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Transient receptor potential vanilloid (TRPV) channels respond to polymodal stresses to induce pain, inflammation and tissue fibrosis. In this study, we probed for their functional expression in human conjunctival epithelial (HCjE) cells and ex vivo human conjunctivas. Notably, patients suffering from dry eye syndrome experience the same type of symptomology induced by TRPV channel activation in other ocular tissues. TRPV gene and protein expression were determined by RT-PCR and immunohistochemistry in HCjE cells and human conjunctivas (body donors). The planar patch-clamp technique was used to record nonselective cation channel currents. Ca(2+) transients were monitored in fura-2 loaded cells. Cultivated HCjE cells and human conjunctiva express TRPV1, TRPV2, and TRPV4 mRNA. TRPV1 and TRPV4 localization was identified in human conjunctiva. Whereas the TRPV1 agonist capsaicin (CAP) (5-20 μM) -induced Ca(2+) transients were blocked by capsazepine (CPZ) (10 μM), the TRPV4 activator 4α-PDD (10 μM) -induced Ca(2+) increases were reduced by ruthenium-red (RuR) (20 μM). Different heating (<40°C or >43°C) led to Ca(2+) increases, which were also reduced by RuR. Hypotonic challenges of either 25 or 50% induced Ca(2+) transients and nonselective cation channel currents. In conclusion, conjunctiva express TRPV1, TRPV2, and TRPV4 channels which may provide novel drug targets for dry eye therapeutics. Their usage may have fewer side effects than those currently encountered with less selective drugs.

SignificanceThe spatial structure of correlated activity of neurons in lower-order visual areas has been shown to linearly decrease as a measure of distance. The shape of correlated variability is a defining feature of cortical microcircuits, as it constrains the computational power and diversity of a region. We show here a nonmonotonic spatial structure of functional connectivity in the prefrontal cortex (PFC) where distal interactions are just as strong as proximal interactions during visual engagement of functionally similar PFC neurons. Such a nonmonotonic structure of functional connectivity could have far-reaching consequences in rethinking the nature and role of prefrontal microcircuits in various cognitive states.

In perceptual multistability, the content of consciousness alternates spontaneously between different interpretations of unchanged sensory input. The source of these internally driven transitions in conscious perception is unknown. Here we show that transient, low frequency (1-9 Hz) perisynaptic bursts in the macaque lateral prefrontal cortex precede spontaneous perceptual transitions in a no-report binocular motion rivalry task. These lowfrequency transients suppress 20-40 Hz oscillatory bursts that selectively synchronise the discharge activity of neuronal ensembles signalling conscious content. Similar ongoing state changes, with dynamics resembling the temporal structure of spontaneous perceptual alternations during rivalry, dominate the prefrontal cortex during resting-state, thus pointing to their default, endogenous nature. Our results suggest that prefrontal state fluctuations control access to consciousness through a reorganisation in the activity of feature-specific neuronal ensembles. One sentence summaryPrefrontal state transitions precede spontaneous transitions in the content of consciousness. | Pageusing a no-report BR paradigm. This allowed us to detect intrinsically driven transitions in conscious perception of opposing directions-of-motion. We combined this task with multielectrode recordings of local field potentials (LFPs) and simultaneously sampled direction-of-motion selective, competing ensembles. By using the optokinetic nystagmus (OKN) reflex as an objective criterion of perceptual state transitions, we removed any effects of voluntary motor reports on neural activity, identifying signals directly related to spontaneous transitions in the content of consciousness. ResultsWe used a no-report paradigm of binocular motion rivalry coupled with multielectrode extracellular recordings of LFPs and direction-of-motion selective neuronal ensembles in the inferior convexity of the macaque PFC ( Fig. 1A). Two types of trials were employed: a) physical alternation (PA) of monocular alternating, opposing directions of motion and b) binocular rivalry (BR) where the initial direction of motion was not removed but was followed by a flashed, opposing direction of motion in the contralateral eye ( Fig. 1B, upper panel).Initially, this manipulation results in an externally induced period of perceptual suppression of variable duration for the first stimulus (binocular flash suppression -BFS) which is followed by spontaneous perceptual transitions since the two competing representations start to rival for access to consciousness. In order to exclude the effect of voluntary perceptual reports on neural activity the macaques were not trained to report their percept. Instead, the polarity of their motion-induced optokinetic nystagmus reflex (OKN) elicited during passive observation of the stimuli (in both conditions, i.e. BR and PA), and previously shown to provide an accurate perceptual state read-out in both humans and macaques, was used to infer perceptual dominance periods (Fig. 1B, lower panel). These domin...

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Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in non-monotonic correlation structures. Here we show such a spatially non-monotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A non-monotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes. KeywordsMacaque electrophysiology, single units, Utah arrays, noise correlations, functional connectivity, prefrontal cortex, network structure Significance statementThe spatial structure of correlated activity of neurons in lower-order visual areas has been shown to linearly decrease as a measure of distance. The shape of correlated variability is a defining feature of cortical microcircuits as it constrains the computational power and diversity of a region. We show here for the first time a non-monotonic spatial structure of functional connectivity in the pre-frontal cortex where distal interactions are just as strong as proximal interactions during visual engagement of functionally similar PFC neurons. Such a nonmonotonic structure of functional connectivity could have far-reaching consequences in rethinking the nature and the role of prefrontal microcircuits in various cognitive states.

Previous studies on mental rotation (i.e., the ability to imagine objects undergoing rotation; MR) have mainly focused on visual input, with comparatively less information about tactile input. In this study, we examined whether the processes subtending MR of 3D stimuli with both input modalities are perceptually equivalent (i.e., when learning within-modalities is equal to transfers-of-learning between modalities). We compared participants' performances in two consecutive task sessions either in no-switch conditions (Visual→Visual or Tactile→Tactile) or in switch conditions (Visual→Tactile or Tactile→Visual). Across both task sessions, we observed MR response differences with visual and tactile inputs, as well as difficult transfer-of-learning. In no-switch conditions, participants showed significant improvements on all dependent measures. In switch conditions, however, we only observed significant improvements in response speeds with tactile input (RTs, intercepts, slopes: Visual→Tactile) and close to significant improvement in response accuracy with visual input (Tactile→Visual). Model fit analyses (of the rotation angle effect on RTs) also suggested different specification in learning with tactile and visual input. In "Session 1", the RTs fitted similarly well to the rotation angles, for both types of perceptual responses. However, in "Session 2", trend lines in the fitting analyses changed in a stark way, in the switch and tactile no-switch conditions. These results suggest that MR with 3D objects is not necessarily a perceptually equivalent process. Specialization (and priming) in the exploration strategies (i.e., speed-accuracy trade-offs) might, however, be the main factor at play in these results-and not MR differences in and of themselves.