Activity in Barrel Cortex Related to Trace Eyeblink Conditioning.

In mammals several memory systems are responsible for learning and storage of associative memory. Even apparently simple behavioral tasks, like pavlovian conditioning, have been suggested to engage, for instance, implicit and explicit memory processes. Here, we used single-whisker tactile trace eyeblink conditioning (TTEBC) to investigate learning and its neuronal bases in the mouse barrel column, the primary neocortical tactile representation of one whisker. Behavioral analysis showed that conditioned responses (CRs) are spatially highly restricted; they generalize from the principal whisker only to its direct neighbors. Within the respective neural representation, the principal column and its direct neighbors, spike activity showed a learning-related spike rate suppression starting during the late phase of conditioning stimulus (CS) presentation that was sustained throughout the stimulus-free trace period (Trace). Trial-by-trial analysis showed that learning-related activity was independent from the generation of eyelid movements within a trial, and set in around the steepest part of the learning curve. Optogenetic silencing of responses and their learning-related changes during CS and Trace epochs blocked CR acquisition but not its recall after learning. Silencing during the Trace alone, which carried major parts of the learning-related changes, had no effect. In summary, we demonstrate specific barrel column spike rate plasticity during TTEBC that can be partially decoupled from the CR, the learned eye closure, a hallmark of implicit learning. Our results, thus, point to a possible role of the barrel column in contributing to other kinds of memory as well.

Temporally Local Tactile Codes Can Be Stored in Working Memory.

Tactile exploration often involves sequential touches interspersed with stimulus-free durations (e.g., the time during which the hand moves from one textured surface to the other). Whereas it is obvious that texture-related perceptual variables, irrespective of the encoding strategy, must be stored in memory for comparison, it is rather unclear which of those variables are held in memory. There are two established variables-"intensity" and "frequency", which are "temporally global" variables because of the long stimulus integration interval required to average the signal or derive spectral components, respectively; on the other hand, a recently established third contender is the "temporally local" variable that codes for kinematic profiles of very short, suprathreshold events in the vibrotactile signal. Here, we present the first psychophysical evidence that temporally local variables can be stored in memory. To that end, we asked participants to detect changes in pulsatile indentation stimuli at their fingertips with and without a gap of 1 s between stimulus presentations. The stimuli either contained global variables alone (change of pulse rate), or a mix of local and global variables (change of pulse shape). We found, first, that humans are much better at detecting a change in stimuli when local variables are available rather than global ones alone-as evident by the fact that 21 compared to only 6 participants out of 25 yielded a valid psychophysical curve, respectively. Second, this observation persists even when there is a gap between the stimuli, implying local variables must be stored in memory. Third, an extensive array of relevant intensity definitions failed to explain participants' performance in any consistent manner, which implies that perceptual decisions were less likely to be driven by intensity coding. Taken together, our results suggest that humans perform pulsatile change detection utilizing local pulse shape, and to a lesser degree global pulse rate, and that both parameters can be stored in memory.

Local Neuronal Responses to Intracortical Microstimulation in Rats' Barrel Cortex Are Dependent on Behavioral Context.

The goal of cortical neuroprosthetics is to imprint sensory information as precisely as possible directly into cortical networks. Sensory processing, however, is dependent on the behavioral context. Therefore, a specific behavioral context may alter stimulation effects and, thus, perception. In this study, we reported how passive vs. active touch, i.e., the presence or absence of whisker movements, affects local field potential (LFP) responses to microstimulation in the barrel cortex in head-fixed behaving rats trained to move their whiskers voluntarily. The LFP responses to single-current pulses consisted of a short negative deflection corresponding to a volley of spike activity followed by a positive deflection lasting ~100 ms, corresponding to long-lasting suppression of spikes. Active touch had a characteristic effect on this response pattern. While the first phase including the negative peak remained stable, the later parts consisting of the positive peak were considerably suppressed. The stable phase varied systematically with the distance of the electrode from the stimulation site, pointing to saturation of neuronal responses to electrical stimulation in an intensity-dependent way. Our results suggest that modulatory effects known from normal sensory processing affect the response to cortical microstimulation as well. The network response to microstimulation is highly amenable to the behavioral state and must be considered for future approaches to imprint sensory signals into cortical circuits with neuroprostheses.

Humans Use a Temporally Local Code for Vibrotactile Perception.

Sensory environments are commonly characterized by specific physical features, which sensory systems might exploit using dedicated processing mechanisms. In the tactile sense, one such characteristic feature is frictional movement, which gives rise to short-lasting (<10 ms), information-carrying integument vibrations. Rather than generic integrative encoding (i.e., averaging or spectral analysis capturing the "intensity" and "best frequency"), the tactile system might benefit from, what we call a "temporally local" coding scheme that instantaneously detects and analyzes shapes of these short-lasting features. Here, by employing analytic psychophysical measurements, we tested whether the prerequisite of temporally local coding exists in the human tactile system. We employed pulsatile skin indentations at the fingertip that allowed us to trade manipulation of local pulse shape against changes in global intensity and frequency, achieved by adding pulses of the same shape. We found that manipulation of local pulse shape has strong effects on psychophysical performance, arguing for the notion that humans implement a temporally local coding scheme for perceptual decisions. As we found distinct differences in performance using different kinematic layouts of pulses, we inquired whether temporally local coding is tuned to a unique kinematic variable. This was not the case, since we observed different preferred kinematic variables in different ranges of pulse shapes. Using an established encoding model for primary afferences and indentation stimuli, we were able to demonstrate that the found kinematic preferences in human performance, may well be explained by the response characteristics of Pacinian corpuscles (PCs), a class of human tactile primary afferents.

Conveyance of texture signals along a rat whisker.

Neuronal activities underlying a percept are constrained by the physics of sensory signals. In the tactile sense such constraints are frictional stick-slip events, occurring, amongst other vibrotactile features, when tactile sensors are in contact with objects. We reveal new biomechanical phenomena about the transmission of these microNewton forces at the tip of a rat's whisker, where they occur, to the base where they engage primary afferents. Using high resolution videography and accurate measurement of axial and normal forces at the follicle, we show that the conical and curved rat whisker acts as a sign-converting amplification filter for moment to robustly engage primary afferents. Furthermore, we present a model based on geometrically nonlinear Cosserat rod theory and a friction model that recreates the observed whole-beam whisker dynamics. The model quantifies the relation between kinematics (positions and velocities) and dynamic variables (forces and moments). Thus, only videographic assessment of acceleration is required to estimate forces and moments measured by the primary afferents. Our study highlights how sensory systems deal with complex physical constraints of perceptual targets and sensors.

Functional analysis of information rates conveyed by rat whisker-related trigeminal nuclei neurons.

The rat whisker system connects the tactile environment with the somatosensory thalamocortical system using only two synaptic stages. Encoding properties of the first stage, the primary afferents with somas in the trigeminal ganglion (TG), has been well studied, whereas much less is known from the second stage, the brainstem trigeminal nuclei (TN). The TN are a computational hub giving rise to parallel ascending tactile pathways and receiving feedback from many brain sites. We asked the question, whether encoding properties of TG neurons are kept by two trigeminal nuclei, the principalis (Pr5) and the spinalis interpolaris (Sp5i), respectively giving rise to two "lemniscal" and two "nonlemniscal" pathways. Single units were recorded in anesthetized rats while a single whisker was deflected on a band-limited white noise trajectory. Using information theoretic methods and spike-triggered mixture models (STM), we found that both nuclei encode the stimulus locally in time, i.e., stimulus features more than 10 ms in the past do not significantly influence spike generation. They further encode stimulus kinematics in multiple, distinct response fields, indicating encoding characteristics beyond previously described directional responses. Compared with TG, Pr5 and Sp5i gave rise to lower spike and information rates, but information rate per spike was on par with TG. Importantly, both brainstem nuclei were found to largely keep encoding properties of primary afferents, i.e. local encoding and kinematic response fields. The preservation of encoding properties in channels assumed to serve different functions seems surprising. We discuss the possibility that it might reflect specific constraints of frictional whisker contact with object surfaces.NEW & NOTEWORTHY We studied two trigeminal nuclei containing the second neuron on the tactile pathway of whisker-related tactile information in rats. We found that the subnuclei, traditionally assumed to give rise to functional tactile channels, nevertheless transfer primary afferent information with quite similar properties in terms of integration time and kinematic profile. We discuss whether such commonality may be due the requirement to adapt to physical constraints of frictional whisker contact.

Adaptive Whisking in Mice.

Rodents generate rhythmic whisking movements to explore their environment. Whisking trajectories, for one, appear as a fixed pattern of whisk cycles at 5-10 Hz driven by a brain stem central pattern generator. In contrast, whisking behavior is thought to be versatile and adaptable to behavioral goals. To begin to systematically investigate such behavioral adaptation, we established a whisking task, in which mice altered the trajectories of whisking in a goal-oriented fashion to gain rewards. Mice were trained to set the whisker to a defined starting position and generate a protraction movement across a virtual target (no touch-related tactile feedback). By ramping up target distance based on reward history, we observed that mice are able to generate highly specific whisking patterns suited to keep reward probability constant. On a sensorimotor level, the behavioral adaptation was realized by adjusting whisker kinematics: more distant locations were targeted using higher velocities (i.e., pointing to longer force generation), rather than by generating higher acceleration (i.e., pointing to stronger forces). We tested the suitability of the paradigm of tracking subtle alteration in whisking motor commands using small lesions in the rhythmic whisking subfield (RW) of the whisking-related primary motor cortex. Small contralateral RW lesions generated the deterioration of whisking kinematics with a latency of 12 days post-lesion, a change that was readily discriminated from changes in the behavioral adaptation by the paradigm.

Propofol Affects Cortico-Hippocampal Interactions via ß3 Subunit-Containing GABAA Receptors.

BACKGROUND: General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABAA receptors, especially the type with ß3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABAA receptors with ß3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions. METHODS: We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and ß3(N265M) knock-in mice. In the ß3(N265M) mice, the action of propofol via ß3subunit containing GABAA receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2-16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions. RESULTS: Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the ß3(N265M) mutant. Propofol strongly decreased phase locking of 6-12 Hz oscillations in wild-type mice. This decrease was attenuated in the ß3(N265M) mutant. Finally, propofol reduced the mutual information between 6-16 Hz in wild-type mice, but only between 6 and 8 Hz in the ß3(N265M) mutant. CONCLUSIONS: GABAA receptors containing ß3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol.

Mapping the Brain-Wide Network Effects by Optogenetic Activation of the Corpus Callosum.

Optogenetically driven manipulation of circuit-specific activity enables causality studies, but its global brain-wide effect is rarely reported. Here, we applied simultaneous functional magnetic resonance imaging (fMRI) and calcium recording with optogenetic activation of the corpus callosum (CC) connecting barrel cortices (BC). Robust positive BOLD was detected in the ipsilateral BC due to antidromic activity, spreading to the ipsilateral motor cortex (MC), and posterior thalamus (PO). In the orthodromic target, positive BOLD was reliably evoked by 2 Hz light pulses, whereas 40 Hz light pulses led to reduced calcium, indicative of CC-mediated inhibition. This presumed optogenetic CC-mediated inhibition was further elucidated by pairing light pulses with whisker stimulation at varied interstimulus intervals. Whisker-induced positive BOLD and calcium signals were reduced at intervals of 50/100 ms. The calcium-amplitude-modulation-based correlation with whole-brain fMRI signal revealed that the inhibitory effects spread to contralateral BC, ipsilateral MC, and PO. This work raises the need for fMRI to elucidate the brain-wide network activation in response to optogenetic stimulation.

A Tactile Virtual Reality for the Study of Active Somatosensation.

Natural exploration of textures involves active sensing, i.e., voluntary movements of tactile sensors (e.g., human fingertips or rodent whiskers) across a target surface. Somatosensory input during moving tactile sensors varies according to both the movement and the surface texture. Combining motor and sensory information, the brain is capable of extracting textural features of the explored surface. Despite the ecological relevance of active sensing, psychophysical studies on active touch are largely missing. One reason for the lack of informative studies investigating active touch is the considerable challenge of assembling an appropriate experimental setup. A possible solution might be in the realm of virtual tactile reality that provides tactile finger stimulation depending on the position of the hand and the simulated texture of a target surface. In addition to rigorous behavioral studies, the investigation of the neuronal mechanisms of active tactile sensing in humans is highly warranted, requiring neurophysiological experiments using electroencephalography (EEG), magnetoencephalography (MEG) and/or functional magnetic resonance imaging (fMRI). However, current neuroimaging techniques impose specific requirements on the tactile stimulus delivery equipment in terms of compatibility with the neurophysiological methods being used. Here, we present a user-friendly, MEG compatible, tactile virtual reality simulator. The simulator consists of a piezo-electric tactile stimulator capable of independently protruding 16 plastic pistons of 1 mm diameter arranged in a 4 × 4 matrix. The stimulator delivers a spatial pattern of tactile stimuli to the tip of a finger depending on the position of the finger moving across a 2-dimensional plane. In order to demonstrate the functionality of the tactile virtual reality, we determined participants' detection thresholds in active and passive touch conditions. Thresholds in both conditions were higher than reported in the literature. It could well be that the processing of the piston-related stimulation was masked by the sensory input generated by placing the finger on the scanning probe. More so, the thresholds for both the active and passive tasks did not differ significantly. In further studies, the noise introduced by the stimulator in neuromagnetic recordings was quantified and somatosensory evoked fields for active and passive touch were recorded. Due to the compatibility of the stimulator with neuroimaging techniques such as MEG, and based on the feasibility to record somatosensory-related neuromagnetic brain activity the apparatus has immense potential for the exploration of the neural underpinnings of active tactile perception.

Effects of Diazepam on Low-Frequency and High-Frequency Electrocortical γ-Power Mediated by α1- and α2-GABAA Receptors.

Patterns of spontaneous electric activity in the cerebral cortex change upon administration of benzodiazepines. Here we are testing the hypothesis that the prototypical benzodiazepine, diazepam, affects spectral power density in the low (20-50 Hz) and high (50-90 Hz) γ-band by targeting GABAA receptors harboring α1- and α2-subunits. Local field potentials (LFPs) and action potentials were recorded in the barrel cortex of wild type mice and two mutant strains in which the drug exclusively acted via GABAA receptors containing either α1- (DZα1-mice) or α2-subunits (DZα2-mice). In wild type mice, diazepam enhanced low γ-power. This effect was also evident in DZα2-mice, while diazepam decreased low γ-power in DZα1-mice. Diazepam increased correlated local LFP-activity in wild type animals and DZα2- but not in DZα1-mice. In all genotypes, spectral power density in the high γ-range and multi-unit action potential activity declined upon diazepam administration. We conclude that diazepam modifies low γ-power in opposing ways via α1- and α2-GABAA receptors. The drug's boosting effect involves α2-receptors and an increase in local intra-cortical synchrony. Furthermore, it is important to make a distinction between high- and low γ-power when evaluating the effects of drugs that target GABAA receptors.

Cortical modulation of sensory flow during active touch in the rat whisker system.

Sensory gating, where responses to stimuli during sensor motion are reduced in amplitude, is a hallmark of active sensing systems. In the rodent whisker system, sensory gating has been described only at the thalamic and cortical stages of sensory processing. However, does sensory gating originate at an even earlier synaptic level? Most importantly, is sensory gating under top-down or bottom-up control? To address these questions, we used an active touch task in behaving rodents while recording from the trigeminal sensory nuclei. First, we show that sensory gating occurs in the brainstem at the first synaptic level. Second, we demonstrate that sensory gating is pathway-specific, present in the lemniscal but not in the extralemniscal stream. Third, using cortical lesions resulting in the complete abolition of sensory gating, we demonstrate its cortical dependence. Fourth, we show accompanying decreases in whisking-related activity, which could be the putative gating signal.

Biomechanical Texture Coding in Rat Whiskers.

Classically, texture discrimination has been thought to be based on 'global' codes, i.e. frequency (signal analysis based on Fourier analysis) or intensity (signal analysis based on averaging), which both rely on integration of the vibrotactile signal across time and/or space. Recently, a novel 'local' coding scheme based on the waveform of frictional movements, discrete short lasting kinematic events (i.e. stick-slip movements called slips) has been formulated. We performed biomechanical measurements of relative movements of a rat vibrissa across sandpapers of different roughness. We find that the classic global codes convey some information about texture identity, but are consistently outperformed by the slip-based local code. Moreover, the slip code also surpasses the global ones in coding for active scanning parameters. This is remarkable as it suggests that the slip code would explicitly allow the whisking rat to optimize perception by selecting goal-specific scanning strategies.

Primary Tactile Thalamus Spiking Reflects Cognitive Signals.

Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling.SIGNIFICANCE STATEMENT It is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first-order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected.

Barrel cortex: What is it good for?

The rodent whisker system, with barrel cortex as its most prominent structure, has evolved into a powerful model system to study sensory processing. However, despite the vast amount of data collected on barrel cortex neural activity patterns, as well as its circuitry and plasticity, the precise behavioral and cognitive operations for which this structure is needed are still elusive. Proposed functions of barrel cortex include detection, discrimination, coordination of whisker movements during exploratory locomotion or active touch, and associative learning. Departing from a definition of what exactly constitutes a function and how the involvement of a brain area in a specific task can be established conclusively, we here review the arguments suggesting barrel cortex is involved in either of these functions. We conclude that currently available data do not unequivocally support a crucial role of barrel cortex in core sensorimotor functions like sensory processing for detection and discrimination or motor processing for movement. Instead, it appears that barrel cortex' contribution to behavior becomes ever more critical for performance with increasing cognitive load. We argue that our ignorance about barrel cortex' involvement in behavior is partly due to the lack of basic experiments employing permanent lesioning of the barrel field, as well as neglect of procedural parameters determining cognitive load in behavioral tasks. It is our belief that close attention to these factors in future experiments will help to eventually discover what barrel cortex is actually good for.

Global Tactile Coding in Rat Barrel Cortex in the Absence of Local Cues.

Although whisker-related perception is based predominantly on local, near-instantaneous coding, global, intensive coding, which integrates the vibrotactile signal over time, has also been shown to play a role given appropriate behavioral conditions. Here, we study global coding in isolation by studying head-fixed rats that identified pulsatile stimuli differing in pulse frequency but not in pulse waveforms, thus abolishing perception based on local coding. We quantified time locking and spike counts as likely variables underpinning the 2 coding schemes. Both neurometric variables contained substantial stimulus information, carried even by spikes of single barrel cortex neurons. To elucidate which type of information is actually used by the rats, we systematically compared psychometric with neurometric sensitivity based on the 2 coding schemes. Neurometric performance was calculated by using a population-encoding model incorporating the properties of our recorded neuron sample. We found that sensitivity calculated from spike counts sampled over long periods (>1 s) matched the performance of rats better than the one carried by spikes time-locked to the stimulus. We conclude that spike counts are more relevant to tactile perception when instantaneous kinematic parameters are not available.

Lifting the veil on the dynamics of neuronal activities evoked by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a widely used non-invasive tool to study and modulate human brain functions. However, TMS-evoked activity of individual neurons has remained largely inaccessible due to the large TMS-induced electromagnetic fields. Here, we present a general method providing direct in vivo electrophysiological access to TMS-evoked neuronal activity 0.8-1 ms after TMS onset. We translated human single-pulse TMS to rodents and unveiled time-grained evoked activities of motor cortex layer V neurons that show high-frequency spiking within the first 6 ms depending on TMS-induced current orientation and a multiphasic spike-rhythm alternating between excitation and inhibition in the 6-300 ms epoch, all of which can be linked to various human TMS responses recorded at the level of spinal cord and muscles. The advance here facilitates a new level of insight into the TMS-brain interaction that is vital for developing this non-invasive tool to purposefully explore and effectively treat the human brain.

The Slip Hypothesis: Tactile Perception and its Neuronal Bases.

The slip hypothesis of epicritic tactile perception interprets actively moving sensor and touched objects as a frictional system, known to lead to jerky relative movements called 'slips'. These slips depend on object geometry, forces, material properties, and environmental factors, and, thus, have the power to incorporate coding of the perceptual target, as well as perceptual strategies (sensor movement). Tactile information as transferred by slips will be encoded discontinuously in space and time, because slips sometimes engage only parts of the touching surfaces and appear as discrete and rare events in time. This discontinuity may have forced tactile systems of vibrissae and fingertips to evolve special ways to convert touch signals to a tactile percept.

Information Coding through Adaptive Gating of Synchronized Thalamic Bursting.

It has been posited that the regulation of burst/tonic firing in the thalamus could function as a mechanism for controlling not only how much but what kind of information is conveyed to downstream cortical targets. Yet how this gating mechanism is adaptively modulated on fast timescales by ongoing sensory inputs in rich sensory environments remains unknown. Using single-unit recordings in the rat vibrissa thalamus (VPm), we found that the degree of bottom-up adaptation modulated thalamic burst/tonic firing as well as the synchronization of bursting across the thalamic population along a continuum for which the extremes facilitate detection or discrimination of sensory inputs. Optogenetic control of baseline membrane potential in thalamus further suggests that this regulation may result from an interplay between adaptive changes in thalamic membrane potential and synaptic drive from inputs to thalamus, setting the stage for an intricate control strategy upon which cortical computation is built.