Acute Gravitational Stress Selectively Impairs Dynamic Cerebrovascular Reactivity in the Anterior Circulation Independent of Changes to the Central Respiratory Chemoreflex

Cerebrovascular reactivity (CVR) to changes in the partial pressure of arterial carbon dioxide (PaCO2) is an important mechanism that maintains CO2 or pH homeostasis in the brain. To what extent this is influenced by gravitational stress and corresponding implications for the regulation of cerebral blood flow (CBF) remain unclear. The present study examined the onset responses of pulmonary ventilation (V̇E) and anterior middle (MCA) and posterior (PCA) cerebral artery mean blood velocity (Vmean) responses to acute hypercapnia (5% CO2) to infer dynamic changes in the central respiratory chemoreflex and cerebrovascular reactivity (CVR), in supine and 50° head-up tilt (HUT) positions. Each onset response was evaluated using a single-exponential regression model consisting of the response time latency [CO2-response delay (t0)] and time constant (τ). Onset response of V̇E and PCA Vmean to changes in CO2 was unchanged during 50° HUT compared with supine (τ: V̇E, p = 0.707; PCA Vmean, p = 0.071 vs. supine) but the MCA Vmean onset response was faster during supine than during 50° HUT (τ: p = 0.003 vs. supine). These data indicate that gravitational stress selectively impaired dynamic CVR in the anterior cerebral circulation, whereas the posterior circulation was preserved, independent of any changes to the central respiratory chemoreflex. Collectively, our findings highlight the regional heterogeneity underlying CBF regulation that may have translational implications for the microgravity (and hypercapnia) associated with deep-space flight notwithstanding terrestrial orthostatic diseases that have been linked to accelerated cognitive decline and neurodegeneration.

Low frequency conduction block: a promising new technique to advance bioelectronic medicines

Nerve conduction block is an appealing way to selective target the nervous system for treating pathological conditions. Several modalities were described in the past, with the kilohertz frequency stimulation generating an enormous interest and tested successfully in clinical settings. Some shortcomings associated with different modalities of nerve blocking can limit its clinical use, as the “onset response”, the high demand of energy supply, among others. A recent study by Muzquiz and colleagues describes the efficacy and reversibility of low frequency alternating currents in blocking the cervical vagus in the pig, in the absence of an onset effect and apparent lack of neuronal damage.

An electrophysiological measure of tonotopic selectivity in normal-hearing humans and cats

We describe a non-invasive electrophysiological (EEG) measure of tonotopic selectivity and compare the results between humans and cats. Sequences of 50-ms tone-burst probes were presented at 1-second intervals against a continuous noise masker, and the averaged cortical onset response (COR) to the probe was measured using EEG electrodes placed on the scalp. The noise masker had a bandwidth of 1 or 1/8th octave, geometrically centred on 4000 Hz for humans and 8000 Hz for cats. Probe frequency was either -0.5, -0.25, 0, 0.25 or 0.5 octaves re 4000/8000 Hz. The COR was larger for probe frequencies more distant from the noise geometrical centre, and this effect was greater for the 1/8th-octave than for the 1-octave masker. This pattern broadly reflected the masked excitation patterns obtained psychophysically with similar stimuli in a companion paper. However, the positive signal-to-noise ratio used to obtain reliable COR measures meant that some aspects of the data differed from those obtained psychophysically, in a way that could be partly explained by the upward spread of the probe’s excitation pattern. We argue that although COR measures are affected by some factors that differ from those that influence psychophysical masked detection thresholds, they can reveal differences in the width of excitation patterns produced by different stimuli. We also argue that the paradigm may be effectively applied to cochlear-implant experiments in humans and animals.

Mechanisms of lactic acid gustatory attraction in Drosophila

SUMMARYSour has been studied almost exclusively as an aversive taste modality. Yet, recent work in Drosophila demonstrates that specific carboxylic acids are attractive at ecologically relevant concentrations. Here, we demonstrate that lactic acid is an appetitive and energetic tastant, which stimulates feeding through activation of sweet gustatory receptor neurons (GRNs). This activation displays distinct, mechanistically separable, stimulus onset and removal phases. Ionotropic receptor 25a (IR25a) primarily mediates the onset response, which shows specificity for the lactate anion and drives feeding initiation. Conversely, sweet gustatory receptors (Gr64a-f) mediate a non-specific removal response to low pH that primarily impacts ingestion. While mutations in either receptor family have marginal impacts on feeding, lactic acid attraction is completely abolished in combined mutants. Thus, specific components of lactic acid are detected through two classes of receptors to activate a single set of sensory neurons in physiologically distinct ways, ultimately leading to robust behavioural attraction.

The additive nature of the human multisensory evoked pupil response

Pupillometry has received increased interest for its usefulness in measuring various sensory processes as an alternative to behavioural assessments. This is also apparent for multisensory investigations. Studies of the multisensory pupil response, however, have produced conflicting results. Some studies observed super-additive multisensory pupil responses, indicative of multisensory integration (MSI). Others observed additive multisensory pupil responses even though reaction time (RT) measures were indicative of MSI. Therefore, in the present study, we investigated the nature of the multisensory pupil response by combining methodological approaches of previous studies while using supra-threshold stimuli only. In two experiments we presented auditory and visual stimuli to observers that evoked a(n) (onset) response (be it constriction or dilation) in a simple detection task and a change detection task. In both experiments, the RT data indicated MSI as shown by race model inequality violation. Still, the multisensory pupil response in both experiments could best be explained by linear summation of the unisensory pupil responses. We conclude that the multisensory pupil response for supra-threshold stimuli is additive in nature and cannot be used as a measure of MSI, as only a departure from additivity can unequivocally demonstrate an interaction between the senses.

Anesthetic Drug Concentration Rather Than Abrupt Behavioral Unresponsiveness Linearly Degrades Responses in the Rat Primary Auditory Cortex

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration vs. behavioral unresponsiveness, since these are typically confounded. To address these questions, we employed slow gradual intravenous propofol anesthesia induction (from 100 to 900-1200 mcg/kg/min) together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording neuronal spiking activity in the primary auditory cortex (PAC) of eight male rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, post-onset neuronal silence duration, and late-locking to 40Hz clicktrains, gradually deteriorated by 6-60% in a dose-dependent manner with increasing anesthesia levels, without showing abrupt changes around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings recapitulate, within one experiment, a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (just-hypnotic vs. deep surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

Oculomotor Target Selection is Cortically Mediated by Complex Objects

Successful oculomotor target selection often requires discriminating visual features but it remains contentious whether oculomotor substrates encoding saccade vectors functionally contribute to this process. One possibility is that visual features are discriminated cortically and oculomotor modules select the object with the highest activation in the set of all preprocessed cortical object representations, while an alternative possibility is that oculomotor modules actively discriminate potential targets based on visual features. If the latter view is correct, these modules should not require input from specialized visual cortices encoding the task relevant features. We therefore examined whether the latency of visual onset responses elicited by abrupt distractor onsets is consistent with input from specialized visual cortices by non-invasively measuring human saccade metrics (saccade curvature, endpoint deviations, saccade frequency, error proportion) as a function of distractor processing time for novel, visually complex distractors that had to be discriminated from a target to guide saccades. Visual onset response latencies were ~110 ms, consistent with projections from anterior cortical sites specialized for object processing. Surprisingly, oculomotor visual onset responses encoded features, as we manipulated the visual similarity between targets and distractors and observed an increased visual onset response magnitude and duration when the distractor was highly similar to the target, which was not attributable to an inhibitory processing delay. Visual onset responses were dynamically modulated by executive function, as these responses were anticipatorily extinguished over the time course of the experiment. As expected, the latency of distractor-related inhibition was modulated by the behavioral relevance of the distractor.Significance StatementWe provide novel insights into the role of the oculomotor system in saccadic target selection by challenging the convention that neural substrates that encode oculomotor vectors functionally contribute to target discrimination. Our data show that the oculomotor system selects a winner from amongst the preprocessed object representations output from specialized visual cortices as supposed to discriminating visual features locally. We also challenge the convention that oculomotor visual onset responses are feature-invariant, as they encoded task-relevance.

Task-induced modulations of neuronal activity along the auditory pathway

Sensory processing varies depending on behavioral context. Here, we asked how task-engagement modulates neurons in the auditory system. We trained mice in a simple tone-detection task, and compared their neuronal activity during passive hearing and active listening. Electrophysiological extracellular recordings in the inferior colliculus, medial geniculate body, primary auditory cortex and anterior auditory field revealed widespread modulations across all regions and cortical layers, and in both putative regular and fast-spiking cortical neurons. Clustering analysis unveiled ten distinct modulation patterns that could either enhance or suppress neuronal activity. Task-engagement changed the tone-onset response in most neurons. Such modulations first emerged in subcortical areas, ruling out cortical feedback from primary auditory areas as the only mechanism underlying subcortical modulations. Half the neurons additionally displayed late modulations associated with licking, arousal or reward. Our results reveal the presence of functionally distinct subclasses of neurons, differentially sensitive to specific task-related variables but anatomically distributed along the auditory pathway.