Mechanisms underlying a thalamocortical transformation during active tactile sensation
[['Thalamocortical circuits represent model systems for multi-area computations [1] .', 'Sensory information enters the cortex through the thalamus .', 'Transformations in thalamocortical circuits have mostly been studied in anesthetized animals with passive sensory stimuli [2–8] or with artificial whisking [9] .', 'In the somatosensory system these studies have revealed subtle differences in receptive field structure across neurons in the thalamocortical circuit [2–4] .', 'However , active sensation in awake animals involves dynamic interactions with the world , such as saccades [10] , palpation with the digits of the hand [11] , or movements of the whiskers on the face of rodents [12–14] .', 'During active sensation , movement of the sensors produces ‘reafferent’ signals , whereas interactions with the world generate ‘exafferent’ signals .', 'During haptic exploration , movement activates peripheral sensors to produce reafference and touch generates exafference [15–21] .', 'The brain needs to parse these different signals for perception [13] .', 'During active sensation , movement attenuates the transmission of certain sensory signals to the cortex [22–24] .', 'Tactile suppression is thought to enhance perception of salient events that cannot be predicted based on movement .', 'Tactile suppression is an example of adaptive filtering [25 , 26] , which is critical for low-noise encoding of relevant sensory stimuli .', 'Here we identify the mechanisms of adaptive filtering in the thalamocortical circuit of the mouse whisker system .', 'Whisker touch and movement are transduced by mechanosensory afferents in the whisker follicle .', 'Information then flows through the trigeminal ganglion , to the brainstem , thalamus ( barreloids in the ventral posterior medial thalamic nucleus , VPM ) and terminates in the primary somatosensory cortex ( vS1 ) .', 'The main target of VPM axons is the Layer 4 ( L4 ) barrels in vS1 .', 'The microcircuit of each L4 barrel is mostly contained within the barrel , and the connections between specific cell types within the barrel have been mapped: L4 excitatory neurons and L4 fast-spiking , parvalbumin ( PV ) -expressing GABAergic interneurons ( FS ) are connected within type and across types [27 , 28] .', 'Apart from neuromodulation , the only known long-range input to L4 originates in VPM [29–31] .', 'VPM excites all L4 neuron types , and L4 FS neurons inhibit the excitatory neurons to implement feedforward inhibition [32–35] .', 'Cell type-specific recordings from VPM , L4 excitatory [36] and L4 FS neurons [37] uncovered a fundamental computation performed by L4 barrels .', 'Neurons in VPM respond to touch , but they also increase their activity during whisker movement ( ‘whisking’ ) [17–21] .', 'L4 FS neurons have nearly identical dynamics as VPM neurons .', 'In contrast , L4 excitatory neuron spikes are strongly coupled to touch , but respond only weakly to whisking [36] .', 'L4 microcircuits therefore transmit touch signals and suppress reafferent signals generated by whisking .', 'These observations indicate that the thalamocortical circuit accentuates salient tactile information by suppressing signals related to self-movement .', 'Multiple observations regarding the L4 circuit remain to be explained [37] .', 'First , the circuit suppresses self-movement signals but transmit touch signals .', 'From a theoretical perspective , this selective filtering violates the linear response expected from theories of strongly coupled cortical networks [38 , 39] .', 'Second , whereas the baseline spike rates of VPM and L4 FS neurons are substantial during baseline conditions and more than double during whisking , the spike rate of L4 excitatory neurons is very low at baseline and does not increase during whisking .', 'Third , when an inhibitory opsin ( halorhodopsin ) is photostimulated in L4 FS neurons , the spike rates of FS neurons decrease and the spike rates of L4 excitatory neurons increase [37] .', 'Although this result is naively expected , it contradicts the "paradoxical effect" predicted from models of neural circuits that are stabilized by inhibition and from models of strongly-coupled networks [40–42] .', 'According to these models , both inhibitory and excitatory neurons should respond with increased spike rates at modest levels of inactivation of inhibitory neurons [41] .', 'To understand the mechanisms underlying these experimental observations we constructed and analyzed a conductance-based model of the L4 circuit .', 'The synaptic circuits of L4 of the barrel cortex have been studied in great detail in brain slices [27–29 , 43–46] .', 'These measurements allowed us to constrain the numbers of neurons , neuronal properties , the patterns of connectivity , and the average synaptic strengths in the model .', 'We set parameter values near values extracted from these measurements .', 'This "reference set of parameters" was adjusted over a restricted range , such that the model circuit displayed dynamics similar to the actual L4 circuit .', 'We then varied parameters to explore their roles in controlling system dynamics .', 'We studied how the model network responds to thalamic input at baseline , during whisker movement and during touch .', 'We used the model to disentangle the roles of feedforward synaptic connections from the thalamus and recurrent intracortical connections in shaping L4 dynamics .', 'The model revealed an important role for synaptic delays , fast synaptic kinetics , and inhibitory and excitatory conductance strengths in shaping the L4 responses during behavior .'], ['We first summarize recordings made in VPM and in L4 from excitatory and FS GABAergic interneurons in mice performing an object location discrimination behavior ( Fig 1a and 1b ) .', 'Head-restrained mice had to localize a vertical pole with their whiskers for a water reward [47 , 48] .', 'Whisker movement and touch were tracked on millisecond time scales with high-speed videography [49 , 50] ( Fig 1a ) .', 'Recordings were made with extracellular silicon probe recordings in VPM [37] , and loose-seal cell-attached and whole cell recordings in L4 [36 , 37 , 51] .', 'VPM neurons have significant spike rates ( mean , 5 . 1 Hz ) , even in the absence of whisker movement and touch ( Table 1; Fig 1c and 1d; see Figs 2 and 3 for representative examples ) [37] .', 'VPM neurons were also highly sensitive to whisking ( Fig 2b and 2c ) [17 , 18 , 21] .', 'Spike rates increased after whisking onset ( average , 3-fold; Fig 1c and 1d ) .', 'Given that mice whisk at approximately 15 Hz under these conditions [36] , the spike rates during whisking correspond to approximately one spike per whisking cycle , on average .', 'The modulation depths with whisking amplitude and phase ( Supplementary Figure 2 in [37] ) were similar to published studies in rats [18] .', 'VPM neurons also responded to active touch with a brief increase in spike rate ( 0 . 6 spikes per touch ) ( Fig 1e ) .', 'The peri-stimulus time histogram ( PSTH ) aligned to touch onset shows a sharp peak in spike rate , with short latency after touch ( 3 . 1±0 . 6 ms ) and brief duration ( 2 . 9±1 . 7 ms ) ( Fig 2i , 2n and 2s ) .', 'Exafferent touch signals and reafferent whisking signals were multiplexed in individual VPM neurons ( Fig 2 ) .', 'The modulation of L4 FS neurons to touch and whisker movement were similar to VPM neurons ( Figs 1c–1e , 2 and 3 ) .', 'L4 FS neurons increased their spike rate after onset of whisking ( average , 3-fold ) .', 'L4 FS neurons responded reliably to touch .', 'The response onset had slightly longer latency ( 5–15 ms ) and longer duration ( 2–15 ms ) than for VPM neurons .', 'The increased latency is expected from the propagation time delay between VPM and L4 ( 2 ms ) [37 , 53] .', 'The responses of L4 excitatory neurons differed profoundly from those of VPM and L4 FS neurons [36] ( Figs 1c–1e and 3 ) .', 'The baseline spike rate of L4 excitatory neurons was much lower and did not increase significantly after onset of whisking .', 'The response after touch onset occurred with longer latency and longer duration than for the VPM neurons , and similar to L4 fast-spiking neurons ( Fig 1e ) .', 'The transformation performed by L4 circuits can be summarized by three main findings ( Fig 1c–1e; Table 1 ) .', 'First , baseline spike rates are high in VPM and L4 FS neurons , and low in L4 excitatory neurons .', 'Second , VPM and L4 FS neurons elevate their spike rates further during periods of whisker movement , whereas L4 excitatory neuron spike rates remain low .', 'The spike rates of VPM and L4 FS neurons during periods of whisking are more than one order of magnitude larger than those of L4 excitatory neurons .', 'Third , all three neuron types respond to touch reliably ( Table 1; Fig 1e ) .', 'The touch responses of the three neuronal populations are the integrals under the curve in Fig 1e .', 'The average touch response of L4 excitatory neurons ( 0 . 3 spikes/touch ) is about half of the average touch response of VPM neurons , whereas the spike rates of L4 excitatory neurons are lower than those of VPM neurons by a factor of 20–30 .', 'The VPM response is more transient than the L4E response .', 'The L4 circuit therefore performs a behaviorally relevant computation by propagating information related to external stimuli and suppressing responses to whisker movement , a predictable stimulus .', 'The dynamics of FS neurons during whisker movement suggest that these neurons suppress whisker movement-related activity in L4 excitatory cells .', 'Consistent with this view , optogenetic reduction of activity in a subset of L4 FS neurons expressing the light-gated , inhibitory chloride pump eNphHR3 . 0 ( L4I-Hr+ ) unmasks movement-related activity in L4 excitatory neurons [37] ( Fig 4a and 4b ) .', 'Photostimulation of L4I-Hr+ neurons decreases the activity in L4 FS neurons on average and increases the activity in L4 excitatory neurons .', 'The suppression of L4I-Hr+ neurons causes an increase in response in L4 excitatory neurons during whisker movements ( Fig 4c ) and an overall increase in the number of spikes per touch ( Fig 4d ) .', 'This result implies that suppression of whisking response in L4 excitatory neurons involves inhibition from FS neurons .', 'It remains unclear , however , why touch responses in L4 excitatory neurons are not suppressed as well .', 'Membrane potential measurements with whole-cell recordings provide additional clues about mechanisms [37] .', 'L4 excitatory neurons depolarize substantially ( 6 mV ) and briefly after touch .', 'Touch-related inhibitory input ( from FS neurons ) to L4 excitatory neurons is delayed by approximately 0 . 5 ms with respect to excitatory input ( Fig 1e ) .', 'It has been proposed that this short ‘window of opportunity’ [2 , 35] allows L4 excitatory neurons to spike after touch , typically with one spike [36] , before inhibition suppresses L4 excitatory activity .', 'During whisker movement , excitation is matched by inhibitory input , keeping the L4 excitatory neuron membrane potential well below spike threshold .', 'Suppression of self-movement signals is therefore implemented by inhibition within L4 .', 'Yu et al . [37] also showed that activating halorhodopsin in L4I-Hr+ neurons during whisker movement suppresses activity in these neurons .', 'This result poses a new question .', 'The major cellular effect of activation of halorhodopsin is hyperpolarization [54 , 55] .', 'Theoretical investigations of cortical circuits , consisting of recurrently connected excitatory neurons stabilized by inhibitory neurons , have investigated the effects of hyperpolarization of inhibitory neurons [41] .', 'Over a large range of conditions , hyperpolarization of inhibitory neurons leads to increased spike rates in both excitatory and also inhibitory neurons .', 'This "paradoxical effect" is common to multiple network regimes , including networks with strong synaptic conductances that fire in an asynchronous manner [40] and networks with moderate synaptic conductances , if the excitatory-to-excitatory synaptic coupling gEE is sufficiently strong [41] .', 'Does the L4 circuit lie outside of the modeled parameter regimes , or can other factors explain the lack of paradoxical effect ?', 'To explain the dynamical response of the L4 circuits to thalamic input , and to understand the roles of feedforward and recurrent connections , we constructed and analyzed a detailed computational model of the L4 circuit .', 'L4 excitatory and L4 FS neurons make connections within type and across types with high connection probability ( Fig 5a; Table 2 ) .', 'The thalamocortical circuit of the rodent whisker system is one of the most extensively studied mammalian circuits .', 'In vitro and in vivo studies have measured many fundamental parameters that are required to construct a realistic computational model of the thalamocortical circuit .', 'Our model circuit consists of 1600 L4 excitatory ( E ) neurons and 150 L4 FS ( I ) neurons [28] receiving input from 200 VPM ( T ) neurons ( Fig 5a ) .', 'When referring to modeling results we denote VPM neurons as T , L4 excitatory neurons as L4E , and GABAergic interneurons as L4I ( Fig 5b and 5c ) .', 'Since we know little about non-FS GABAergic interneurons during behavior we model only one inhibitory neuronal population .', 'Cortical neurons were simulated using a conductance-based model with a single compartment per neuron [58 , 59] .', 'Synaptic conductances are denoted as gαβ , where β is the presynaptic population and α is the postsynaptic population ( Fig 5a ) .', 'Model parameters , including numbers of neurons , unitary synaptic conductance , connection probability , resting potential , and membrane time constants are based on neurophysiological measurements in brain slices [27 , 28 , 56 , 60] with small adjustments ( see Methods ) .', 'VPM provides the only external input to the model circuit , with connectivity estimates based on in vivo and brain slice measurements [34 , 53] .', 'Spike trains of T neurons were modeled as independent inhomogeneous Poisson processes with a generating function FT representing thalamic activity during quiescence , whisking or whisking and touch ( Fig 5d; see Methods ) .', 'FT ( t ) =AT[1+BTsin ( 2πtτw+ϕ ) ]+CTτcΘ ( t−nτw−tc ) Θ ( nτw+tc+τc−t )', '( 1 )', 'where AT is the spike rate averaged over a whisker movement cycle , BT is the modulation depth , and CT is the number of spikes per touch , τw is the whisking period , tc is the time of touch onset within a whisking cycle , n is the cycle number , and Θ is the Heaviside function .', 'During whisker movements AT increases above a baseline , with sinusoidal modulation phase-locked to a single preferred phase ϕ .', 'Touch is represented by adding a rectangular function at touch onset t = tc ( with respect to the whisking cycle ) , stretched over τc = 3 ms with an integral of CT = 0 . 6 spikes per touch ( Eq 1 ) .', 'Correlations between thalamic neurons beyond those generated by Eq 1 have not been measured and were thus not modeled .', 'The population-average spike rate of neurons within a population over whisking cycles is denoted by να ( α = T , E , I ) , and the population-average spiking response to touch is denoted by Rα .', 'Note that without touch , νT = AT .', 'A ‘reference parameter set’ is described in Methods and used unless otherwise stated .', 'We start by simulating the model for whisking without touch ( thalamic spikes per touch , CT = 0 ) .', 'L4E spike rates were low ( νE < 1 Hz ) compared to those of L4I neurons ( Fig 6a and 6b ) .', 'The average rates νE and νI depend on AT ( the population- and time-average thalamic spike rate during whisking only ) but are almost independent of the modulation depth BT ( Eq 1 ) .', 'Except near threshold , νI was proportional to AT , in consistent with theoretical results for large and sparse neuronal networks with strong synapses , in which strong excitation is compensated by inhibition ( balanced networks ) [38] .', 'The L4E spike rate νE increased linearly with AT , but with a much smaller slope compared to νI .', 'The linearity of the νI-AT curve fit empirical observations ( Table 1 , Fig 1c; spike rates of both VPM and L4 FS neurons more than double in the transition from non-whisking to whisking ) .', 'The average spike rate of L4 excitatory neurons , νE , is low [37] .', 'During transition from non-whisking to whisking , the average spike rate of L4 excitatory neurons barely changes ( from 0 . 4 Hz to 0 . 6 Hz; Table 1 ) .', 'The spike rates of L4E neurons in our model show similar dynamics .', 'L4E neurons fire at most one spike each after touch , whereas L4I neurons fire more than one ( up to two ) spikes per touch ( Fig 6c and 6d ) .', 'The synaptic delay , τdelayEI , is a critical factor in determining the strength of the touch response ( Fig 7a ) .', 'For τdelayEI=0 , the average normalized response of L4E neurons after touch , RE , is small ( RE = 0 . 01 spikes/touch ) , and L4I neurons fire RI = 0 . 64 spikes/touch .', 'Strong inhibition overwhelms excitation before L4E neurons have a chance to spike .', 'The delay between the appearance of excitation and feed-forward inhibition in the L4E neuron has been termed ‘window of opportunity’ [2 , 35 , 61–63] .', 'This ‘window of opportunity’ increases with τdelayEI , but is not equal to it because it is affected by the durations of thalamocortical synaptic process and the time needed for the L4I to fire in response to the brief and strong thalamic input .', 'For a more realistic value , τdelayEI=0 . 85ms , L4E and L4I fire 0 . 34±0 . 24 and 1 . 3±0 . 07 spikes/touch respectively , similar to experimental measurements ( Table 1 ) .', 'The touch responses for L4E and L4I ( Fig 6d ) are narrower than those seen in real data ( Fig 1e ) .', 'The detailed shapes of the modeled responses depend on network parameters ( e . g . , see Fig 8d–8i below ) .', 'In addition , heterogeneity among neurons , which was not modeled here , is expected to broaden the responses .', 'The response of the network to touch depends on the time-course of synaptic conductances .', 'Without touch signals , L4E neurons are inhibited by L4I neurons and spike at low rates ( Fig 6a and 6b ) .', 'Touch produces strong , brief and synchronous thalamic excitation ( Fig 1e ) , which depolarizes L4E neurons and enables them to fire before inhibition terminates the response .', 'This mechanism demands that excitatory synaptic conductance changes at thalamocortical synapses are brief .', 'Touch responses of L4E and L4I neurons decrease with tAMPA , the decay time of AMPA-mediated EPSCs ( Fig 7b ) .', 'Substantial touch responses in L4E neurons require tAMPA < 2–3 ms , consistent with the brief excitatory conductances measured at thalamocortical synapses [60] .', 'Touch responses of L4E and L4I neurons increased with the strength of the thalamic touch signal ( Fig 7c ) , consistent with graded responses to touch strength measured in L4E neurons [36] .', 'The response saturates at one and two spikes/touch for L4E and L4I respectively; this is in part due to the intrinsic properties of these neurons , which preclude them from firing more spikes in response to brief thalamic input .', 'We have shown that a L4 network with parameters similar to experimentally determined values can replicate major experimental findings .', 'L4E excitatory neurons exhibit low baseline activity , low activity in response whisker movement , and significant response to touch .', 'However , during behavior the responses of L4 excitatory neurons is not all-or-none: L4 excitatory neurons are tuned to multiple sensory features including touch direction , intercontact interval , strength of touch , and likely other factors [36] .', 'Our simulation results indicate that L4E and L4I neurons respond to touch in a graded manner and robustly respond to touch at different whisking amplitudes .', 'Specifically , our simulations show that RE and RI decrease with AT ( Fig 7d ) for all parameter values consistent with the data .', 'Mechanistically , increasing thalamic input causes larger inhibition in the cortical circuit that decreases touch response .', 'Future experiments could test this model prediction .', 'The model allows us to explore how specific synaptic connections within L4 contribute to fine-tuning L4 function .', 'These connections currently cannot be specifically manipulated , making them difficult to evaluate experimentally .', 'Recurrent excitation ( gEE ) can only be tuned over a limited range before runaway excitation is triggered ( for about gEE~0 . 4 mS/cm2 ) , even during baseline or whisking ( Fig 8a and 8b ) .', 'The conductance gEE does not modify the slope of the νE-AT curve ( Fig 8b ) , but shifts this curve upward .', 'gEE amplifies touch responses RE and RI ( Fig 8c ) [64] , mostly by increasing the duration of touch responses ( Fig 8d–8i ) .', 'The dynamics of L4E neurons are shaped in subtle ways by L4 inhibition .', 'Fig 9 shows how parameters involving inhibition ( gII , gEI , gIE ) affect circuit responses , while holding the other parameters at their reference values .', 'Intracortical excitation of inhibition ( gIE ) is necessary to prevent runaway excitation , and thus keeps the spike rates of neurons in the network moderate ( Fig 9a and 9b ) .', 'Reducing gIE shifts the νE-AT curve during whisking upward , without modifying its slope .', 'For touch responses , gIE shifts the touch-response RE-CT curve to the right while decreasing the slope of the linear section of this sigmoid ( Fig 9c ) .', 'Inhibition to L4E neurons ( gEI ) is also required to prevent runaway excitation ( Fig 9d and 9e ) .', 'For low values of gEI ( but above values for runaway excitation ) and large values of gII ( Fig 9g and 9h ) , νE scales linearly with thalamic input AT .', 'This linear scaling is known from balanced networks with strong synaptic coupling [38 , 40] .', 'The situation is different for sufficiently strong inhibition ( relatively high gEI , moderate gII ) , where the response of L4E neurons to slowly-varying thalamic input during whisking , νE , is independent , and even decreasing , with AT ( Fig 9e and 9h ) .', 'For small enough gII , L4E are quiescent except of near firing threshold .', 'In addition , low gET and large gIT values are critical to keep νE low for all whisker movement amplitudes ( Fig 10a , 10b , 10d and 10e ) .', 'Furthermore , these low values νE are nearly independent of AT .', 'This regime is consistent with experimental data , where L4 FS neurons increase their spike rate with whisker movement , whereas L4 excitatory neuron spike rates remain low ( Fig 1d , Table 1 ) .', 'Increasing values of gEI and gII shifts the touch-response RE-CT curve to the right and to the left respectively ( Fig 9f and 9i ) .', 'In addition , gEI , but not gII , decreases the slope of the linear section of this sigmoid ( Fig 9f ) .', 'Similarly , gET and gIT shift the RE-CT curve to the left and to the right respectively ( Fig 10c and 10f ) .', 'Yu et al . ( [37] , Fig 8 , supplementary Fig . 13 ) expressed halorhodopsin in FS neurons in L4 and explored how the responses of excitatory and FS neurons in L4 under baseline conditions , whisking and touch vary under halorhodopsin activation .', 'L4 excitatory neurons increase their spike rates and L4 FS neurons decrease their spike rates , both during baseline and whisking conditions .', 'Similarly , L4 excitatory neurons increase their spiking responses to touch and L4 FS neurons decrease their responses .', 'The halorhodopsin expression levels in FS neurons likely varied widely across individual neurons [65] .', 'We therefore divided the L4I neurons in the model into hr expressing neurons and non-expressing neurons ( Hr+ and Hr- respectively ) .', 'The fraction of Hr+ neurons among L4I neurons is denoted by fhalo .', 'Manipulation of the components of neural networks can cause complex and counterintuitive change in network dynamics ( ‘paradoxical’ response; [40–42 , 66]: injecting negative current to all inhibitory neurons in a network , that includes spiking excitatory neurons , increases the average spike rates in inhibitory neurons ) .', 'If the synaptic conductance strengths are moderate and the excitatory-to-excitatory synaptic conductance is above a certain level , injecting negative current to the inhibitory neurons causes the spike rates of excitatory neurons νE to increase , and as a result the network dynamics causes the spike rates of inhibitory neurons νI to increase as well [41 , 42 , 66] .', 'Alternatively , if synaptic conductances are strong and the excitatory population is active , the condition that the activity of excitatory neurons should be moderate ( non-zero and not epileptic ) causes νI to increase under negative current injection to inhibitory interneurons [40] .', 'The major effect of halorodopsin is to hyperpolarize FS neurons ( see Methods ) .', 'Therefore , if all inhibitory neurons in the model are assumed to express halorodopsin equally ( fhalo = 1 ) , halorhodopsin activation will cause both L4E and L4I neurons to increase their spike rates .', "We simulated the response of L4E and L4I neurons to whisking for fhalo = 1 without and with halorhodopsin activation , and replicated the 'paradoxical effect': the average responses of L4E and L4I neurons to whisking , νE and νI , increase with simulated light activation .", 'The simulation result for L4I neurons is in contrast to experimental observations showing that most L4 FS neurons increase their spike rates .', 'This discrepancy is resolved if we assume fhalo = 0 . 5 .', 'For this value , spike rates during whisking increase , on average , for L4E neurons ( Fig 11a ) , decrease for almost all L4I-Hr+ neurons ( Fig 11b ) , and increase for inhibitory neurons that do not express halorhodopsin ( L4I-Hr- ) .', 'The spike responses of L4E neurons to touch increase moderately for fhalo = 0 . 5 , especially for neurons with low baseline response ( Fig 11c and 11e ) , whereas the spike response of L4I-Hr- inhibitory neurons remains about the same and that of L4I-Hr+ increases somewhat ( Fig 11d and 11f ) .', 'These dynamics stem from the fact that the initial response to touch , before feedforward inhibition hyperpolarizes the neuron , is determined mainly by feedforward excitation .', 'While halorhodopsin activation hyperpolarizes inhibitory neurons and increase the difference between spiking threshold and their membrane potentials before touch onset , the driving force of excitation ( the difference between the reversal potential of APMA-mediated excitation and their membrane potential ) increases as well and enhances excitation .', 'The reduction in response in L4I-Hr+ neurons partially disrupts whisker movement suppression in L4E neurons , and increases the slope of the νE-AT curve ( Fig 11g ) .', 'During photostimulation of L4I-Hr+ neurons , their response to increasing whisker movements becomes shallower ( Fig 11h ) .', 'This change in response of L4-Hr+ neurons in turn causes a steeper response to whisker movements in L4E neurons ( Fig 11g ) .', 'Finally we explored how the previous results depend on fhalo .', 'The mean touch responses for all neuronal populations is non-monotonic: it increases when fhalo increases from zero , and then decreases for higher values ( Fig 12a ) .', 'For our parameter set , simulated halorhodopsin activation increases touch response of L4I-Hr+ neurons ( in comparison with no activation ) for fhalo < 0 . 78 .', 'During whisker movements , the spike rates of all neuronal populations increases with fhalo , and the average spike rate of L4I-Hr+ neurons during simulated halorhodopsin activation is lower than that with no activation for fhalo < 0 . 74 ( Fig 12b ) .', 'Interestingly , L4-Hr+ neurons reduce their spiking response to touch with halorhodopsin activation for large fhalo , but reduce their spike rates in response to whisking for small fhalo .', 'For small fhalo , the spike rates of L4-Hr+ neurons in response to whisking are low ( Fig 12b ) , because this small group of neurons is both suppressed by halorhodopsin activation and inhibited by the majority of L4-Hr- neurons .', 'In contrast , the spiking responses to touch of L4-Hr+ and L4-Hr- neurons are similar and to the responses of L4I neurons without halorhodopsin activation .', 'This behavior is obtained because touch responses are transient and are reduced by the global level of inhibition before touch .', 'For low fhalo , population inhibition is similar to inhibition without halorhodopsin activation .'], ['We compared our model to recordings from VPM projection neurons ( Figs 1–3 ) , L4 FS neurons , and L4 excitatory neurons [37] during performance of an object localization task , while whisker movements and touches were tracked with millisecond time scale precision [36 , 48 , 51 , 67] .', 'VPM and L4 FS neurons respond to whisker movement and touch , whereas L4 excitatory neurons responded almost exclusively to touch .', 'During whisking , excitation to L4 excitatory neurons from VPM is only slowly modulated in time and is matched by feedforward and feedback inhibition from L4 FS neurons , which cancels self-movement signals .', 'In contrast to the self-movement input , touch-related inputs are brief and synchronous ( Fig 1e ) .', 'Our model establishes the conditions for a ‘window of opportunity’ , in which L4 excitatory neurons can fire before inhibition catches up [35 , 62 , 64 , 68 , 69] .', 'The I-to-E synaptic delay τdelayEI must be sufficiently large ( say , ~1 ms ) and the AMPA-mediated synaptic conductances should be brief ( Fig 8a and 8b ) .', 'The brief duration of this window diminishes the chance of L4 excitatory neurons to fire multiple spikes upon touch , producing low trial-to-trial variability in spike count after touch [36 , 70] .', 'During baseline and whisking , L4 FS neurons spike on average at tens of Hz , while L4 excitatory neurons spike on average below 1Hz .', 'The average spike rates of VPM and L4 FS excitatory neurons , νT and νI , more than double after whisking onset , while the average spike rates of L4 excitatory neurons remains below 1 Hz .', 'Low spike rates of L4E neurons require particular combinations of synaptic parameters: gIE , gEI and gIT need to be strong , and gEE , gII and gET should be weak ( Figs 8c , 9 , 10 ) .', 'If gET is too small or gIT is too large , L4E neurons will be quiescent .', 'Similarly , L4E neurons will not spike if gII is too small ( Fig 9h ) .', 'For moderate gII , νE can remain about constant with AT .', 'The response of L4E neurons to touch , RE , increases with CT ( the thalamic response to touch ) in a sigmoid manner , because the intrinsic properties of L4E neurons in the model impose a refractory period that in general precludes rapid firing of more than one spike .', 'Synaptic parameters that increase νE during whisking shift the sigmoid function leftward , and those that decrease νE shift that function rightward ( Figs 9 and 10 ) .', 'In our model , the inhibitory neuronal population spikes at significant rates ( 20–40 Hz ) even at baseline .', 'This allows the number of spikes/touch RE to be smaller than one and vary gradually with input strength ( Fig 9f ) .', 'As a result , stronger thalamic responses to touch , for example as a result of stronger touch , generates proportionally stronger L4E responses , consistent with experimental results ( Fig 1e ) [36] .', 'In response to halorhodopsin activation , L4 excitatory neurons increase their average spike rates and L4-Hr+ FS neurons reduce their spike rates [37] .', 'The model does not replicate this behavior if halorhodopsin is "expressed" in all inhibitory neurons , because νI increases with simulated photostimulation .', 'This discrepancy is resolved if a sufficient number of L4I neurons lack halorhodopsin ( or express halorhodopsin at very low levels ) ( Figs 11 and 12b ) .', 'With photostimulation , L4-Hr+ I neurons decrease their spike rates if their fraction among I neurons , fhalo , is below a certain value ( 0 . 74 in Fig 12a ) , while L4-Hr- FS neurons increase their spike rates .', 'Future work is needed to determine whether including more populations of inhibitory interneurons , for example somatostatin-positive neurons [71] will generate parameter regimes in which L4-Hr+ neurons decrease their responses to both whisking and touch upon light activation .', 'The development of powerful computing resources has enabled simulations of entire cortical columns of diverse neurons with realistic morph
['Introduction', 'Results', 'Discussion', 'Materials and methods']
['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 .']
['We study how information is transformed between connected brain areas: the thalamus , the gateway to the cortex , and layer 4 ( L4 ) in cortex , which is the first station to process sensory input from the thalamus .', 'When mice perform an active object localization task with their whiskers , thalamic neurons and inhibitory fast-spiking ( FS ) interneurons in L4 encode whisker movement and touch , whereas L4 excitatory neurons respond almost exclusively to touch .', 'To explain these observations , we constructed a computational model based on measured circuit parameters .', 'The model reveals that without touch , when thalamic activity varies slowly , strong inhibition from FS neurons prevents activity in L4 excitatory neurons .', 'Brief and strong touch-induced thalamic activity excites both excitatory and FS neurons in L4 .', 'FS neurons inhibit excitatory neurons with a delay of approximately 1 ms relative to ascending excitation , allowing L4 excitatory neurons to spike .', 'Our results demonstrate that cortical circuits exploit synaptic delays for fast computations .', 'Similar mechanisms likely also operate for rapid stimuli in the visual and auditory systems .']
['action potentials', 'medicine and health sciences', 'neural networks', 'nervous system', 'membrane potential', 'social sciences', 'electrophysiology', 'neuroscience', 'animal anatomy', 'interneurons', 'zoology', 'computer and information sciences', 'animal cells', 'neural pathways', 'touch', 'animal physiology', 'cellular neuroscience', 'psychology', 'neuroanatomy', 'cell biology', 'vibrissae', 'anatomy', 'physiology', 'neurons', 'biology and life sciences', 'cellular types', 'sensory perception', 'neurophysiology']