhancing or suppressing specific gene programs. The paralogous transcriptional co-activators and lysine acetyltransferases CBP and p300 are involved in brain plasticity and stimulus-dependent transcription, but their specific roles in neuroadaptation are not fully understood. Here we investigated the impact of eliminating either CBP or p300 in excitatory neurons of the adult forebrain of mice from both sexes using inducible and cell-type restricted knockout strains. The elimination of CBP, but not p300, reduced the expression and chromatin acetylation of plasticity genes, dampened activity-driven transcription, and caused memory deficits. The defects became more prominent in elderly mice and in paradigms that involved enduring changes in transcription, such as kindling and environmental enrichment, in which CBP loss interfered with the establishment ...

Diabetic neuropathic pain (DNP) is a diabetes complication experienced by many patients. Ventrolateral periaqueductal gray (vlPAG) neurons are essential mediators of the descending pain modulation system, yet the role of vlPAG astrocytes in DNP remains unclear. The present study applied a multidimensional approach to elucidate the role of these astrocytes in DNP. We verified the activation of astrocytes in different regions of the PAG in male DNP-model rats. We found that only astrocytes in the vlPAG exhibited increased growth. Furthermore, we described differences in vlPAG astrocyte activity at different time points during DNP progression. After the 14th day of modeling, vlPAG astrocytes exhibited obvious activation and morphological changes. Furthermore, activation of Gq-DREADDs in vlPAG astrocytes in naive male rats induced neuropathic pain-like symptoms and pain-related aversion, whereas activation of Gi-DREADDs in vlPAG astrocytes in male DNP-model rats alleviated sensations of pain and promoted pain-...

Drosophila multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human MEGF8 . MEGF8 encodes a multidomain transmembrane protein which is highly conserved across species. In humans, MEGF8 mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects, and learning disabilities. MEGF8 is also associated with psychiatric disorders. Despite its clinical relevance, MEGF8 remains poorly characterized; and although it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of MEGF8 with psychiatric disorders indicate that mutations in MEGF8 cause underlying defects in synaptic structure and functions. In this study, we investigated the role of Drosophila dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synap...

Alpha-synuclein (αSyn) and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Despite the disease relevance, their physiological roles remain elusive, as mice with knock-out of either of these genes do not exhibit overt phenotypes. To reveal functional cooperation, we generated αSyn−/−tau−/− double-knock-out mice and characterized the functional cross talk between these proteins during brain development. Intriguingly, deletion of αSyn and tau reduced Notch signaling and accelerated interkinetic nuclear migration of G2 phase at early embryonic stage. This significantly altered the balance between the proliferative and neurogenic divisions of progenitor cells, resulting in an overproduction of early born neurons and enhanced neurogenesis, by which the brain size was enlarged during the embryonic stage in both sexes. On the other hand, a reduction in the number of neura...

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic act...

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 (AD). 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 AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of β (20–30 Hz) oscillations (β 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 β bursts. Additionally, θ-α/β cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during β ...

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...

Research into the nature of 1/ f -like, nonoscillatory electrophysiological activity has grown exponentially in recent years in cognitive neuroscience. The shape of this activity has been linked to the balance between excitatory and inhibitory neural circuits, which is thought to be important for information processing. However, to date, it is not known whether the presentation of a stimulus induces changes in the parameters of 1/ f activity in scalp recordings, separable from event-related potentials (ERPs). Here, we analyzed event-related broadband changes in human EEG both before and after removing ERPs to demonstrate their confounding effect, and to establish whether there are genuine stimulus-induced changes in 1/ f . Using data from a passive and an active auditory task ( n = 23, 61% female), we found that the shape of the post-event spectra between 2 and 25 Hz differed significantly from the pre-event spectra even after removing the frequency-content of ERPs. Further, a significant portion of this d...