A Non-canonical Feedback Circuit for Rapid Interactions between Somatosensory Cortices

Sensory perception depends on interactions among cortical areas. These interactions are mediated by canonical patterns of connectivity in which higher areas send feedback projections to lower areas via neurons in superficial and deep layers. Here, we probed the circuit basis of interactions among two areas critical for touch perception in mice, whisker primary (wS1) and secondary (wS2) somatosensory cortices. Neurons in layer 4 of wS2 (S2L4) formed a major feedback pathway to wS1. Feedback from wS2 to wS1 was organized somatotopically. Spikes evoked by whisker deflections occurred nearly as rapidly in wS2 as in wS1, including among putative S2L4 → S1 feedback neurons. Axons from S2L4 → S1 neurons sent stimulus orientation-specific activity to wS1. Optogenetic excitation of S2L4 neurons modulated activity across both wS2 and wS1, while inhibition of S2L4 reduced orientation tuning among wS1 neurons. Thus, a non-canonical feedback circuit, originating in layer 4 of S2, rapidly modulates early tactile processing

Neocortical Rebound Depolarization Enhances Visual Perception

<div><p>Animals are constantly exposed to the time-varying visual world. Because visual perception is modulated by immediately prior visual experience, visual cortical neurons may register recent visual history into a specific form of offline activity and link it to later visual input. To examine how preceding visual inputs interact with upcoming information at the single neuron level, we designed a simple stimulation protocol in which a brief, orientated flashing stimulus was subsequently coupled to visual stimuli with identical or different features. Using in vivo whole-cell patch-clamp recording and functional two-photon calcium imaging from the primary visual cortex (V1) of awake mice, we discovered that a flash of sinusoidal grating per se induces an early, transient activation as well as a long-delayed reactivation in V1 neurons. This late response, which started hundreds of milliseconds after the flash and persisted for approximately 2 s, was also observed in human V1 electroencephalogram. When another drifting grating stimulus arrived during the late response, the V1 neurons exhibited a sublinear, but apparently increased response, especially to the same grating orientation. In behavioral tests of mice and humans, the flashing stimulation enhanced the detection power of the identically orientated visual stimulation only when the second stimulation was presented during the time window of the late response. Therefore, V1 late responses likely provide a neural basis for admixing temporally separated stimuli and extracting identical features in time-varying visual environments.</p></div

Biphasic responses of field potentials in mouse and human visual cortex to grating flashes.

<p>(A) LFPs were recorded from L2/3 of the V1 and retrosplenial cortex, while a full-field grating flash was presented to the contralateral eye of an awake mouse. Two negative potentials appeared after a flash. The gray areas indicate the SDs. The arrows in the bottom cross correlograms indicate the peak offsets, which show that early and late responses occurred earlier in V1 than in the retrosplenial cortex. (B) Human EEGs were recorded from O1 and O2, indicated in the left schematic. ERPs in responses to grating flashes are shown as mean ± SD of 10 participants. The arrows indicate early and late negative potentials. The bottom plot represents the <i>p</i>-values from the prestimulus baseline at the corresponding time points, indicating the presence of early and late responses. (C) Flashes with shorter durations induced more evident late responses in mouse V1 LFPs.</p

Flash-evoked biphasic responses in mouse V1 neurons.

<p>Cell-attached recordings (A and B) and whole-cell recordings (C and D) were acquired from V1 L2/3 neurons in awake, head-restricted mice whose contralateral eyes were presented 0.05-s full-field grating flashes at pseudorandom intervals of 8–10 s for 80–200 trials. (A) Raw traces of cell-attached recordings at 10 consecutive trials, the spike raster plots of the 80 trials and their periflash time histograms of the firing rates for two typical neurons. Cell 24 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002231#pbio.1002231.s001" target="_blank">S1 Data</a>) fired action potentials with short latencies, whereas cell 41 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002231#pbio.1002231.s001" target="_blank">S1 Data</a>) fired action potentials with longer latencies. (B) Data from 76 cells from 58 mice are pooled. The inset pie chart indicates the distribution of cells with early spiking (E), late spiking (L), and no activity change (others). (C) The top raw traces show <i>V</i>_<i>m</i> responses in 10 consecutive trials in a representative neuron. <i>V</i>_<i>m</i> responses for 50 trials in the same neuron (middle pseudocolored map) were averaged in the bottom trace. The gray area indicates the standard errors of the mean (SEMs). (D) Mean ± SD of the subthreshold <i>V</i>_<i>m</i> responses of 34 cells from 30 mice.</p

Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding

<div><p>Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca²⁺ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca²⁺ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca²⁺ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca²⁺ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca²⁺ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.</p></div

Flash-induced facilitation of <i>V</i>_<i>m</i> response to subsequent visual information.

<p>(A) A schematic showing the visual stimulation protocol without (vDrift-only, control) and with (Flash+vDrift) 0.05-s full-field grating flashes followed by 2-s drifting vertical gratings (vDrift) with various SOAs. vDrift-only and Flash+vDrift trials were compared to measure how the preceding flash modulated the <i>V</i>_m response to vDrift. In some of the trials, Flash was presented alone (Flash-only) to record flash-induced responses. (B) Mean subthreshold <i>V</i>_m responses of a representative whole-cell recorded neuron (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002231#pbio.1002231.s004" target="_blank">S4 Data</a>). The timing and pattern of visual stimulation are indicated above the traces. The linear sum of responses was calculated by a simple addition of Flash-only and vDrift-only responses. (C) Means ± SEMs of the amplitudes of the Flash+vDrift responses relative to vDrift-only responses at a SOA of 0.5 s were plotted against the amplitudes of the Flash-only responses. The stimulus combination was described as Δorientation, which indicates the orientation difference between the Drift and vFlash. Black and gray symbols indicate Δorientation = 0° and 90°, respectively. (D) Means ± SEM of the amplitude of the Flash+vDrift response relative to the linear sum at SOA of 0.05, 0.5, and 3 s. Black and gray symbols indicate Δorientation = 0° and 90°, respectively (0.5 s: **<i>p</i> = 5.0 × 10⁻³ versus Δorientation = 90°, <i>t</i>₂₅ = 3.07, <i>n</i> = 26 cells from 25 mice, paired <i>t</i> test). (E) The data at an SOA of 0.5 s in (D) were divided along the orientation preferences of the neurons.</p

Orientation selectivity of late V1 response.

<p>(A) Left, raw traces in 10 trials of cell-attached recordings, raster plots of spike responses in 80 trials, and periflash time histograms of the firing rates for four orientations of the grating flash stimulation in a representative neuron (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002231#pbio.1002231.s003" target="_blank">S3 Data</a>). The orientations are shown in different colors. Right, the orientation tuning curve of the same neuron. The evoked spike counts were normalized to the maximum. (B) The cumulative probability distribution of the OSIs of the 36 late-spiking cells (Real) was compared with its chance distribution (Surrogate) that was obtained by 1,000 random shufflings of the stimulus trials. The real OSIs were biased rightward compared with the surrogate OSIs (<i>p</i> = 3.3 × 10⁻³, <i>D</i> = 0.29, Kolmogorov-Smirnov test). (C) Left traces represent the mean ± SD of subthreshold <i>V</i>_<i>m</i> responses of an example cell (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002231#pbio.1002231.s003" target="_blank">S3 Data</a>) to grating flashes with four orientations. The right plot indicates the orientation tuning curves of the mean amplitude of the early and late <i>V</i>_<i>m</i> depolarizations of the same neuron. (D) The cumulative fraction of the OSIs in the late <i>V</i>_<i>m</i> responses were biased rightward compared with their surrogate OSIs (<i>n</i> = 34 cells, <i>p</i> = 2.7 × 10⁻⁹, <i>D</i> = 0.66, Kolmogorov-Smirnov test). (E) The correlation coefficients between the early and late tuning curves for individual cells were higher compared with their chance values calculated by random trial-shuffling of the early responses (<i>n</i> = 34 cells, <i>p</i> = 0.014, <i>D</i> = 0.27, Kolmogorov-Smirnov test). (F) Scatter plots of the OSIs in early and late responses for individual cells. Each dot indicates a single cell. The gray line is the diagonal, and the dash line is the best linear fit.</p

Excitation-contraction coupling in papillary muscle with and without fibrosis.

<p>Tension and Ca²⁺ transients in papillary muscles simultaneously measured by the aequorin method. A: Representative traces in tension (upper) and intracellular Ca²⁺ (lower) in each sample. B: Summarized data of peak value in each sample. C: Summarized data of the peak time of tension and intracellular Ca²⁺. D: Summarized data of relaxation time. E: Summarized data of tension divided by the cross-sectional area of the muscle in each sample.Values are means ± SE; n = 28 in Sham (S), n = 23 in hypertrophy without fibrosis (F-), and n = 10 in hypertrophy with fibrosis (F+).</p

Myocardial stiffness in papillary muscle with and without fibrosis.

<p>The relationship between muscle stretch and resting tension in papillary muscle. On the x-axis, each muscle length was normalized by Lmax, at which papillary muscle developed maximum active tension. On the y-axis, muscle resting tension was normalized by maximum active tension at Lmax. Filled squares: Sham; open circles: F- (hypertrophy); and gray triangles: F+ (hypertrophy with fibrosis). Values are means ± SE; n = 21 in Sham, n = 17 in F-, and n = 4 in F+.</p