Mechanisms underlying a thalamocortical transformation during active tactile sensation

During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain’s ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior-related computation implemented by the thalamocortical circuit

Laminar analysis of excitatory local circuits in vibrissal motor and sensory cortical areas

Rodents move their whiskers to locate and identify objects. Cortical areas involved in vibrissal somatosensation and sensorimotor integration include the vibrissal area of the primary motor cortex (vM1), primary somatosensory cortex (vS1; barrel cortex), and secondary somatosensory cortex (S2). We mapped local excitatory pathways in each area across all cortical layers using glutamate uncaging and laser scanning photostimulation. We analyzed these maps to derive laminar connectivity matrices describing the average strengths of pathways between individual neurons in different layers and between entire cortical layers. In vM1, the strongest projection was L2/3RL5. In vS1, strong projections were L2/3RL5 and L4RL3. L6 input and output were weak in both areas. In S2, L2/3RL5 exceeded the strength of the ascending L4RL3 projection, and local input to L6 was prominent. The most conserved pathways were L2/3RL5, and the most variable were L4RL2/3 and pathways involving L6. Local excitatory circuits in different cortical areas are organized around a prominen

Neural coding during active somatosensation revealed using illusory touch

Active sensation requires the convergence of external stimuli with representations of body movements. We used mouse behavior, electrophysiology and optogenetics to dissect the temporal interactions between whisker movement, neural activity, and sensation of touch. We photostimulated layer 4 activity in single barrels in closed-loop with whisking. Mimicking touch-related neural activity caused illusory perception of an object at a particular location, but scrambling the timing of spikes over one whisking cycle (tens of milliseconds) did not abolish the illusion, indicating that knowledge of instantaneous whisker position is unnecessary for discriminating object locations. Illusions were induced only during bouts of directed whisking, when mice expected touch, and in the relevant barrel. Reducing activity biased behavior consistent with a spike count code for object detection at a particular location. Our results show that mice integrate coding of touch with movement over timescales of a whisking bout to produce perception of active touch

Procedures for behavioral experiments in head-fixed mice.

The mouse is an increasingly prominent model for the analysis of mammalian neuronal circuits. Neural circuits ultimately have to be probed during behaviors that engage the circuits. Linking circuit dynamics to behavior requires precise control of sensory stimuli and measurement of body movements. Head-fixation has been used for behavioral research, particularly in non-human primates, to facilitate precise stimulus control, behavioral monitoring and neural recording. However, choice-based, perceptual decision tasks by head-fixed mice have only recently been introduced. Training mice relies on motivating mice using water restriction. Here we describe procedures for head-fixation, water restriction and behavioral training for head-fixed mice, with a focus on active, whisker-based tactile behaviors. In these experiments mice had restricted access to water (typically 1 ml/day). After ten days of water restriction, body weight stabilized at approximately 80% of initial weight. At that point mice were trained to discriminate sensory stimuli using operant conditioning. Head-fixed mice reported stimuli by licking in go/no-go tasks and also using a forced choice paradigm using a dual lickport. In some cases mice learned to discriminate sensory stimuli in a few trials within the first behavioral session. Delay epochs lasting a second or more were used to separate sensation (e.g. tactile exploration) and action (i.e. licking). Mice performed a variety of perceptual decision tasks with high performance for hundreds of trials per behavioral session. Up to four months of continuous water restriction showed no adverse health effects. Behavioral performance correlated with the degree of water restriction, supporting the importance of controlling access to water. These behavioral paradigms can be combined with cellular resolution imaging, random access photostimulation, and whole cell recordings

A lick/no-lick object location discrimination task for head-fixed mice [23].

<p>A. Block-diagram of the possible events in a single trial. B. Schematic representation of event timing during a single lick trial. C. Schematic representation of the behavioral contingency. Mice had to lick for a water reward when the pole was in a posterior position and hold their tongue when the pole was in an anterior position. In some experiments, the contingency of the pole positions was reversed. D. Behavioral data from one session. The abscissa shows the time from trial start. Lick and no-lick trials are randomly interleaved. The pink ticks indicate licks. The red ticks indicate the first licks after the grace period. The blue bars correspond to the open times of the reward water valve. The horizontal green and red bars indicate whether each trial is correct or incorrect, respectively. The dark gray shading indicates that the pole is fully descended and in reach of the whiskers.</p

Mice with one or more indicators of stress or pain are placed on detailed health assessment.

<p>Activity levels, grooming, and indicators of eating and drinking are scored daily in a health assessment sheet. The total aggregate health score determines if mice are supplied with additional water (see flowchart in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088678#pone-0088678-g002" target="_blank">Figure 2</a>).</p

Mouse weight and health during water restriction.

<p>All mice were trained in a lick/no-lick object location discrimination task using a single whisker (same mice as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088678#pone-0088678-g002" target="_blank">Figures 2</a> & <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088678#pone-0088678-g003" target="_blank">3</a> of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088678#pone.0088678-OConnor2" target="_blank">[18]</a>). Rewards consisted of approximately 8 µl of water per trial. A. Experimental time-course for one example mouse, from the beginning of water restriction to the end of electrophysiological recordings. An 85 day old mouse (25.4 g) was put on water restriction for eight days, followed by training (starting on day 9) and recording (starting on day 28). B. Body weight as a function of time. Same mouse as in A. The dashed line indicates 30% weight loss. C. Water consumed per day. After start of training mice mostly received their water during the training session. A larger number of correct trials will lead to more consumed water. Same mouse as in A. D. Health score as a function of time. A health score larger than 3 (dashed line) triggers more detailed evaluation and possibly water supplements. Same mouse as in A. E. Experimental time-course for a group of 5 mice. Same format as A. F. Average body weight of 5 mice (black line) and 2 mice with free access to water (grey line). Shading indicates standard deviation. Experimental time-course for all mice was similar, but not identical to A. G. Average water consumed. H. Average health score.</p