Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3 -dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase ( Cre ). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3 -expressing cells in the cochlea included various types of supporting cells (SC), outer hair cells (OHC), inner hair cells (IHC), and spiral ganglion neurons (SGN). Nox3 expr...

A central challenge in the study of conscious perception lies in dissociating the neural correlates of perceptual awareness from those reflecting its precursors and consequences. No-report paradigms have been instrumental in this endeavour, demonstrating that the event-related potential P300, recorded from the human scalp, reflects reports rather than awareness. However, these paradigms cannot probe the degree to which stimuli are consciously processed from trial to trial and thus, leave open the possibility that the P300 is a genuine correlate of conscious access enabling reports. Here, instead of removing report requirements we took the opposite approach and equated post-perceptual task demands across conscious and unconscious trials by orthogonalising target detection and overt reports in a somatosensory detection task. We used Bayesian model selection to track the transformation from physical to perceptual processing stages in the EEG data of 24 male and female participants and show that the early P50 ...

Theoretical and modeling studies demonstrate that heterosynaptic plasticity - changes at synapses inactive during induction - facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1R). Our prior work demonstrated that blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices, and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work we predict that A1 receptor knockout (A1R KO) mice will express (i) impairment of heterosynaptic plasticity, and (ii) behavioral deficits in learning on sequential tasks...

The molecular mechanisms tuning cholinergic interneuron (CIN) activity, although crucial for striatal function and behaviour, remain largely unexplored. Previous studies report that the Etv1/Er81 transcription factor is vital for regulating neuronal maturation and activity. Whilst Er81 is known to be expressed in the striatum during development, its specific role in defining CIN properties and the resulting consequences on striatal function is unknown. We report here that Er81 is expressed in CINs and its specific ablation leads to prominent changes in their molecular, morphological and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further reveal that Er81 expression is required for normal CIN pause and time-locked responses to sensorimotor inputs in awake mice. Overall, this study uncovers a new cell-type specific control of CIN function in th...

The postrhinal area, POR, is a known center for integrating spatial with non-spatial visual information and a possible hub for influencing landmark navigation by affective input from the amygdala. This may involve specific circuits within muscarinic acetylcholine receptor 2 (M2)-positive or M2-negative modules of POR which associate inputs from the thalamus, cortex, and amygdala and send outputs to the entorhinal cortex. Using anterograde and retrograde labeling with conventional and viral tracers in male and female mice we found that all higher visual areas of the ventral cortical stream project to the amygdala, while such inputs are absent from primary visual cortex (V1) and dorsal stream areas. Unexpectedly for the presumed salt-and-pepper organization of mouse extrastriate cortex, tracing results show that inputs from the dLGN (dorsal lateral geniculate nucleus) and LP (lateral posterior nucleus) were spatially clustered in layer (L) 1 and overlapped with M2+ patches of POR. In contrast, input from the...

Human object recognition is dependent on occipito-temporal cortex, but a complete understanding of the complex functional architecture of this area must account for how it is connected to the wider brain. Converging functional magnetic resonance imaging evidence shows that univariate responses to different categories of information (e.g. faces, bodies, & non-human objects) are strongly related to, and potentially shaped by, functional and structural connectivity to the wider brain. However, to date, there have been no systematic attempts to determine how distal connectivity and complex local high-level responses in occipito-temporal cortex (i.e. multivoxel response patterns) are related. Here, we show that distal functional connectivity is related to, and can reliably index, high-level representations for several visual categories (i.e. tools, faces, & places) within occipito-temporal cortex; that is, voxel sets that are strongly connected to distal brain areas show higher pattern discriminability than les...

Human object recognition is dependent on occipito-temporal cortex, but a complete understanding of the complex functional architecture of this area must account for how it is connected to the wider brain. Converging functional magnetic resonance imaging evidence shows that univariate responses to different categories of information (e.g. faces, bodies, & non-human objects) are strongly related to, and potentially shaped by, functional and structural connectivity to the wider brain. However, to date, there have been no systematic attempts to determine how distal connectivity and complex local high-level responses in occipito-temporal cortex (i.e. multivoxel response patterns) are related. Here, we show that distal functional connectivity is related to, and can reliably index, high-level representations for several visual categories (i.e. tools, faces, & places) within occipito-temporal cortex; that is, voxel sets that are strongly connected to distal brain areas show higher pattern discriminability than les...

The neuropeptides CGRP and PACAP have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about a third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex-linked, although there was a trend for greater responses among male mice. RNA-seq analysis of trigeminal ganglia yielded hieriechial clustering of responder and nonresponder mice and reveal...

Multivariate analyses of hemodynamic signals serve to identify the storage of specific stimulus contents in working memory. Representations of visual stimuli have been demonstrated both in sensory regions and in higher cortical areas. While previous research has typically focused on the working memory maintenance of a single content feature, it remains unclear whether two separate features of a single object can be decoded concurrently. Also, much less evidence exists for representations of auditory compared with visual stimulus features. To address these issues, human participants had to memorize both pitch and perceived location of one of two sample sounds. After a delay phase, they were asked to reproduce either pitch or location. At recall, both features showed comparable levels of discriminability. Region-of-interest-based decoding of functional magnetic resonance imaging data during the delay phase revealed feature-selective activity for both pitch and location of a memorized sound in auditory cortex...

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs. central), timing (prevention vs. treatment), and sex (male vs. female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigo...