Complementary control of sensory adaptation by two types of cortical interneurons — TEI-tagged view

NatanpersName, BrigugliopersName, Mwilambwe-TshilobopersName, JonespersName, AizenbergpersName, GoldbergpersName, GeffenpersName, KingpersName (2015date). “Complementary control of sensory adaptation by two types of cortical interneurons.” eLifetitle·j.

Object of study — which cortical cells make a neuron respond less to a frequent toneterm than to a rare one, and by what mechanism each does it

Research question — whether interneuronterm types that are hypothesized to have complementary functions actually drive changes in dynamic auditory processing, which had not been established

Contribution — two interneuronterm types that both amplify the same adaptationterm indexterm, one by uniform inhibition and one by tone-selective suppressionterm

Full text — tagged

Complementary control of sensory adaptationterm by two types of cortical interneuronsterm eLife 4 :e09868.

https://doi.org/10.7554/eLife.09868 Copy to clipboard Download BibTeX Download .RIS Abstract eLife digest Introduction Results Discussion Materials and methods References Article and author information Metrics Reliably detecting unexpected sounds is important for environmental awareness and survival. By selectively reducing responses to frequently, but not rarely, occurring sounds, auditory cortical neurons are thought to enhance the brain's ability to detect unexpected events through stimulus-specific adaptationterm (SSAterm). The majority of neurons in the primary auditory cortexterm exhibit SSAterm, yet little is known about the underlying cortical circuits. We found that two types of cortical interneuronsterm differentially amplify SSAterm in putative excitatoryterm neurons. Parvalbumin-positive interneuronsterm (PVsterm·def) amplify SSAterm by providing non-specific inhibition: optogeneticterm·mth suppressionterm of PVsterm·def led to an equal increase in responses to frequent and rare tonesterm. In contrast, somatostatin-positive interneuronsterm (SOMsterm·def) selectively reduce excitatoryterm responses to frequent tonesterm: suppressionterm of SOMsterm·def led to an increase in responses to frequent, but not to rare tonesterm. A mutually coupled excitatory-inhibitory network modelterm·mth accounts for distinct mechanisms by which cortical inhibitory neurons enhance the brain's sensitivity to unexpected sounds.

https://doi.org/10.7554/eLife.09868.001 In everyday life, we are often exposed to a mix of different sounds. An essential task for our brain is to separate the important sounds from the unimportant ones. For example, stepping out onto a busy street, you may at first be very aware of the noise of traffic. Later, you may start to ignore the din and instead only notice sounds that break the monotony: a honking car horn or maybe a stranger's voice. This is because the neurons in the auditory pathway respond differently to common and rare sounds. In particular, excitatoryterm neurons in the region termed the ‘auditory cortexterm’ send fewer nerve impulses in response to frequent sounds, but respond vigorously to rare sounds. This phenomenon is called ‘stimulus-specific adaptationterm’, but it is not known exactly which neurons in this brain region enable this process to occur.

Now, NatanpersName et al. have combined different cutting-edge neuroscience techniques to identify the circuit of brain cells that drives this stimulus specific adaptationterm. A technique called optogeneticsterm·mth was used to effectively ‘turn off’ each of two kinds of inhibitory neuron in the auditory cortexterm of mice, by exposing the brain to colored light from a laser.

NatanpersName et al. found that both kinds of inhibitory neuron amplified stimulus-specific adaptationterm, but via different mechanisms. One of these neuron types, called ‘parvalbumin-positive interneuronsterm’, exerted a general effect on excitatoryterm neurons and suppressed responses to both frequent and rare sounds As the responses to rare sounds started off greater than the responses to frequent sounds, suppressing both by an equal amount actually led to an increase in the relative difference between them. On the other hand, the second kind of inhibitory neuron, called ‘somatostatin-positive interneuronsterm’, only reduced the excitatoryterm neurons' responses to frequent sounds; these neurons had no effect on responses to rare noises.

Future studies will test how specific adaptationterm in different contexts can help us to behaviorally detect rare sounds while ignoring common ones, and search for the circuits beyond the auditory cortexterm that support hearing in complex sound environments.

https://doi.org/10.7554/eLife.09868.002 Across sensory modalities, cortical neurons exhibit adaptationterm, attenuating their responses to redundant stimuli ( Das and Gilbert, 1999 ; Ulanovsky et al., 2003 ; Garcia-Lazaro et al., 2007 ; Asari and Zador, 2009 ; Khatri et al., 2009 ). Adaptationterm to stimulus context is thought to increase efficiency of sensory coding under the constraints of limited resources ( Barlow, 1961 ). Yet, the neuronal-circuit mechanisms that facilitate adaptationterm in the cortexterm remain poorly understood. In the primary auditory cortexterm (A1), the vast majority of neurons exhibit stimulus-specific adaptationterm (SSAterm, Figure 1 ). When presented with a sequence of two tonesterm, one of which occurs frequently (termed ‘standardterm’) and another rarely (termed ‘deviantterm’), the neuron's response to the standardterm toneterm becomes weaker, but the response to the deviant toneterm·def remains strong ( Ulanovsky et al., 2003 ; Szymanski et al., 2009 ; Farley et al., 2010 ; Fishman and Steinschneider, 2012 ). Whereas SSAterm has also been found in sub-cortical structures e.g. in the auditory midbrain ( Malmierca et al., 2009 ; Zhao et al., 2011 ; Thomas et al., 2012 ) and the auditory thalamus ( Kraus et al., 1994 ; Anderson et al., 2009 ; Antunes et al., 2010 ; Bauerle et al., 2011 ), it is weak in the lemniscal areas of the auditory pathway, which project to A1, and stronger in those non-lemniscal areas which receive feedback from A1 ( Ulanovsky et al., 2004 , Perez-Gonzalez et al., 2005 , Duque et al., 2012 ). Therefore, cortical circuits are proposed to contribute to and amplify SSAterm in A1 ( Ulanovsky et al., 2003 , Szymanski et al., 2009 , Bauerle et al., 2011 , Fishman and Steinschneider, 2012 , Escera and Malmierca, 2014 ), through a combination of plastic modulation of thalamocortical inputs and intra-cortical inhibitory circuits, which would allow for selective suppressionterm of neuronal responses to specific stimuli ( Nelken, 2014 ). Our study tests whether and how inhibitory neurons contribute to cortical SSAterm.

Figure 1 with 1 supplement see all Download asset Open asset Nearly all recorded A1 neurons exhibit stimulus-specific adaptationterm.

( A ) Diagrams of oddball stimuli; oddball stimuli are composed of a 2.5-Hz train of 100-ms long sine-wave toneterm pips separated by 300 ms of silence (gray and red dots). Each toneterm pip is at one of two frequencies, toneterm A or B. In oddball stimulus 1, 10% of all pips are toneterm A and 90% of pips are toneterm B. In oddball stimulus 2, the toneterm probabilities are reversed. The less frequent toneterm is referred to as the deviant toneterm·def (red dots). The more frequent toneterm is referred to as the standardterm (gray dots). ( B ) Left: diagram of recording. Electrode was lowered perpendicular to the brain surface. Virus was injected in A1. Right: the frequencies of tonesterm A and B (dashed black and gray lines) are selected based on the frequency response functions of neurons of interest. Mean firing rate (FR) of five co-tuned neurons (colored lines) recorded simultaneously in a single session in response to 65 dB toneterm pips at 50 frequencies logarithmically spaced from 1 to 80 kHz. FR is normalized to the peak response of each neuron. ( C ) A representative neuron exhibited suppressed responses to a toneterm presented as a standardterm (gray raster and PSTH) compared to the same toneterm presented as a deviantterm (red raster and PSTH). Left: responses to toneterm A, presented as a deviantterm in oddball stimulus 1, and a standardterm in oddball stimulus 2. Right: responses to toneterm B. Shaded regions indicate standardterm (gray) and deviantterm (red) tonesterm trials. Gray dashed lines indicate toneterm onset and offset times. ( D ) Population histogram of stimulus-specific adaptationterm (SSAterm) indexterm exhibited by all neurons included in the analysis. Gray and white bars indicate neurons expressing significant and non-significant SSAterm, respectively. Spike count for response to deviant tonesterm·def was significantly greater than for response to standardterm tonesterm (Wilcoxon rank sum testterm·stat, one tail, p < 0.05). The black marker indicates the population average SSA indexterm·var. ( E ) Left: diagram of electrode spanning A1. Right: representative peri-stimulus current source density (CSD)term·def. Top: mean response to deviant tonesterm·def. Bottom: mean response to standardterm tonesterm. Gray dashed lines indicate toneterm onset and offset. Green dashed lines indicate the location of the granular layer. Negative CSD values (blue) indicate current sinks, while positive CSD values (red) indicate current sources. ( F ) Mean CSD collected from the thalamo-recipient layer, in response to standardterm (gray) and deviantterm (red) tonesterm. Gray dashed lines indicate toneterm onset and offset. ( G ) Mean SSA indexterm·var across sessions measured from thalamo-recipient granular layer CSD, infra- and supra-granular layer cortical CSD and mean neuronal spiking activity SSA indexterm·var averaged over sessions.

https://doi.org/10.7554/eLife.09868.003 Auditory cortexterm, like other sensory cortices, contains morphologically and physiologically diverse inhibitory interneuronsterm, which form dense interconnected networks with excitatoryterm neurons ( DeFelipe, 2002 ; Douglas and Martin, 2004 ). While different interneuronterm types have been hypothesized to carry out specialized complementary functions in sensory processing ( DeFelipe, 2002 ; Markram et al., 2004 ; Isaacson and Scanziani, 2011 ; Kepecs and Fishell, 2014 ; Marlin et al., 2015 ), their function in driving changes in dynamic auditory processing has not been previously established. We hypothesized that the two most common types of interneuronsterm in the cortexterm, parvalbumin- (PVsterm·def) and somatostatin-positive interneuronsterm (SOMsterm·def) ( Xu et al., 2010 ; Rudy et al., 2011 ), facilitate SSAterm in excitatoryterm neurons of A1 in a complementary fashion. PVsterm·def, a subset of which receive direct thalamicterm inputs ( Staiger et al., 1996 ), may amplify SSAterm in excitatoryterm neurons by providing a constant inhibitory drive; equally strong inhibitory drive would attenuate the weak response to standardterm tonesterm relatively more than the strong response to deviant tonesterm·def, leading to a greater differential between standardterm vs deviant toneterm·def spiking response. SOMsterm·def, which target distal dendrites of pyramidal cells ( McGarry et al., 2010 ; Gentet et al., 2012 ), have excitatoryterm synapses that exhibit facilitation upon repetitive stimulation ( Reyes et al., 1998 ; Silberberg and Markram, 2007 ). Therefore, inputs from SOMsterm·def may exert a stimulus-specific increase in suppressionterm of excitatoryterm neurons that is selective to the standardterm toneterm and does not generalize to the deviant toneterm·def. Alternatively, they may contribute to selective adaptationterm in excitatoryterm neurons through differential post-synaptic integration.

To tease apart the function of different inhibitory types in SSAterm, we tested whether optogeneticterm·mth suppressionterm of either PVterm or SOMterm interneuronsterm during sound presentation reduced SSAterm in putative excitatoryterm neurons in the auditory cortexterm ( Hamilton et al., 2013 ; Pi et al., 2013 ; Weible et al., 2014 ). We found that both types of interneuronsterm contribute to SSAterm in the cortexterm, with PVsterm·def providing constant inhibition, and SOMsterm·def increasing their effect with repeated tonesterm.

We recorded spiking activity of neurons as well as local field potentials (LFPs) in A1 in head-fixed mice under light isoflurane anesthesiaterm. SSAterm was measured from the firing rate (FR) of neurons in response to tonesterm presented as a series of ‘oddball’ stimuli. Each oddball stimulus consisted of a sequence of toneterm pips at one of two frequencies (tonesterm A and B). In each oddball stimulus, one toneterm was presented as the rare (deviantterm) toneterm, while the other was presented as the frequent (standardterm) toneterm (A to B ratio of 90:10 or 10:90, Figure 1A ). A third stimulus was also presented (equal stimulus), with tonesterm A and B being presented equally often (50:50). The frequencies of toneterm A and B were selected at 0.39 octave intervals, narrower than the typical tuning bandwidth of A1 neurons ( Hackett et al., 2011 ; Guo et al., 2012 ; Kanold et al., 2014 ), such that they activated the majority of recorded neurons on each session ( Figure 1B ).

As expected, for a representative neuron recorded in A1, the mean FR in response to a toneterm was lower when the toneterm was presented as the standardterm than as the deviantterm ( Figure 1C ), exhibiting SSAterm. To quantify the level of adaptationterm for each neuron, we computed the indexterm of the change in FR to the same toneterm when it was presented as the deviantterm vs the standardterm (SSA indexterm·var). SSA indexterm·var is 1 when adaptationterm is complete (i.e., no response to the standardterm, and significant response to the deviantterm), and 0 when there is no adaptationterm (i.e., the response to the standardterm and deviantterm is equal). Almost all neurons recorded in A1 exhibited significant SSAterm ( Figure 1D , standardterm tone-evoked FRterm·var significantly lower than the deviantterm tone-evoked FRterm·var in N = 138 out of 147 neurons, Wilcoxon rank sum testterm·stat p < 0.05).

We first tested whether SSAterm is present in inputs from the thalamus. Current source density (CSD)term·def analysis has been extensively used to quantify inputs from the thalamus ( Metherate and Cruikshank, 1999 ; Kaur et al., 2005 ; Szymanski et al., 2009 ; Happel et al., 2014 ). We used a linear probe to record LFPs using electrodes spaced 50 microns apart inserted perpendicularly to brain surface in the primary auditory cortexterm. The multi-electrode probe is 775-µm long, spanning layers 1–6 of mouse A1. CSD is computed as the second spatial derivative of the LFPs across the depth of the cortexterm ( Figure 1E , Figure 1—figure supplement 1A , 20 sessions, 15 mice). Typically, in response to tonesterm, CSD exhibits a negative basin, termed sink, within a short delay of toneterm onset, localized to electrodes in thalamo-recipient layer ( Figure 1F , Figure 1—figure supplement 1B ) ( Kaur et al., 2005 ; Szymanski et al., 2009 ). The amplitude of current in the sink was taken as a measure of the combined strength of post-synaptic inputs onto layer 4 neurons, which should reflect the strength of the thalamicterm inputs to the cortexterm ( Metherate and Cruikshank, 1999 ; Kaur et al., 2005 ; Szymanski et al., 2009 ; Happel et al., 2014 ).

We compared the amplitude of the CSD sink for each toneterm when presented as a deviantterm or standardterm, and computed their ratio ( Figure 1F ). The sink amplitude was lower for the standardterm as compared to the deviant tonesterm·def ( Figure 1F,G ), suggesting that excitatoryterm signals produced by thalamo-cortical inputs exhibit SSAterm, consistent with previous findings ( Szymanski et al., 2009 ). This finding supports the ‘adaptationterm in narrowly tuned inputs’ modelterm·mth, which postulates that SSAterm in broadly tuned neurons in A1 reflects adaptationterm in either thalamocortical inputs or at the stage of integration of thalamocortical inputs, specific to inputs tuned to the standardterm toneterm ( Mill et al., 2011 ; Taaseh et al., 2011 ; Nelken, 2014 ). Importantly, across sessions, the SSA indexterm·var of the granular layer CSD sinks was significantly lower than that of either the non-thalamo-recipient layers (Δ = −28%, p-value from one-sided test after correction (p1term·def) = 6e −4 , z = −3.4, Bonferroni corrected for two tests (C = 2)) or the SSA indexterm·var of the mean spiking activity of A1 neurons (Δ = 23%, p1term·def = 0.029, z = −2.1, C = 2) in each session (N = 20 sessions in 15 mice, Figure 1G ), suggesting that additional intra-cortical mechanisms may contribute to SSAterm in the cortexterm.

We next tested whether cortical inhibitory interneuronsterm may contribute to SSAterm. Since different inhibitory neuronal subtypes can differentially affect sensory responses of putative excitatoryterm neurons ( Lee et al., 2012 ; Wilson et al., 2012 ; Cottam et al., 2013 ), we separately tested the role of PVsterm·def and SOMsterm·def. We used targeted viral delivery in the auditory cortexterm of mice to drive Archaerhodopsin (Arch) expression, which hyperpolarizes neurons when stimulated by light, in either PVsterm·def or SOMsterm·def ( Chow et al., 2010 ). A modified adeno-associated virus (AAV) encoding anti-sense code for Arch and a fluorescent reporter, under the FLEX cassette, was injected into PV-Cre or SOM-Cre mice ( Boyden et al., 2005 ; Sohal et al., 2009 ; Cardin et al., 2010 ; Zhang et al., 2010 ; Deisseroth, 2011 ) ( Figure 2A ). 2 weeks following virus injection, Arch was expressed selectively in PVsterm·def or SOMsterm·def in auditory cortexterm at expected levels ( Kvitsiani et al., 2013 ) ( Figure 2B,C PV-Cre: N = 250 neurons in 4 mice, specificity = 92 ± 1%, efficiency = 73 ± 5%. SOM-Cre: N = 149 neurons in 5 mice, specificity = 95 ± 2%, efficiency = 86 ± 5%). To activate Arch, a light guide was positioned to cast 180 mW/mm 532-nm light onto A1 surface, perpendiular to cortical layers. In vitro intracellular recordings from optically identified PVsterm·def or SOMsterm·def ( Figure 2—figure supplement 1 , Figure 2—figure supplement 2 ) demonstrate that light cast over the auditory cortexterm in vitro drives a strong suppressive current ( Figure 2D , Figure 2—figure supplements 1C,D, 2C,D ) and hyperpolarizes the membrane potential in these neurons ( Figure 2—figure supplements 1B, 2B ). Assuming a 100-fold attenuation of light over 1 mm of brain tissue ( Aravanis et al., 2007 ), the estimated irradiance in the deepest cortical layer (1.8 mW/mm 2 ) was strong enough to induce hyperpolarizing current in neurons in vitro ( Figure 2D ). In vivo, in both PV-Cre and SOM-Cre mice, illuminating the auditory cortexterm suppressed spiking activity in a small subset of recorded neurons ( Figure 2E,F , left, putative inhibitory neurons) and increased activity in a great majority of recorded neurons ( Figure 2E,F right, putative excitatoryterm neurons). Shining light over A1 increased spontaneous neuronal activity in the majority of the recorded neurons in both PV-Cre mice (N = 115 neurons, 102 increased, 0 decreased, in 10 mice) ( Figure 2G ) and SOM-Cre mice (N = 104 neurons, 61 increased, 3 decreased, in 9 mice) ( Figure 2H ). These measurements demonstrate that casting light over A1 selectively and effectively suppresses the activity of either PVsterm·def or SOMsterm·def.

Figure 2 with 2 supplements see all Download asset Open asset Cell type-specific optogeneticterm·mth suppressionterm of parvalbumin-positive and somatostatin-positive neurons.

( A ) Optogeneticterm·mth methods diagram. Top: A1 was injected with AAV-FLEX-Arch-GFP. During experiments, an optic fiber was positioned to target A1 and neuronal activity was recorded using a multichannel silicon probe in A1. Bottom: green light (532 nm) suppresses PVsterm·def in PV-Cre mice or SOMsterm·def in SOM-Cre mice. ( B ) Transfection of interneuronsterm with Archaerhodopsin (Arch). Immunohistochemistry demonstrating co-expression of the Arch and an interneuron-type reporter in A1. Top: PV-Cre mouse A1. Red: anti-body stain for parvalbumin. Green: Arch-GFP. Merge; co-expression of Arch and parvalbumin. Bottom: SOM-Cre mouse A1. Red: anti-body stain for somatostatin. Green: Arch-GFP. Merge; co-expression of Arch and somatostatin. Scale Bar = 25 µm. ( C ) Efficiency and specificity of transfection of interneuronsterm with Arch. Bar Plots: efficiency (Ef) and specificity (Sp) of visual transfection of PVsterm·def (top) and SOMsterm·def (bottom) with Arch. Ef, percent of labeled interneuronsterm expressing Arch. Sp, percent of Arch-expressing cells, which are also labeled interneuronsterm. ( D ) Mean Arch-mediated outward current evoked in response to increasing photostimulation power, recorded in vitro by whole-cell patch recording in putative excitatoryterm neurons from PV-Cre (blue, N = 5) and Som-Cre (orange, N = 5) mice. The gray dashed line indicates the level of irradiance expected in in vivo experiments at the deepest recording sites, in cortical layer 6. ( E , F ) Toneterm responses of representative neurons, which are suppressed (left) or activated (right) by photostimulation, from PV-Cre ( E ) and SOM-Cre ( F ) mice. Raster plot of spike times (bottom) and PSTH (top) of a single neuron response to a 100-ms long toneterm (gray dashed lines, shaded region) on light-on (overlapping 250-ms light pulse, green shading) and light-off trials. Light-on trials: green. Light-off trials: black. ( G , H ) Modulation of spontaneous FRterm·var by interneuronterm photosuppression recorded in PV-Cre ( G ) and SOM-Cre ( H ) mice. Each neuron is represented by a circle that is filled for those with significantly increased (green) or decreased (red) FR or unfilled for those without significant modulation. Gray dashed line, identity line.

https://doi.org/10.7554/eLife.09868.005 To test the function of PVsterm·def and SOMsterm·def in SSAterm, their activity was suppressed during every fifth toneterm of the oddball stimulus by illuminating A1 ( Figure 3A ). To directly test the effect of interneuronterm suppressionterm, we computed the SSA indexterm·var separately on light-on and light-off trials for neurons responsive to both tonesterm A and B (SSAterm was found in 63 out of 67 tone-responsive neurons in PV-Cre mice, 42 out of 43 tone-responsive neurons in SOM-Cre mice). Photosuppression of either PVsterm·def or SOMsterm·def affected the responses of neurons to the tonesterm ( Figure 3B,C ), resulting in a significant reduction in SSA indexterm·var across the population ( Figure 3E,F , PV-Cre: Δ = −41%, p1term·def = 1e −12 , t(66) = 8.6. SOM-Cre: Δ = −25%, p1term·def = 2e −6 , t(42) = 5.4). Photo-manipulation-affected responses only to the toneterm during which it was presented, but not to subsequent tonesterm ( Figure 3—figure supplement 1 ). Additionally, photo-manipulation was limited to cortexterm since it did not affect thalamo-recipient layer CSD toneterm responses and SSAterm ( Figure 3—figure supplement 2 ). In a control groupterm·var of PV-Cre or SOM-Cre mice (6 mice), we injected a modified AAV, which encoded anti-sense fluorescent reporter alone under the FLEX cassette, and computed the effect of casting light on SSAterm (SSAterm was found in 33 out of 37 tone-responsive neurons in control mice). In this control groupterm·var, SSAterm was not affected by light ( Figure 3D,G , p > 0.05, t(36) = −2.0), confirming that Arch expression was required for the effect of the light. Therefore, the effects of interneuronsterm are specific to intra-cortical mechanisms. These results demonstrate that both types of interneuronsterm contribute to the reduction of the response of the neuron to the stimulus during SSAterm.

Figure 3 with 2 supplements see all Download asset Open asset Optogeneticterm·mth suppressionterm of either PVsterm·def or SOMsterm·def reduces SSAterm in putative excitatoryterm neurons in the auditory cortexterm.

( A ) Diagram of oddball stimuli with light; two oddball stimuli are presented (as in Figure 1A ), with 250-ms light pulses (green bars) delivered during every fifth toneterm, starting 100 ms before toneterm onset. ( B – D ) Representative neuron PSTH in response to toneterm A (left) and B (right) as a standardterm (gray) or deviantterm (red) on light-on (light colors) and light-off trials (dark colors). Neurons recorded in PV-Cre ( B , E ), SOM-Cre ( C , F ), and control ( D , G ) mice. ( E – G ) Effect of interneuronterm photosuppression on SSAterm. Left: SSA indexterm·var on light-on vs light-off trials. Each neuron is represented by a circle that is filled if the neuron exhibits significant SSAterm, that is, its FR in response to deviant tonesterm·def is greater than that to standardterm tonesterm. The respective representative neuron in B , C , and D is indicated by a red circle. Gray dashed line, identity line. Right: mean SSA indexterm·var on light-on (green) and light-off (gray) trials over neuronal population.

https://doi.org/10.7554/eLife.09868.008 A decrease in the SSA indexterm·var may be due to several factors: (1) an increase in response to the standardterm only, (2) a decrease in response to the deviantterm, or (3) an increase in response both to the standardterm and the deviantterm, but with a relatively greater increase for the standardterm. Therefore, we next investigated the effect of interneuronterm photosuppression on FR of putative excitatoryterm neurons evoked by the standardterm and deviant tonesterm·def separately. The effects of PVsterm·def and SOMsterm·def diverged; in addition to increasing spontaneous activity (Δ = 185%, p-value from one-sided t-testterm·stat after correction (p2term·def) = 3e −11 , t(159) = −7.2), suppressing PVsterm·def led to increased FR to both the standardterm (Δ = 102%, p2term·def = 3e −11 , t(159) = −7.2) and deviantterm (Δ = 56%, p2term·def = 9e −12 , t(159) = −7.4) tonesterm (N = 160, Figure 4A–C , Figure 4—figure supplement 1A ). 83% of neurons exhibited greater FR to the standardterm and 46% to the deviantterm during PVterm suppressionterm ( Figure 4—figure supplement 1B ). The difference in FR due to suppressionterm of PVsterm·def was not significantly different between the standardterm and deviant tonesterm·def (p2term·def > 0.05, t(159) = −0.1, C = 2) but both were greater than the difference in the spontaneous FRterm·var (standardterm: Δ = 25%, p2term·def = 0.001, t(159) = −3.6, C = 2. Deviantterm: Δ = 26%, p2term·def = 0.039, t(159) = −2.4, C = 2), indicating that the change in tone-evoked FRterm·var was similar regardless of toneterm probabilityterm ( Figure 4B , bottom panel). Because an equal increase in the FR produces a weaker relative effect on the response to the deviantterm (which is higher than to the standardterm), PVterm inactivation decreases SSA indexterm·var ( Figure 3E ).

Figure 4 with 8 supplements see all Download asset Open asset PVsterm·def and SOMsterm·def differentially affect response to standardterm and deviant tonesterm·def.

( A , D ) Top: mean response to deviantterm (left, red) and standardterm (right, black) tonesterm, during light-on (light colors) and light-off trials (dark colors). Bottom: mean of the difference between responses on light-on and light-off trials for each neuron for deviantterm (left, red) and standardterm (right, black) toneterm. Each trace is a population average of putative excitatoryterm neuron PSTHs normalized to each neuron's maximum deviantterm tone-evoked FRterm·var on light-off trials. Shaded regions around traces indicate standardterm error (SE). Dashed lines indicate light onset (green) and toneterm onset and offset (gray). Neurons recorded in PV-Cre ( A ), SOM-Cre ( D ) mice. ( B , E ) (Top) Mean population FR on light-on and light-off trials; (bottom) mean population FR difference between light-on and light-off conditions for deviantterm (red) and standardterm (gray) tonesterm and spontaneous activity (blue). Normalization as in A . Neurons recorded in PV-Cre ( B ), SOM-Cre ( E ) mice. ( C , F ) Modulation of PV-Cre mouse putative excitatoryterm neuron FR response to tonesterm by interneuronterm photosuppression. Neuronal responses to each toneterm are represented by two circles, one for standardterm (black) and one for deviantterm (red) toneterm responses. Filled circles represent significantly increased (gray, pink) or decreased (black, red) response; unfilled circles: responses without significant modulation. Gray dashed line, identity line. Neurons recorded in PV-Cre ( C ), SOM-Cre ( F ) mice.

https://doi.org/10.7554/eLife.09868.011 By contrast, suppressing SOMsterm·def led to an increase in FR for spontaneous activity (Δ = 46%, p2term·def = 2e −9 , t(113) = −6.5) and during the standardterm (Δ = 29%, p2term·def = 2e −8 , t(113) = −6.1) but not deviantterm (p2term·def > 0.05, t(113) = −0.8) toneterm (N = 114, Figure 4D–F , Figure 4—figure supplement 1C ). 52% of neurons exhibited greater FR to the standardterm and only 11% to the deviantterm during PVterm suppressionterm ( Figure 4—figure supplement 1D ). The increase in FR for spontaneous activity was not different than that during the standardterm toneterm (p2term·def > 0.05, t(113) = 0.2, C = 2) and the differences in FR due to suppressionterm of SOMsterm·def were stronger for spontaneous activity and the standardterm toneterm than the deviant toneterm·def (spontaneous: Δ = 390%, p2term·def = 0.004, t(113) = 3.1. Standardterm: Δ = 378%, p2term·def = 0.005, t(113) = 3.1) ( Figure 4E , bottom panel), thereby accounting for the change in SSAterm with SOMterm inactivation ( Figure 3F ). Responses to the equal stimulus evoked consistent, yet weaker effects ( Figure 4—figure supplement 2 ).

PVsterm·def and SOMsterm·def differ in their density among different layers of the cortexterm and in laminar sources and targets of their inputs and outputs ( Markram et al., 2004 ; Xu and Callaway, 2009 ; Fino et al., 2013 ). The effects of PVterm and SOMterm suppressionterm on SSAterm had differential laminar distribution ( Figure 4—figure supplement 3 ). The effect of PVsterm·def on SSAterm was equally strong in the supra-granular and infra-granular layers, but stronger in the granular layer, that is, the thalamo-recipient layer. This differential effect is consistent with the relative proportion of cortical interneuronsterm that are PVsterm·def, which is higher in granular than either in infra- or supra-granular layers ( Lee et al., 2010 ; Xu et al., 2010 ; Ouellet and de Villers-Sidani, 2014 ). In contrast, suppressing SOMsterm·def reduced SSAterm in the granular and infra-granular, but not supra-granular layers. The relative proportion of cortical interneuronsterm that are SOMsterm·def is greatest in the granular and infra-granular layers, but still present in supra-granular layers ( Lee et al., 2010 ; Xu et al., 2010 ; Ouellet and de Villers-Sidani, 2014 ). As some SOMsterm·def predominantly target the distal dendrites of pyramidal neurons ( Markram et al., 2004 ), the effect of suppressing SOMsterm·def in supra-granular layers may be evident in recordings of pyramidal neurons with cell bodies in deeper layers, supporting our results. In addition, cortical extracellular recordings may be biased toward neurons in granular and infra-granular layers, precluding adequate sampling of activity in superficial layers. In controls, we did not observe a difference in the effect of light on SSAterm across layers, demonstrating that the differences are not due to differential artifact of light stimulation.

Our results indicate that both PVsterm·def and SOMsterm·def affect SSAterm, but in different ways: (1) the increase in the FR of putative excitatoryterm neurons due to PVterm suppressionterm is constant, either during presentation of the standardterm or the deviantterm, and greater than changes in spontaneous activity. Thus, PVsterm·def amplify SSAterm in excitatoryterm neurons by exerting a relatively stronger inhibitory drive for the standardterm than for the deviantterm. (2) Suppressionterm of SOMsterm·def leads to increased putative excitatoryterm neuron activity only during the spontaneous firing or the presentation of the standardterm, but not for the deviantterm. This suggests that the strength of SOM-mediated inhibitory drive is not significant in response to the deviantterm but increases with repeated presentations of the standardterm.

In neurons exhibiting SSAterm, responses to the deviantterm are stronger than to the standardterm. This difference might lead to a ‘ceiling’ effect, reducing the effect of PVterm photosuppression on FR to the deviantterm, but not standardterm ( Olsen et al., 2012 ). However, restricting the analysis to two subpopulations of neurons, which have matched mean and standardterm deviation of FR to the standardterm vs the deviant tonesterm·def ( Ulanovsky et al., 2004 ; Rust and Dicarlo, 2010 ), preserved the observed effects of photosuppression ( Figure 4—figure supplement 4 ). Suppressing PVsterm·def led to an equal increase in FR to both the standardterm and the deviant toneterm·def (N = 54—standardterm: Δ = 62%, p2term·def = 6e −8 , t(53) = 6.3. Deviantterm: Δ = 55%, p2term·def = 3e −5 , t(53) = 4.5. Standardterm vs deviantterm: p2term·def > 0.05, t(53) = 0.5). In contrast, suppressing SOMsterm·def led to a significant increase in FR to the standardterm, but no change in FR to the deviantterm (N = 44—standardterm: Δ = 30%, p2term·def = 7e −6 , t(43) = 5.1. Deviantterm: p2term·def > 0.19, t(43) = 1.3. Standardterm vs deviantterm: Δ = 382%, p2term·def = 6e −4 , t(43) = 3.7).

For neurons that responded more strongly to one of the tonesterm (‘strong’ vs ‘weak’ toneterm), a ceiling effect would predict that the effect of interneuronterm suppressionterm would be stronger for the weak than the strong toneterm. However, PVterm and SOMterm suppressionterm exhibited a similar effect on responses to the strong and the weak tonesterm in neurons that exhibited differential responses to two tonesterm ( Figure 4—figure supplements 5, 6 ). Suppressing PVsterm·def led to similar increases in tone-evoked FRterm·var between weak and strong tonesterm for both deviantterm (N = 51, p2term·def > 0.05, t(50) = 1.0) and standardterm tonesterm (p2term·def > 0.05, t(50) = −1.9). Suppressing SOMsterm·def also led to similar differential effects between strong and weak tonesterm; standardterm tone-evoked FRterm·var increased equally (N = 34, p2term·def > 0.05, t(33) = 1.1) and deviantterm tone-evoked FRterm·var was equally unchanged (p2term·def = 0.05, t(33) = −0.1). Combined, these analyses demonstrate that the effect of PVterm photosuppression on SSAterm cannot be explained by the ceiling effect for either PVsterm·def or SOMsterm·def.

Although Arch drove strong currents in both SOMterm and PVterm neurons ( Figure 2D , Figure 2—figure supplements 1, 2 ), there might be a difference in expression level or efficacy of Arch between SOM-Cre and PV-Cre mice, leading to a stronger effect of photosuppression in PV-Cre than in SOM-Cre mice on tone-evoked FRsterm·var ( Figure 4B,E ). Alternatively, the difference might be attributable to the morphological or functional differences between SOMsterm·def and PVsterm·def. To address this confound, we selected toneterm responses that exhibited matched difference in standardterm tone-evoked FRterm·var between light-on and light-off trials (N = 66, Figure 4—figure supplement 7 ). Within these matched subpopulations, PVterm and SOMterm photosuppression exhibited differential effects similar to those of the whole population. The change in FR due to PVterm suppressionterm was not significantly different between responses to the standardterm and deviantterm (p2term·def > 0.05, t(65) = −0.3, C = 3). By contrast, the change in deviantterm tone-evoked FRterm·var due to SOMterm suppressionterm was significantly weaker than that for the standardterm toneterm (Δ = −78%, p2term·def = 0.003, t(3.5), C = 3). By the design of the analysis, the effect of PVterm or SOMterm suppressionterm on standardterm tone-evoked FRterm·var was nearly identical (p1term·def > 0.05, t(65) = −0.1, C = 3). However, the change in deviantterm tone-evoked FRterm·var was greater for PVterm photosuppression than SOMterm photosuppression (Δ = 404%, p1term·def = 0.029, t(65) = 2.4, C = 3). Since the observed differential effects of PVterm and SOMterm suppressionterm persisted in subsets of neurons that were matched for photosuppression-induced change in standardterm tone-evoked FRterm·var, these differences are unlikely due to differential expression or efficacy of Arch in the PV-Cre and SOM-Cre mice, but rather reflect functional differences between the two types of interneuronsterm.

Within the oddball sequence, after the presentation of the deviant toneterm·def, SSAterm takes several repeats of the standardterm toneterm to reach an adapted state ( Ulanovsky et al., 2004 ). Consistent with previous findings ( Ulanovsky et al., 2004 ), presentation of the deviant toneterm·def temporarily reduced SSAterm without photosuppression ( Figure 5A–C , dark color bars); following the deviant toneterm·def (T 0 ), the first two standardterm tonesterm (T 1 and T 2 ) evoked elevated FRs compared to the fourth standardterm toneterm (T 4 ) (PV-Cre, Figure 5B —N = 148, T 1 : Δ = 60%, p2term·def = 3e −8 , t(146) = 6.3, C = 11, T 2 : Δ = 26%, p2term·def = 0.043, t(146) = 2.9, C = 11. SOM-Cre, Figure 5C —N = 102, T 1 : Δ = 72%, p2term·def = 1e −5 , t(101) = 5.2, C = 11, T 2 : Δ = 31%, p2term·def = 0.013, t(101) = 3.3, C = 11). The third standardterm toneterm (T 3 ) and the toneterm prior to the deviant toneterm·def (T −1 ) evoked responses similar to T 4 (PV-Cre, Figure 5B —T −1 and T 3 : p2term·def > 0.05, t(146) < 2.5, C = 11. SOM-Cre, Figure 5C —T −1 and T 3 : p2term·def > 0.05, t(101) < 2.9, C = 11). Neurons in which response to T 0 did not produce spikes were excluded. Suppressing PVsterm·def led to a significant and equal increase in FR to four consecutive presentations of the standardterm following the deviantterm ( Figure 5B , left, for each toneterm, T −1 through T 4 , with light-on compared to T 4 with light-off: Δ > 132%, p2term·def < 2e −9 , t(146) ≥ 6.8, C = 11. Figure 5B , right, change in FR between light-on and light-off responses to each T −1 through T 3 as compared to T 4 : p > 0.05, t(146) < 1.8, C = 5). In contrast with PVsterm·def, suppressing SOMsterm·def led to a progressively increasing effect on FR to consecutive presentations of the standardterm toneterm following the deviantterm ( Figure 5C , left, for each standardterm toneterm, T −1 through T 4 , with light-on compared to T 4 with light-off: Δ > 64%, p2term·def < 9e −4 , t(101) ≥ 4.1, C = 11. Figure 5C , right, difference between FR change in T 1 and T 4 with light-on: p = 0.008, t(101) = −3.2, C = 5. Repeated measures ANOVAterm·stat with toneterm number (T 1 through T 4 ) as a factor: F(3, 300) = 4.30, p = 0.0054). These results are consistent with the interpretation that the inhibitory drive from PVsterm·def is constant throughout the stimulus regardless of toneterm history, whereas the effect of SOMterm modulation increases with repeated presentations of the standardterm toneterm.

Figure 5 with 1 supplement see all Download asset Open asset Post-deviant time course of interneuron-mediated effect on SSAterm.

( A ) Diagram of oddball stimuli illustrating post-deviant toneterm number used in subsequent analysis; Tonesterm and light pulses are as indicated in Figure 3A . Numbers indicate each toneterm position relative to deviant tonesterm·def. Responses to any standardterm tonesterm following light-on standardsterm were excluded from the analysis. ( B , C ) Left: mean population FR in response to standardterm tonesterm (gray) subsequent to deviant tonesterm·def (red) within the oddball sequence on light-off (dark colors) and light-on (light colors) trials. All responses are normalized to the response to the fourth post-deviant standardterm toneterm on light-off trials (green dashed line). Right: difference between FR on light-on and light-off trials in response to standardterm (gray) and deviantterm (red) tonesterm. ( B ): PV-Cre mice. ( C ): SOM-Cre mice.

https://doi.org/10.7554/eLife.09868.020 The time course of the effect of interneuronterm photosuppression on FR of the putative excitatoryterm neurons at the beginning of each oddball sequence exhibited similar differences between PVsterm·def and SOMsterm·def. After the onset of each oddball sequence, SSAterm develops over the course of several standardterm toneterm presentations ( Ulanovsky, 2004 ). As expected, on light-off trials, FR decreased in response to the standardterm toneterm over the first 20 repetitions of the toneterm ( Figure 5—figure supplement 1 ). For PV-Cre mice, the difference in FR to the standardterm toneterm between light-on and light-off trials did not change over this time and stayed positive for the remainder of the oddball stimulus ( Figure 5—figure supplement 1A ). Over the first 20 trials, FR adapted with a similar time course for both the light-on and light-off trials, so the change due to PVterm photosuppression in FR to standardterm stayed constant ( Figure 5—figure supplement 1A,B ). In contrast, for SOM-Cre mice, FR on light-on trials increased over the first 40 trials, whereas on light-off trials, it decreased ( Figure 5—figure supplement 1A ). As a result, the difference due to photo-manipulation in FR to the standardterm toneterm increased over the first 40 trials and then stayed consistently positive throughout the stimulus presentation ( Figure 5—figure supplement 1C ). These results demonstrate that the PV-mediated effect on putative excitatoryterm neuronal responses did not change with repeated presentations of the standardterm toneterm, whereas the SOM-mediated effect increased with the repeated stimulus.

In order to understand how PVsterm·def and SOMsterm·def exert differential control of SSAterm in putative excitatoryterm neurons, we used optogeneticterm·mth tagging to identify the specific interneuronsterm and to quantify whether PVsterm·def and SOMsterm·def exhibited SSAterm ( Lima et al., 2009 ). Through targeted viral delivery to AC, we drove Channelrhodopsin-2 (ChR2) expression, which depolarizes neurons when stimulated by light, in either PVsterm·def or SOMsterm·def ( Chow et al., 2010 ) ( Figure 6A,D , Figure 6—figure supplement 1A ). A modified AAV encoding anti-sense code for ChR2 and a fluorescent reporter, under the FLEX cassette, was injected into PV-Cre or SOM-Cre mice ( Boyden et al., 2005 ; Sohal et al., 2009 ; Cardin et al., 2010 ; Zhang et al., 2010 ; Deisseroth, 2011 ) and resulted in specific expression of ChR2, localized to PVsterm·def or SOMsterm·def ( Figure 6—figure supplement 1B , c PV-Cre; N = 183 neurons in 3 mice, specificity = 67 ± 1%, efficiency = 76 ± 5%. SOM-Cre: N = 202 neurons in 4 mice, specificity = 90 ± 3%, efficiency = 81 ± 4%). Neurons were identified as PVsterm·def or SOMsterm·def if they responded to brief (5 ms) flashes of light with spikes within 1.5–4.5 ms of laser pulse onset ( Figure 6A,D ).

Figure 6 with 2 supplements see all Download asset Open asset PVterm and SOMterm interneuronsterm exhibit SSAterm.

( A , D ) Optogeneticterm·mth methods. A1 was injected with AAV-FLEX-ChR2-tdTomato. During experiments, an optic fiber was positioned to target A1 and neuronal activity was recorded using a multichannel silicon probe in A1. Top diagram: blue light (473 nm) excites PVsterm·def in PV-Cre mice or SOMsterm·def in SOM-Cre mice. Bottom: peri-stimulus spike raster of a representative optogenetically identified PVterm (top) or SOMterm (bottom). Shaded region, blue light on. ( A ) PV-Cre. ( D ) SOM-Cre. ( B , E ) PSTH of PVsterm·def ( B ) or SOMsterm·def ( E ) FR response to deviantterm (red) and standardterm (black) tonesterm. Normalization and dashed lines as in Figure 4A,B . ( C , F ) Mean PVsterm·def ( C ) or SOMsterm·def ( F ) FR response over the 100 ms of deviantterm (red) and standardterm tonesterm (gray), and 100 ms of spontaneous activity prior to toneterm onset (blue). Each line represents a single neuron's response to each conditions, and its color indicates the magnitude of significant differences between two conditions; pink, gray, blue, and dashed black lines indicate a greater response to deviant toneterm·def, standardterm toneterm, silence and no significant change, respectively. ( G ) Mean SSA indexterm·var of putative excitatoryterm neurons, PVsterm·def, and SOMsterm·def. Circles represent SSA indexterm·var values of individual neurons.

https://doi.org/10.7554/eLife.09868.022 Both PVsterm·def and SOMsterm·def exhibited SSAterm, evidenced by a significant reduction in standardterm tone-evoked FRterm·var compared to the deviant toneterm·def response ( Figure 6B,C,E,F , PVterm: N = 16, Δ = −32%, p2term·def = 0.023, z = −2.5, C = 2. SOMterm: N = 28, Δ = −41%, p2term·def = 0.002, z = −3.3, C = 2. Signed-rank test) . The SSA indexterm·var was not significantly different between PVsterm·def and SOMsterm·def ( Figure 6G , neurons responsive to both tonesterm A and B—PVterm: N = 5, SOMterm: N = 12. PVterm and SOMterm: p2term·def > 0.05, C = 2. Rank sum test) and both were similar to the mean SSA indexterm·var in putative excitatoryterm neurons ( Figure 6G —Exc: N = 67. Exc vs PVterm: p > 0.05, z = 0.7, C = 2. Exc vs SOMterm: p > 0.05, z = 0.4, C = 2). PVsterm·def and SOMsterm·def exhibited some differences in relative response changes between the deviantterm, the standardterm, and the equal tonesterm ( Figure 6 , Figure 6—figure supplement 2B,D ); PVsterm·def' response to the equal tonesterm did not decrease significantly as compared to deviant tonesterm·def (N = 16 p2term·def > 0.05, z = −1.7, C = 2), whereas SOMsterm·def adapted in their response to equal tonesterm (Δ = −36%, p2term·def = 0.049, z = −2.3, C = 2), and then further to standardterm tonesterm (N = 28, Δ = −49%, p2term·def = 0.022, z = −2.6, C = 2). These results suggest that SOMsterm·def may adapt at a faster time scale than PVsterm·def with repeated presentation of tonesterm.

Our results of recordings from PVsterm·def and SOMsterm·def present a surprising finding that PVsterm·def and SOMsterm·def adapt in response to repeated tonesterm, countering our initial hypothesis that SOMsterm·def saturate in responses to the deviantterm, or facilitate with repeated presentation of a toneterm. How can an adapting interneuronterm contribute to added adaptationterm in excitatoryterm neurons? To address this question, we next developed a modelterm·mth of coupled excitatoryterm–inhibitory neuronal populations. Excitatoryterm and inhibitory neurons form tight mutually coupled networks in A1, and we hypothesized that through differential post-synaptic integration by excitatoryterm neurons, interneuronsterm can amplify adaptationterm in excitatoryterm neurons.

As a proof-of-principle that would account for our findings that PVsterm·def and SOMsterm·def exhibit similar magnitude of SSAterm, yet have a differential effect on SSAterm in putative excitatoryterm neurons, we constructed a simplified modelterm·mth of mutually coupled inhibitory–excitatoryterm neuronal populations. We tested how responses of the modelterm·mth putative excitatoryterm neurons are affected by manipulation of activity of PVsterm·def or SOMsterm·def ( Figure 7A ). Thalamocortical tone-evoked inputs were modeled including an adaptationterm term and resulted in reduced responses of excitatoryterm, PVterm, and SOMterm populations to repeated tonesterm ( Figure 7—figure supplement 1A,B ). The modelterm·mth replicated the differential effects of manipulation of PVterm and SOMterm activity on responses to standardterm and deviant tonesterm·def in putative excitatoryterm neurons ( Figure 7B–E ): when PVsterm·def were suppressed optogenetically, the responses to both the standardterm and the deviant tonesterm·def increased ( Figure 7B,C ). By contrast, when SOMsterm·def were suppressed, although the spontaneous FRterm·var and standardterm tone-evoked FRterm·var were elevated, the responses to the deviant toneterm·def remained constant, whereas the responses to the standardterm toneterm increased ( Figure 7D,E ). SOMsterm·def have been shown to inhibit PVsterm·def ( Cottam et al., 2013 ; Pfeffer et al., 2013 ; Sturgill and Isaacson, 2015 ). Including inhibition between SOMsterm·def and PVsterm·def did not affect the modelterm·mth outcome, with suppressionterm of PVsterm·def resulting in suppressionterm of excitatoryterm responses to both the standardterm and the deviantterm, and suppressionterm of SOMsterm·def driving specific suppressionterm of excitatoryterm responses to the standardterm, but not the deviantterm ( Figure 7—figure supplement 2 ).

Figure 7 with 2 supplements see all Download asset Open asset Mutually coupled excitatory-PV-SOM neuronal modelterm·mth accounts for differential effects of PVsterm·def and SOMsterm·def on SSAterm in putative excitatoryterm neurons.

( A ) Center: diagram of coupled network modelterm·mth. Excitatoryterm (Exc) and two types of inhibitory interneuronsterm (PVterm and SOMterm) receive tone-evoked inputs. They make reciprocal connections on each other; Exc makes excitatoryterm synapses on PVterm or SOMterm; PVterm and SOMterm inhibit Exc. Closed circles: excitatoryterm synapses. Open circles: inhibitory synapses. Orange outlines: excitatoryterm input–output pathway. Purple outlines: PVterm input–output pathway. Green outlines: SOMterm input–output pathway. The effect of optogeneticterm·mth modulation was modeled as an additional input current delivered to inhibitory neuronal populations. Adaptationterm was modeled as decaying synaptic coefficient with slow adaptationterm. Left and right inset plots: combined input–output transfer function that represents the transformation between synaptic inputs and the activity of excitatoryterm neurons. The values of inputs are depicted by arrows for the spontaneous and tone-evoked activity in response to deviantterm and standardterm tonesterm under light-off (dark color) and light-on (light color) conditions, with change due to light highlighted by light green arrows. ( B , D ) Tone-evoked responses of modelterm·mth neuronal excitatoryterm population to deviantterm (red) and standardterm tonesterm (gray), that is, the first and fourth consecutive toneterm presented, under light-off (dark colors) and light-on (light colors) conditions. Dashed lines indicate light onset and offset (green) and toneterm onset and offset (gray). ( B ) Light suppresses PVsterm·def. ( D ) Light suppresses SOMsterm·def. ( C , E ) Left: spontaneous FRterm·var (blue) and standardterm (black) and deviantterm (red) tone-evoked FRsterm·var on light-off (dark colors) and light-on (light colors) conditions. Right: mean difference between responses on light-on and light-off conditions. ( C ) Light suppresses PVsterm·def. ( E ) Light suppresses SOMsterm·def.

https://doi.org/10.7554/eLife.09868.025 An explanation for the difference of the effects of PVsterm·def and SOMsterm·def can be provided by examining the combined transfer function between pre-synaptic inputs and post-synaptic activity of excitatoryterm neurons separately for PVsterm·def and SOMterm suppressionterm ( Figure 7A , insets): light-driven modulation of PVterm activity has the same effect on excitatoryterm neuron responses at spontaneous, standardterm tone-evoked, and deviantterm tone-evoked activity ( Figure 7A , left inset). Spontaneous, standardterm, and deviantterm input levels all fall within the linear portion of the transfer function between inputs and change in the excitatoryterm neuron activity. On the other hand, for SOMsterm·def, modulation of their activity in the deviantterm tone-evoked regime drives small to no changes in excitatoryterm neuronal activity, whereas modulation of SOMterm activity in the spontaneous and standardterm tone-evoked regime drives significant changes in excitatoryterm neuronal activity ( Figure 7A , right inset). The deviantterm tone-evoked activity falls on the saturating part of the input–output transfer function, whereas the standardterm tone-evoked and spontaneous inputs fall on the linear part of the transfer function. Then, shifts in SOMterm inputs due to photosuppression evoke small changes during deviant toneterm·def responses, but larger changes during either standardterm or spontaneous activity. Either PVterm or SOMterm manipulation would result in reduction of combined SSAterm of excitatoryterm neurons.

The majority of neurons in the auditory cortexterm selectively reduce their responses to frequent, but not rare sounds, exhibiting SSAterm. However, the cortical mechanisms involved in the production and stimulus-specificity of SSAterm within the auditory cortexterm are not well understood. Here, we found that, in addition to adaptationterm at the level of thalamocortical inputs, two distinct types of interneuronsterm, PVsterm·def and SOMsterm·def, differentially contributed to SSAterm in the primary auditory cortexterm. Optogeneticterm·mth suppressionterm of either PVsterm·def or SOMsterm·def led to a reduction in SSAterm in putative excitatoryterm neurons ( Figure 3 ). Suppressionterm of PVsterm·def led to an equal increase in the FR of the putative excitatoryterm neurons in response to the standardterm toneterm and the deviant toneterm·def ( Figure 4 ). By contrast, suppressionterm of SOMsterm·def significantly increased the response to the standardterm toneterm but lacked a significant effect on the response to the deviant toneterm·def ( Figure 4 ). This series of findings expands on the ‘adaptationterm in narrowly tuned units’ modelterm·mth, which proposes that repeated presentation of the standardterm stimulus drives adaptationterm within more narrowly tuned inputs, such as thalamocortical inputs ( Mill et al., 2011 ; Taaseh et al., 2011 ; Nelken, 2014 ). Our data indicate dual effects of cortical inhibition on SSAterm: (1) PVsterm·def contribute to SSAterm by providing a constant level of inhibition, resulting in a relatively higher inhibitory drive during the presentation of the standardterm, as compared to the deviantterm. Taking into account the non-linear synaptic input to FR output function of a typical pyramidal neuron, the constant inhibition amplifies the effect of thalamocortical depression in suppressing the response of the neuron to repeated stimulus ( Figure 7A ). (2) The selective increase of the inhibitory drive from SOMsterm·def for standardterm stimulus as compared to the deviantterm stimulus responses might be explained by a shift in the non-linear transfer function between inputs to SOMsterm·def and their outputs to excitatoryterm neurons, possibly due to facilitation of SOM-to-excitatory neuron synapses ( Beierlein et al., 2003 ; Silberberg and Markram, 2007 ) ( Figure 7A ).

Surprisingly, we found that, despite the differential effect of PVterm and SOMterm suppressionterm on tone-evoked responses in putative excitatoryterm neurons, both PVsterm·def and SOMsterm·def exhibit SSAterm. This finding is consistent with previous results that found that thalamocortical synapses onto inhibitory neurons and synapses from inhibitory neurons to excitatoryterm cells can be depressing ( Tan et al., 2008 ; Ma et al., 2012 ). How does suppressionterm of these interneuronsterm result in differential reduction in SSAterm in excitatoryterm neurons? Our modelterm·mth provides an intuition for this effect: the mutually coupled excitatoryterm–inhibitory network modelterm·mth demonstrates that the observed differential effects of PVterm and SOMterm suppressionterm may be due to their differential action on excitatoryterm neuronal responses in the unadapted and adapted state ( Figure 7 ). Tone-evoked responses of PVsterm·def would fall on the linear portion of the transfer function between PVterm activity and excitatoryterm neuron depolarization, while the same tonesterm maximally affect inputs from SOMsterm·def onto excitatoryterm neurons, with SSAterm shifting the inputs to the linear, more sensitive range of inputs from SOMsterm·def. Thus, SSAterm may serve an additional function: to adjust the responses of neurons in a range that is more sensitive to small changes in the inputs from both excitatoryterm and inhibitory neuronal populations. More generally, the simulation demonstrates that a circuit element, such as PVsterm·def or SOMsterm·def, that itself adapts may further amplify adaptationterm in the excitatoryterm neurons.

To estimate the differential contribution of PVsterm·def or SOMsterm·def inputs to the excitatoryterm neurons, we measured the difference in the FR of neurons due to optogeneticterm·mth partial suppressionterm of their firing. This measurement provides an estimate of the change in the FR of the putative excitatoryterm neurons with the change in combined inputs to the inhibitory neurons, thereby allowing estimation of the synaptic transfer function ( Figure 7A , insets). A simple biologically plausible network incorporating these transfer functions can reproduce the observed responses ( Figure 7 ). There are several caveats to this interpretation. First, the FR may not linearly translate onto synaptic input strength because of the spiking non-linear rectification between the inputs and outputs of the putative excitatoryterm neuron: a small change in FR in the low-FR regime might correspond to a greater change in the synaptic drive than a similar-sized change in FR in the high-FR regime. However, our findings would still hold were this the case: in examining the effect of SOMterm suppressionterm on response to the deviantterm, the actual difference in the synaptic drive between the deviantterm and the standardterm would then be even greater than observed. At the other end of the non-linearity, the analysis of neuronal responses sorted based on their FR to the standardterm toneterm and the deviant toneterm·def revealed that the ‘ceiling effect’ would not contribute to a decreased effect of photostimulation on the response to the deviantterm in SOM-Cre mice ( Figure 4—figure supplements 4–7 ). Second, PVsterm·def and SOMsterm·def may inhibit not only the excitatoryterm neurons, but also each other. SOMsterm·def make synapses onto PVsterm·def ( Isaacson and Scanziani, 2011 ; Ma et al., 2012 ; Cottam et al., 2013 ), thereby potentially suppressing them with repeated presentation of the standardterm. Therefore, when SOMsterm·def are suppressed, some PVsterm·def may be disinhibited and provide a stronger suppressionterm of excitatoryterm neurons. The null effect on responses to the deviant toneterm·def during SOMterm suppressionterm could result from a combination of increase in inhibition from disinhibited PVsterm·def in addition to reduced inhibition of SOMsterm·def onto excitatoryterm neurons. Including inhibition from SOMsterm·def to PVsterm·def in the proof-of-principle modelterm·mth supported experimental findings ( Figure 7—figure supplement 2 ). Third, other interneuronterm types, such as vasopressin-positive interneuronterm may be involved in the circuit ( Pi et al., 2013 ), and the changes that we observe may reflect several inhibitory stages of processing.

One must be cautious in translating the data from our experiments as a strict description of neuronal activity in awake animals, as our results were based on recordings from mice under light isoflurane anesthesiaterm. Other forms of anesthesiaterm, such as pentobarbital-based ( Cheung et al., 2001 ; Gaese and Ostwald, 2001 ), ketamine ( Otazu et al., 2009 ) and high concentrations of isoflurane ( Cheung et al., 2001 ; Ter-Mikaelian et al., 2007 ), can affect multiple aspects of sound-evoked responses in the auditory cortexterm. Nonetheless, our results are likely to extend for awake mice, since isoflurane anesthesia-induced effects on neuronal activity decrease as the concentration of isoflurane is reduced to the levels used in our recordings ( Land et al., 2012 ). In addition, all recordings and manipulations were performed under identical anesthetic conditionsterm·var, and our conclusions are based on the relative comparison of the effects of suppressing PVsterm·def and SOMsterm·def, which are expected to hold under awake conditions ( Centanni et al., 2013 ).

While not demonstrated directly, SSAterm has been linked to detection of deviantterm sounds ( Ulanovsky et al., 2003 ), which may be facilitated by a relatively enhanced neuronal response to a change in the ongoing sound ( Nelken et al., 2003 ; Winkler et al., 2009 ; Grimm and Escera, 2012 ). By suppressing the responses to a frequently presented toneterm, the responses of neurons to a rare stimulus become relatively enhanced. However, whether and how modulating SSAterm in the auditory cortexterm affects auditory behavior has not yet been tested. Inhibitory interneuronsterm may prove to have a complementary role in shaping auditory perception in addition to receptive field reorganization driven by synaptic plasticity ( Froemke et al., 2013 ). The use of optogeneticterm·mth methods to test the function of inhibitory interneuronsterm in SSAterm overcomes the limitations of lesion or pharmacological studies ( Elliott and Trahiotis, 1972 ; Duque et al., 2014 ), which only allow for prolonged, non-selective inactivation ( Moore et al., 2001 ). By combining optogeneticterm·mth manipulation of interneuronterm activity with behavioral measurements, future experiments will explore whether interneuron-mediated SSAterm indeed affects the auditory behavior of the subject, such as enhanced ability to detect unexpected events.

All experiments were performed in adult male mice (Jackson Laboratories, Bar Harbor, ME, United States; age, 12–15 weeks; weight, 22–32 g; PV-Cre mice, strain: B6;129P2-Pvalbtm1(cre)Arbr/J ; SOM-Cre: Ssttm2.1(cre)Zjh/J ) housed at 28°C on a 12-hr light:dark cycle with water and food provided ad libitum. In PV-Cre mice, Cre recombinase (Cre) is expressed in parvalbumin-positive interneuronsterm; in SOM-Cre mice, Cre is expressed in somatostatin-positive interneuronsterm ( Taniguchi et al., 2011 ). This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to a protocol approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania (Protocol Number: 803266). All surgery was performed under isoflurane anesthesiaterm, and every effort was made to minimize suffering.

Modified AAVs were obtained from Penn Vector Core (Philadelphia, PA, United States). Modified AAV encoding Arch under FLEX promoter was used for selective suppressionterm of PVsterm·def or SOMsterm·def (catalog number AV-9-PV2432, AAV9.CBA.Flex.Arch-GFP.WPRE.SV40, Addgene22222, serotype 2/9) ( Chow et al., 2010 ). Modified AAV encoding GFP alone under FLEX promoter was used as a control for the specific action of Arch on the neuronal populations (catalog number AV-9-ALL854, AAV9.CAG.Flex.eGFP.WPRE.bGH, Allen Institute 854, serotype 2/9). Modified AAV encoding ChR2 under FLEX promoter was used for selective excitation of PVsterm·def or SOMsterm·def (catalog number AV-9-18917P, AAV9.CAGGS.Flex.ChR2-tdTomato.WPRE.SV40, Addgene18917, serotype 2/9).

2–3 weeks prior to the start of experimental recordings, a 0.5-mm diameter craniotomy was drilled over primary auditory cortexterm (2.6 mm caudal and 4.1 mm lateral from bregma) under aseptic conditions while the mouse was anesthetized with isoflurane. A 750 nl bolus of AAV in water was injected into A1 (1 mm ventral from pia mater) using a stereotaxic syringe pump (Pump 11 Elite Nanomite, Havard Apparatus, Holliston, MA, United States). The craniotomy was covered with bone wax and a small custom head-post was secured to the skull with dental acrylic.

All recordings were carried out inside a double-walled acoustic isolation booth (Industrial Acoustics, Bronx, NY, United States). Electrodes were targeted to A1 on the basis of stereotaxic coordinates and in relation to blood vessels. In electrophysiological recordings, the location was confirmed by examining the click and tone-pip responses of the recorded units for characteristic responses of neurons in core auditory areas, as described previously by our group in the rat ( Carruthers et al., 2013 ) and by other groups in the mouse ( Linden and Schreiner, 2003 ; Guo et al., 2012 ; Marlin et al., 2015 ). While the electrodes were targeted to A1, some recordings may include data from the anterior auditory field, adjacent to A1 ( Linden et al., 2003 ). Mice were placed in the recording chamber, anesthetized with isoflurane, and the headpost secured to a custom base, immobilizing the head. After drilling a craniotomy and creating a durotomy exposing auditory cortexterm, a silicon multi-channel probe (A1x32-Poly2-5mm-50s-177 [Poly-2] or A1x32-tri-5mm-91-121-A32 [Triode], Neuronexus Ann Arbor, MI, United States) was slowly lowered to between 750 µm and 1 mm into the cortexterm, perpendicular to the cortical surface and used to record electrical activity. Raw signals from 32 channels were bandpass filtered at 600–6000 Hz and thresholded for spike analysis, or at 10–300 Hz for LFP and CSD analysis (Poly-2 probe only), digitized at 32 kHz and stored for offline analysis (Neuralynx, Bozeman, MT, United States). Common-mode noise was removed by referencing a probe inserted in the brain outside the auditory cortexterm. On the Poly-2 probe, two rows of 16 electrodes each on a single shank were arranged such that each electrode site was 50 µm away from all three closest neighbors. This arrangement allowed us to record densely across depth, that is, one electrode for every 25 µm in depth. On the triode, electrodes were arranged in groups of three equidistant sites, forming an equilateral triangle (25-µm separation). The triodes were separated vertically by 91-µm center-to-center distance, spanning 1 mm, with two additional single sites, one on each end.

Spike sorting was performed using commercial software (Offline Sorter, Plexon, Dallas, TX, United States) ( Carruthers et al., 2013 ). In order to improve isolation of single units from recordings using low-impedance probes, spiking activity was sorted across three (triode, 25-µm separation) or four (poly-2, 50-µm separation) adjacent electrode sites ( Niell and Stryker, 2008 ; Olsen et al., 2012 ). We used a stringent set of criteria to isolate single units from multiunit clusters ( Otazu et al., 2009 ; Bizley et al., 2010 ; Brasselet et al., 2012 ; Durand et al., 2012 ; Carruthers et al., 2013 ; Picard et al., 2014 ; Carruthers et al., 2015 ). Single-unit clusters contained <1% of spikes within a 1.0-ms interspike interval, and the spike waveforms across 3 or 4 channels had to form a visually identifiable distinct cluster in a projection onto a three-dimensional subspace. Putative excitatoryterm neurons were identified based on their expected response patterns to sounds and the lack of significant suppressionterm of the spontaneous FRterm·var due to light ( Lima et al., 2009 ; Moore and Wehr, 2013 ). While this subpopulation may still contain inhibitory neurons, only 2% of all recorded neurons were significantly photosuppressed at baseline (one-sided paired t-testterm·stat, significance taken at p < 0.05). The low impedance of the extracellular probes precluded us from conducting a more detailed analysis of cortical subpopulations based on the spike waveform ( Bartho et al., 2004 ; Moore and Wehr, 2013 ).

Stimuli were delivered via a magnetic speaker (Tucker-David Technologies, Alachua, FL, United States), directed toward the mouse's head. Speakers were calibrated prior to the experiments to ±3 dB over frequencies between 1 and 40 kHz, by placing a microphone (Brüel and Kjaer, Denmark) in the location of the ear contralateral to the recorded A1 hemisphere, recording speaker output and filtering stimuli to compensate for acoustic aberrations ( Carruthers et al., 2013 ). First, to measure tuning, a train of 50 pure tonesterm of frequencies spaced logarithmically between 1 and 80 kHz, at 65-dB sound pressure level (SPL) relative to 20 µPa, in pseudorandom order, was presented 20 times. Each toneterm was 100-ms long, with an inter-stimulus interval (ISI) of 300 ms. Frequency response functions were calculated online for several multiunits, and two frequencies (separated by 0.39 octaves), which elicited spiking responses of similar strength, were selected as toneterm A and B. Next, a series of stimuli composed of tonesterm A and B were presented in interleaved blocks, repeated four times. Each oddball stimulus consisted of a train of 653 A and B tonesterm (100-ms long, 300-ms ISI, 65-dB SPL). In oddball stimulus 1, 90% of the tonesterm were A (standardterm), while 10% of the tonesterm were B (deviantterm). We used a frozen sequence of standardterm and deviant tonesterm·def in pseudorandom order and counterbalanced with respect to the number of standardterm tonesterm preceding each deviantterm. In oddball 2, the probabilities of tonesterm·var A and B were reversed so that toneterm B was the standardterm and A the deviantterm. In the equal probabilityterm stimulus, A and B each comprised 50% of tonesterm.

An optic fiber was use to direct 532-nm laser light (Shanghai Laser & Optics Century, China). After positioning the silicon probe, an optic fiber was placed over the surface of auditory cortexterm. To limit Becquerel effect artifacts due to light-striking electrodes, we positioned the optical fiber parallel to the silicon probe ( Han et al., 2009 ; Kvitsiani et al., 2013 ). During every fifth toneterm of the oddball and equal probabilityterm stimuli, light was cast over A1 to suppress interneuronsterm. The light onset was 100 ms prior to toneterm onset, and lasted for 250 ms. At 180 mW/mm 2 , light pulses were intense enough to significantly modulate multiunit activity throughout all cortical layers. The effect of optical stimulation was not significant for responses to subsequent tonesterm ( Figure 3—figure supplement 1 ).

Brains were post-fixed in paraformaldehyde (4%, PFA) and cryoprotected in 30% sucrose. Coronal sections (40 µm) were cut using a cryostat (CM1860, Leica, Allendale, NJ, United States), washed in PBS containing 0.1% Triton X-100 (PBST; three washes, 5 min), incubated at room temperature in blocking solution (for PVterm, 10% normal goat serum and 5% bovine serum albumin in PBST; for SOMterm, 10% normal goat serum with 0.1% sodium azide and 2% cold water fish gelatin in PBS; 3 hr), and then incubated in primary antibody diluted in blocking solution overnight at 4°C. The following primary antibodies were used: anti-PV (PVterm 25 rabbit polyclonal, 1:500, Swant, Switzerland) or anti-SOM (AB5494 rabbit polyclonal, 1:200, Millipore, Billerica, MA, United States). After incubation, sections were washed in blocking solution (three washes, 5 min), incubated for 2 hr at room temperature with secondary antibodies (Alexa 594 goat anti-rabbit IgG; for PVterm 1:1000 and SOMterm 1:400), and then washed in PBS (three washes, 5 min each). Sections were mounted using Fluoromount-G (Southern Biotech, Birmingham, AL, United States) and confocal images were acquired (Leica SP5). Cells were identified in independent fluorescent channels and subsequently scored for co-localization by hand using ImageJ's cell counter plug-in. Transfection efficiencyterm·def is the percent of antibody-labeled neurons, which are co-labeled with GFP. Transfection specificityterm·def is the percent of GFP-expressing neurons, which are co-labeled with the antibody.

Acute brain slices were prepared from mice using standardterm techniques essentially as previously described ( GoldbergpersName et al., 2011 ). Mice were anesthetized via inhaled isoflurane and then transcardially perfused with 10 ml of oxygenated, ice-cold artificial cerebrospinal fluid (ACSF) at a rate of 5 ml/min, that contained, in mM: 87 NaCl, 75 sucrose, 2.5 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 10 glucose, 0.5 CaCl 2 , 4 MgSO 4 . Slices (300-µm thick) were cut on a Leica VT1200S and incubated in cutting solution in a holding chamber at 32°C for approximately 30 min followed by continued incubation at room temperature prior to electrophysiological recording, at which point slices were transferred to a submersion-type recording chamber attached to the microscope stage. ACSF used for recording contained, in mM: 125 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 10 glucose, 2 CaCl 2 , and 1 MgSO 4 . The solution was continuously bubbled with 95% O 2 and 5% CO 2 throughout cutting, slice incubation, and recording, so as to maintain a pH of approximately 7.4.

Cells were identified via GFP expression under epifluorescence microscopy and subsequently visualized using a 40×, 0.8 NA water-immersion objective (Olympus, Center Valley, PA, United States) on an Olympus BX-61 upright microscope equipped with infrared differential interference contrast optics. Recordings were performed using the whole-cell patch clamp technique. Access resistance (Ra) was <25 MΩ upon break-in; data obtained from a given cell were rejected if Ra changed by >20% during the course of the experiment. Internal solution contained, in mM: potassium gluconate, 130; potassium chloride, 6.3; EGTA, 0.5; MgCl 2 , 1.0; HEPES, 10; Mg-ATP, 4; Na-GTP, 0.3; biocytin, 0.1%. Osmolarity was adjusted to 285–290 mOsm using 30% sucrose. Voltage was recorded using a MultiClamp 700B amplifier (Molecular Devices, Union City, CA, United States), lowpass filtered at 10 kHz, digitized at 16-bit resolution (Digidata 1550, Axon Instruments, Sunnyvale, CA, United States), and sampled at 20 kHz. pCLAMP 10 software was used for data acquisition, and analysis was performed using the Clampfit module of pCLAMP.

Cells were illuminated with a 561-nm solid state laser (Coherent, Santa Clara, CA, United States) routed to the standardterm X-Y galvanometer of a two-photon microscope (Bruker Corporation, Billerica, MA, United States) via a single-mode fiber. Illuminance at the specimen was estimated using a 10-µm pinhole aperture (Edmund Optics, Barrington, NJ, United States) and a photodiode power sensor (Thorlabs, Newton, NJ, United States).

For each putative excitatoryterm neuron, the spontaneous FRterm·var and tone-evoked FRsterm·var were measured as the mean FR over 50 ms pre- and post-tone onset, respectively. For each identified interneuronterm, FRs were measured 100 ms pre- and post-tone onset. FR was measured separately for each toneterm, A and B, as standardterm, deviantterm, and equal probabilities, and for light-off and light-on trials. FR normalization was carried out separately for each toneterm, A and B, for each neuron by dividing the response under all conditions by the maximum FR (across 5-ms bins) of the deviant toneterm·def, light-off condition. Performing this normalization by dividing response in all conditions by the mean, rather than maximum FR of the deviant toneterm·def, light-off condition did not alter significant results ( Figure 4—figure supplement 8 ). For all FR analyses, each neuron's responses to tonesterm A and B were treated separately, and each was only included if the light-off deviantterm tone-evoked FRterm·var was significantly greater than the spontaneous FRterm·var (Wilcoxon signed-rank test p < 0.05). Further, toneterm responses were only included in analysis if the neuronal FR during each oddball stimulus exceeded 0.02 Hz, and the neuron was significantly tuned to the toneterm. Tuning was considered significant if the spike count in response to a toneterm (A or B) was significantly higher than the pool of spike counts across all tonesterm outside one octave band centered on tonesterm A and B (N = 42, t-testterm·stat, p1term·def < 0.05). Population responses in each condition were measured as the mean and standard error of FRsterm·stat across toneterm responses in each experimental group.

For each neuron, SSA indexterm·var is a measure of the strength of SSAterm based on its mean FR with respect to toneterm probabilityterm. FRs to tonesterm A and B were summed according to their standardterm or deviantterm probabilityterm within each oddball stimulus ( Ulanovsky et al., 2003 ). Thus, SSA indexterm·var was computed as: S S A I n d e x = ( D A + D B ) − ( S A + S B ) D A + D B + S A + S B , where S and D indicate the mean FR for standardterm and deviantterm trials, respectively, and their subscripts indicate the toneterm frequency condition. SSA indexterm·var was computed separately for light-off and light-on conditions. Population SSAterm indices were measured as the mean and standardterm error of SSAterm indices across all neurons of each population. Criteria for inclusion in the analysis were the same as in toneterm response FR analysis described above, with the added criterion that the deviantterm tone-evoked FRterm·var must be greater than spontaneous FRterm·var for each of tonesterm A and B (Wilcoxon signed-rank test p < 0.05).

To calculate the CSD, the net current density moving through cortical tissue at 32 positions along the cortical axis was calculated based on LFPs of responses to tonesterm recorded on each electrode, by using the second order central finite difference to calculate the second spatial derivative across the LFPs over the vertically arranged electrodes ( Szymanski et al., 2009 ). Across the CSD profile, the deepest current sink corresponds to the thalamo-recipient granular layer ( Kaur et al., 2005 ; Szymanski et al., 2009 ) allowing us to reconstruct the laminar location of recorded neurons. Neurons recorded on electrodes falling within the deepest sink were assigned to the granular layer, while those superior and inferior were assigned to the supra-granular and infra-granular layers ( Figure 1E,F , Figure 4—figure supplement 3 ). The tone-evoked amplitude of the CSD was measured by first calculating root mean square of each channel during the first 50-ms post-tone onset, and then calculating the mean across all electrodes determined to fall within either the deepest short latency sink (granular layer) or pooled across all electrodes either above (supra-granular layer) or below (infra-granular layer). For each session, the granular layer CSD amplitude for all toneterm conditions was normalized across conditions by the deviant toneterm·def, light-off condition, and the mean across sessions was statistically analyzed. The SSA indexterm·var was calculated as described in SSA indexterm·var on the basis of the amplitude.

For all statistical tests in which N ≥ 30, we applied the Student's t -testterm·stat (Matlab, Mathworks, Natick, MA, United States) unless specified otherwise, and reported the p-value, degrees of freedom, and t-statistic. For all tests with N < 30, sample variance was tested for normality using the Komogorov–Smirnov testterm·stat. If any group's variance was non-normal, we applied a non-parametric test, for example, Wilcoxon sign rank or rank sum testterm·stat (Matlab), and provided the z-statistic for any group with a normal distribution. For all tests, Bonferroni correction was applied for multiple comparisonsterm·stat and reported as ‘C = X’ where X is the factor by which the p-value was adjusted. Statistical tests were single-tailedterm·stat if there was a reasonable prior expectation about the direction of the difference between samples. p1term·def refers to one-sided, and p2term·def refers to two-sided statistics set. In all figures, single, double, and triple stars indicate p < 0.05, 0.01, and 0.001, respectively. Error bars in all figures represent the standard error of the meanterm·stat, unless otherwise noted.

We constructed modelsterm·mth of the excitatoryterm–inhibitory neuronal circuit to understand the coupling of excitatoryterm interneuronsterm with PVterm and SOMterm interneuronsterm. We constructed firing-rate modelsterm·mth based on Wilson–Cowan dynamics ( Staiger et al., 1996 ; Xu et al., 2010 , Rudy et al., 2011 ). The parameters were chosen in order to achieve a match to experimental data. The mean activity level of each population was modeled as: dE dt = 1 τ E [ − E ( t ) + ( k − r ) S ( j ETone ( t ) + S inh ( j IE I ( t ) ) ) ] , dI dt = 1 τ I [ − I ( t ) + ( k − r ) S ( j inh ( t ) + j ITone ( t ) + j EI E ( t ) ) ] , where E(t) is the activity of the excitatoryterm population; I(t) is the activity of the inhibitory population; S(x) is the transfer function between the combined ‘synaptic’ input and the neuronal FR. S(x) is linear with respect to intermediate inputs, but imposes a minimum and maximum activation limits. S inh (x) is the transfer function between the inhibitory FR and excitatoryterm post-synaptic current; j EI and j IE are excitatoryterm–inhibitory and inhibitory–excitatoryterm synaptic weights (0.2 and −1.0 for PVsterm·def, 0.05 and −0.39 for SOMsterm·def, respectively); j ETone (t) and j ITone (t) are tone-evoked input currents to excitatoryterm and inhibitory neurons, respectively, modeled as 50-ms long exponentially decaying inputs of maximum amplitude 3 (delayed by 7 ms for SOMsterm·def, which do not receive direct thalamicterm inputs, relative to PVsterm·def, which receive direct thalamicterm inputs); τ E (10 ms) and τ I (10 ms) are synaptic time constants for excitatoryterm and inhibitory neurons; k and r represent the maximum and minimum FR of neurons, respectively, (k = 15, r = 1); j inh (t) is the negative input to inhibitory neurons due to Arch. The optogeneticterm·mth modulation was modeled as a unitary 250-ms pulse. To capture the differences in inputs due to repeated toneterm exposures, we modeled thalamicterm inputs reflecting the toneterm inputs with synaptic depression. We modeled the conductance of the thalamicterm projections, g Inp , as changing according to the equation: dg Inp dt = ( g 0 − g Inp ) / T g − ( g Inp r ) / T r , where g 0 is the maximum conductance (g 0 = 1), r is the gating coefficient representing tone-evoked thalamicterm input, T g is the time scale for replenishment (T g = 3 s), T r is the time scale for depletion (T r = 80 ms). We took r to be a step function with an exponential decay (with 40-ms time constant and amplitude of 3). The full input to auditory cortical neural populations is then equal to g Inp r. In a train of four tonesterm, the first tone-evoked response was taken as the deviant toneterm·def, and the fourth toneterm as the standardterm toneterm.

For the inhibitory-to-excitatory inputs, we used a sigmoidal transfer function and showed the existence of parameter regimes consistent with our results. For PVsterm·def, we used a sigmoid of the form: S PVterm ( r PVterm ) = 1 1 + exp [ − p ( r PVterm − θ ) ] , where p = 0.3 and θ = 9. This gives a facilitating response at low input levels and a linear response at high input levels. For SOMsterm·def, we used a hyperbolic tangent that provided a saturating non-linearity: S SOMterm ( r SOMterm ) = 1 − exp [ − 2 r SOMterm / s ] 1 + exp [ − 2 r SOMterm / s ] , where s = 3. For visualization, the baseline FR of neurons was removed and the peak response to a ‘deviantterm’ toneterm without optogeneticterm·mth manipulation normalized to 1.

We also constructed a modelterm·mth with additional coupling between the PVterm and SOMterm interneuronsterm using a generalization of the above dynamics, which may be written as: dN i dt = 1 T i ( − N i + ( k − r ) S ( j toneterm , i ( t ) + j ext , i ( t ) + ∑ k j ki *S k ( N k ) ) ) , where N i is the FR of the ith population (EXC, PVterm, SOMterm), T i = 10 ms is the time constant for each population, k = 15, r = 1, S has different maximum and minimum values for each population (x min,E = −1, x max,E = 1.75, x min,PVterm = −0.5, x max,PVterm = 4, x min,SOMterm = 0, x max,SOMterm = 3). S E (x) = x, and S SOMterm and S PVterm use the definitions above. j E,E = j SOMterm,SOMterm = j PVterm,PVterm = j PVterm,SOMterm = 0, j E,SOMterm = 0.25, j SOMterm,E = −0.25, j E,PVterm = 0.4, j PVterm,E = −1, and j SOMterm,PVterm = −0.1. j ext,PVterm = 1.5, j ext,SOMterm = 1. Toneterm inputs are the same as described above.

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https://doi.org/10.1016/j.neuroscience.2011.01.060 Google Scholar Author details Ryan G NatanpersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution RGN, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article Competing interests The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3123-4833 John J BrigugliopersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution JJB, Analysis and interpretation of data, Drafting or revising the article Competing interests The authors declare that no competing interests exist.

Laetitia Mwilambwe-TshilobopersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution LM-T, Acquisition of data, Analysis and interpretation of data Competing interests The authors declare that no competing interests exist.

Sara I JonespersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution SIJ, Acquisition of data, Analysis and interpretation of data Competing interests The authors declare that no competing interests exist.

Mark AizenbergpersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution MA, Acquisition of data, Analysis and interpretation of data Competing interests The authors declare that no competing interests exist.

Ethan M GoldbergpersName Department of Neurology, University of Pennsylvania, Philadelphia, United States Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United States Contribution EMG, Acquisition of data, Analysis and interpretation of data Competing interests The authors declare that no competing interests exist.

Maria Neimark GeffenpersName Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Contribution MNG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article For correspondence mgeffen@med.upenn.edu Competing interests The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3022-2993 Maria Neimark GeffenpersName Maria Neimark GeffenpersName Maria Neimark GeffenpersName Maria Neimark GeffenpersName Mark AizenbergpersName Maria Neimark GeffenpersName Ethan M GoldbergpersName Ryan G NatanpersName John J BrigugliopersName John J BrigugliopersName Maria Neimark GeffenpersName Ethan M GoldbergpersName The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

This work was supported by NIH R03DC013660, NIH R01DC014479, Klingenstein Award in Neuroscience, Human Frontier in Science Foundation Young Investigator Award, and the Pennsylvania Lions Club Hearing Research Fellowship to MNG and NARSAD Young Investigator Award to MA. RGN is supported by NIH NIMH T32MH017168. JJB is supported by NSF PHY1058202 and US-Israel BSF 2011058. EMG is partially supported by NINDS K12 NS049453 and the Burroughs Wellcome Fund Career Award for Medical Scientists. MNG is the recipient of the Burroughs Wellcome Fund Award at the Scientific Interface. EMG is the recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. The authors thank Jennifer Blackwell, Lisa Liu, Anh Nguyen, Daniel Feingold, Danielle Mohabir, Joshua Margolis, and Andrew Chen for technical support with experiments; Vijay Balasubramanian, Yale Cohen, Steven Eliades, Diego Contreras, Andrea Hasenstaub, and the members of the GeffenpersName laboratory for insightful discussions and helpful comments; and Karl Deisseroth for providing the MTA for the use of some of the viruses.

Animal experimentation: All experimental procedures are in accordance with NIH guidelines and approved by the IACUC at University of Pennsylvania (protocol number 803266).

© 2015, NatanpersName et al.

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