Temporal expectation is the ability to construct predictions regarding the timing of events, based on previously-experienced temporal regularities of different types. For example, cue-based expectations are constructed when a cue validly indicates when a target is expected to occur. However, in the absence of such cues, expectations can be constructed based on contextual temporal information, including the event’s onset distribution and recent prior experiences, both providing implicit probabilistic information regarding the event’s timing. It was previously suggested that cue-based temporal expectation is exerted via synchronization of spatially-specific neural activity at a target's predictable time, within receptive fields corresponding to the target’s expected location. Here, we tested if the same theoretical model holds for contextual temporal effects. Participants (n = 40; 25 females) performed a speeded spatial-cueing detection task, with two-thirds valid spatial cues. The target’s hazard-rate func...

The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends upon tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse ( Mus musculus ), we studied a single-site D167A mutation of the gene for the alpha subunit of rod photoreceptor phosphodiesterase ( PDEA ), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the beta subunit gene ( PDEB ) to about 5 – 10% of wild-type (WT). The remaining phosphodiesterase had nearly normal specific activity; degeneration was slow, with 50–60% of rods remaining after 6 months. Responses were larger and more sensitive than normal but slower in rise and decay, probably from slower dark turnover of cGMP. Remarkably, responses became much less reproducible than WT, with response variance increasing for amplitude by ov...

α-synuclein (αS) plays a key role in Parkinson’s disease (PD). Although PD is typically ‘sporadic’, inherited αS missense mutations provide crucial insights into molecular mechanisms. Here, we examine two clinical mutants, E46K and G51D, which are both in the conserved N-terminus that mediates transient αS-membrane interactions. However, E46K increases and G51D decreases αS-membrane interactions. Previously, we amplified E46K via the 11-residue repeat motifs, creating “3K” (E35K+E46K+E61K). Here, we engineered these motifs to amplify G51D (V40D+G51D+V66D = “3D”) and systematically compared E46K/3K vs. G51D/3D. We found that G51D increased cytosolic αS in neural cells and 3D aggravates this. G51D, and 3D even more, reduced αS multimer-to-monomer (αS60:αS14) ratio. Both amplified variants caused cellular stress in rat primary neurons and reduced growth in human neuroblastoma cells. Importantly, both 3K- and 3D-induced stress were ameliorated by pharmacologically inhibiting stearoyl-CoA desaturase (SCD) or by...

The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in male rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control ...

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer’s Disease (AD), the present study aimed at i) investigate whether MTL atrophy propagates specifically within the AT and PM networks, and ii) evaluate the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: i) resting-state functional MRI from the Aging Brain Cohort to define the AT and PM networks (n=68), ii) longitudinal structural MRI from ADNIGO/2 to highlight structural covariance patterns (n=349), and iii) PET data from ADNI3 to evaluate the networks’ vulnerability to amyloid and tau (n=186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann Area 35 structurally covaried ...

During multisensory speech perception, slow delta oscillations (∼1 - 3 Hz) in the listener’s brain synchronize with the speech signal, likely engaging in speech signal decomposition. Notable fluctuations in the speech amplitude envelope, resounding speaker prosody, temporally align with articulatory and body gestures and both provide complementary sensations that temporally structure speech. Further, delta oscillations in the left motor cortex seem to align with speech and musical beats, suggesting their possible role in the temporal structuring of (quasi)-rhythmic stimulation. We extended the role of delta oscillations to audio-visual asynchrony detection as a test case of the temporal analysis of multisensory prosody fluctuations in speech. We recorded EEG responses in an audio-visual asynchrony detection task while participants watched videos of a speaker. We filtered the speech signal to remove verbal content and examined how visual and auditory prosodic features temporally (mis-)align. Results confirm...

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)—a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases—in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels irrespective of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice express...

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal ...

When we look at our body parts, we are immediately aware that they belong to us and we rarely doubt about the integrity, continuity, and sense of ownership of our body. Despite this certainty, immersive virtual reality (IVR) may lead to a strong feeling of embodiment over an artificial body part seen from a first-person perspective (1PP). Although such feeling of ownership (FO) has been described in different situations, it is not yet understood how this phenomenon is generated at neural level. To track the real-time brain dynamics associated with FO, we delivered transcranial magnetic stimuli over the hand region in the primary motor cortex (M1) and simultaneously recorded electroencephalography (EEG) in 19 healthy volunteers (11 male/8 female) watching IVR renderings of anatomically plausible (full-limb) versus implausible (hand disconnected from the forearm) virtual limbs. Our data show that embodying a virtual hand is temporally associated with a rapid drop of cortical activity of the onlookers' hand r...

In the article, “Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling,” by Salim Megat, Pradipta R. Ray, Diana Tavares-Ferreira, Jamie K. Moy, Ishwarya Sankaranarayanan, Andi Wanghzou, Tzu Fang Lou, Paulino Barragan-Iglesias, Zachary T.