Article

A Top-Down Cortical Circuit for Accurate Sensory Perception

Authors:
  • University of Yamanashi, Division of Medicine
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Abstract

A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. In vivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit. Copyright © 2015 Elsevier Inc. All rights reserved.

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... While L5 distal tufts are electrically remote and far from the soma, they are in close proximity to the highly electrogenic calcium spike initiation zone at the main bifurcation of the apical dendrite, and form a separate biophysical and processing compartment from the proximal dendrites (Amitai et al., 1993;Yuste et al., 1994;Schiller et al., 1997;Larkum et al., 2009;Sandler et al., 2016). Top-down signals arriving at the tuft can trigger tuft-wide dendritic calcium spikes in L5 neurons (Manita et al., 2015), which can modulate synaptic plasticity across the entire dendritic tree Roelfsema and Holtmaat, 2018 and potently drive somatic burst firing (Larkum et al., 2009;Larkum and Zhu, 2002;Larkum et al., 2004;Schwindt and Crill, 1999;Larkum et al., 2001;Manita et al., 2017). Consistent with this observation, L5 apical dendrite activity is highly correlated with somatic activity (Francioni et al., 2019;Beaulieu-Laroche et al., 2019). ...
... L5 pyramidal neurons are the major source of output from cortex, targeting numerous subcortical structures that affect behavior. The activity of apical dendrites is known to correlate with stimulus intensity, and manipulating L5 apical dendrites and their inputs impacts performance of sensory tasks (Manita et al., 2015;Xu et al., 2012;Takahashi et al., 2020;Takahashi et al., 2016). Apical dendritic calcium spikes of pyramidal cells could be a crucial cellular mechanism in learning-related plasticity and behavioral modification (Roelfsema and Holtmaat, 2018;Bittner et al., 2017;Doron et al., 2020). ...
... and CS-reliably evoked an influx of calcium that robustly activated the tuft (examples in Figure 2c). Successful calcium events across tufts averaged 28% ΔF/F, consistent with previous studies of layer 5 apical dendrites (Manita et al., 2015;Xu et al., 2012). Interestingly, during intermediate but not early learning, the average population response to the CS+ exhibited a two-peak structure ( Figure 2-figure supplement 1, session 4) similar to tuft reward-related signals we observed previously in barrel cortex (Lacefield et al., 2019). ...
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Learning alters cortical representations and improves perception. Apical tuft dendrites in cortical layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of layer 5 pyramidal neurons in barrel cortex as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task.
... In order to constrain the functional range of the model to a regime comparable to in vivo data, we performed a calibration of three parameters in order to reproduce observed latencies in L5 (Manita et al., 2015) of the first and second components of evoked responses in area X (∼ 23 ms and ∼ 110 ms, respectively) and the first component of the response in area Y (∼ 80 ms). These parameters are (described in detail in Isbister et al., 2023): R OU , the ratio of standard deviation 6 to mean of the Ornstein-Uhlenbeck (OU) noise process injected to each cell, P F R , the fraction of the target per-layer in vivo firing rates, and F p , the fraction of thalamic fibers activated in a stimulus (a measure of stimulus strength). ...
... We have exhibited a well-defined cortico-cortical loop between the two areas, wherein thalamic inputs to area X produce an activation of area X that propagates to area Y through feed-forward pathways, and then comes back to area X through feedback pathways. Notably, we have reproduced peak latencies in L5 firing (Manita et al., 2015) and observed responses with comparable amplitude in both areas. This behavior was found to be robust, showing a gradual variation in peak latencies and amplitudes of the responses (see Suppl. ...
... Functional expression of the cortico-cortical loop. A. Mean PSTH (N = 30) of L5 excitatory neurons in response to the stimulus in both areas in the baseline condition. It exhibits a second component in the response of area X as a result of feedback from area Y. Dotted lines show experimentally measured latencies (mouse S1 ↔ M2,Manita et al., 2015) to which the stimulus setup was calibrated. B. Mean PSTHs (N = 30) of L5 excitatory neurons showing the impact of different circuit manipulations: applying TTX to either area, blocking all connections in either or both directions, blocking L5 in the forward direction and L4 in the backwards direction, and blocking forward connections plus optogenetic stimulus to L4 in area Y. Legend and axes from the bottom left corner plot apply to all plots equally. ...
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Mechanisms of top-down modulation in sensory perception and their relation to underlying connectivity are not completely understood. We present here a biophysically-detailed computational model of two interconnected cortical areas, representing the first steps in a cortical processing hierarchy, as a tool for potential discovery. The model integrates a large body of data from rodent primary somatosensory cortex and reproduces biological features across multiple scales: from a handful of ion channels defining a diversity of electrical types in hundreds of thousands of morphologically detailed neurons, to local and long-range networks mediated by hundreds of millions of synapses. Notably, long-range connectivity in the model incorporates target lamination patterns associated with feed-forward and feedback pathways. We use the model to study the impact of inter-areal interactions on sensory processing. First, we exhibit a cortico-cortical loop between the two model areas (X and Y), wherein sensory input to area X produces a response with two components in time, the first driven by the stimulus and the second by feedback from area Y. We perform a structural and functional characterization of this loop, finding a differential impact of layer-specific pathways in the feed-forward and feedback directions. Second, we explore stimulus discrimination by presenting four different spatially-segregate stimulus patterns. We observe well-defined temporal sequences of functional cell assembly activation, with stimulus specificity in early but not late assemblies in area X, i.e., in the stimulus-driven component of the response but not in the feedback-driven component. We also find the earliest assembly in area Y to be specific to pairs of patterns, consistent with the topography of connections. Finally, we examine the integration of bottom-up and top-down signals. When presenting a second stimulus coincident with the feedback-driven component, we observe an approximate linear superposition of responses. We find the implied lack of interaction consistent with the naive connectivity in the model and the absence of plasticity mechanisms that would underlie the learning of top-down influences. This work represents a first step in the study of inter-areal interactions with biophysically-detailed simulations.
... In this scenario, Go and No-Go trials should evoke waves of activity, including actively engaging higher-order feedback in the C1 and D1 barrels, allowing us to test for goal-directed changes to traveling waves ( Figure 3A). This is further strengthened by the growing evidence that higher-order wMC feedback plays a role in shaping behavior 47 and is fundamental during active-touch 48 After training animals to expertly discriminate (Figure S3B), we performed NeuroGrid surface recordings and high-speed whisker imaging as animals undertook the behavioral task. We then used whisker tracking with DeepLabCut 49 to detect the precise C1 and D1 touch times during Go and No-Go trials ( Figure 3D, see Methods). ...
... Indeed, previous reports have suggested that somatic activity cannot fully explain delayed potentials driven by sensory input and is likely dendritic in origin 63 . In wS1, in addition to having a depolarization effect on L2/3 64 , studies have demonstrated the critical requirement of wMC feedback in gating L5 dendritic activity 26,47 , This is further substantiated by the fact that direct wMC inputs to wS1 synapse onto both L5 apical and somatic compartments 65 , suggesting coincidence detection, while also indirectly targeting L5 activity via the secondary thalamic nuclei (PoM) 66 . Moreover, this premise of a dendritic origin to surface potentials is also prevalent in human recordings 67 . ...
... Within this context, the interaction between sensory and motor cortices is crucial in accurate sensory perception and discrimination and controlling what sensory information the brain will receive 87 . In the barrel cortex, interactions between sensory and motor cortices are of fundamental importance for accurate sensory perception and discrimination 47,48,[88][89][90] . wMC projections show a strong preference for deep layers (L5/6) and L1, but are known to also broadly engage different excitatory and inhibitory cell types in sensory cortex 25,65 . ...
Preprint
Linking sensory-evoked traveling waves to underlying circuit patterns is critical to understanding the neural basis of sensory perception. To form this link, we performed simultaneous electrophysiology and two-photon calcium imaging through transparent NeuroGrids and mapped touch-evoked cortical traveling waves and their underlying microcircuit dynamics. In awake mice, both passive and active whisker touch elicited traveling waves within and across barrels, with a fast early component followed by a variable late wave that lasted hundreds of milliseconds post-stimulus. Strikingly, late-wave dynamics were modulated by stimulus value and correlated with task performance. Mechanistically, the late wave component was i) modulated by motor feedback, ii) complemented by a sparse ensemble pattern across layer 2/3, which a balanced-state network model reconciled via inhibitory stabilization, and iii) aligned to regenerative Layer-5 apical dendritic Ca ²⁺ events. Our results reveal a translaminar spacetime pattern organized by cortical feedback in the sensory cortex that supports touch-evoked traveling waves. GRAPHICAL ABSTRACT AND HIGHLIGHTS Whisker touch evokes both early- and late-traveling waves in the barrel cortex over 100’s of milliseconds Reward reinforcement modulates wave dynamics Late wave emergence coincides with network sparsity in L23 and time-locked L5 dendritic Ca ²⁺ spikes Experimental and computational results link motor feedback to distinct translaminar spacetime patterns
... This fact is increasingly recognized in neuroscience. [16][17][18] The gamma-band oscillation has been associated with bottom-up processes, whereas top-down processes are likely mediated by beta-band oscillation. 19,20 It has long been noted that an imbalance between top-down and bottom-up information can cause hallucinations and illusions. ...
... Continuous epochs of 600 s free from artifacts were extracted from each participant's data. Subsequently, bandpass filtering was carried out for each epoch to separate the conventional frequency bands, including delta (2-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma . To eliminate the line noise at 60 Hz introduced by the notch filter, a bandpass was applied. ...
... Human cognitive functions are known to be affected by both bottom-up and top-down processes. [16][17][18] An imbalance between these can cause hallucinations and illusions. 21 Several studies have shown that in SZ, such imbalances are related to the background of psychiatric symptoms. ...
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Aim This study aimed to identify atypical hubs in the whole‐brain networks of patients with schizophrenia (SZ) and examine the effects of antipsychotic medications, using electroencephalography (EEG) data. Methods We estimated the functional connectivity across all electrodes by applying the phase lag index to the EEG signals of 21 drug‐naïve patients with SZ and 31 age‐matched healthy controls. Betweenness centrality (BC), a measure of hub status, was calculated for each electrode and frequency band. Data from 14 patients were re‐evaluated after initiating treatment with antipsychotic medications. Results BC values decreased significantly at the Fz site in the beta band, decreased significantly at Pz in the gamma band, and increased significantly at O1 in the gamma band among patients with SZ. These changes persisted after antipsychotic treatment and were unrelated to clinical symptoms. Conclusion The abnormal hub topology we observed, especially in the high‐frequency band, may reflect the pathophysiology of SZ, and this study highlights the utility of BC analysis of EEG data for detecting alterations in the whole‐brain networks of patients with SZ.
... Consistent with a previous report, 35 we confirmed that the female presence increased the density of c-Fos+ cells in the BLA ( Figure 2C). Since our previous study showed that top-down inputs from the M2 to the S1 are essential for accurate texture perception in the awake state 36 and texture memory consolidation during the NREM sleep, 17 we investigated the connections among the BLA, M2, and S1. Using an anterograde tracer, an adenoassociated virus (AAV) vector expressing green fluorescent protein (AAV1-hSyn-GFP), injected into the BLA (Figures 2D and 2E), we observed substantial axonal projections from the BLA to frontal cortical regions, including the M2 ( Figures 2F and 2G), while little projection to the S1 ( Figures 2H and 2I). ...
... Article M2 as the hub linking BLA and S1 (Figure 2). Our prior study showed M2-S1 top-down inputs generate dendritic calcium spikes followed by burst spiking in S1 neurons, 36,68 which are critical for the induction of plasticity. 69 This aligns with a recent theoretical study suggesting that burst-dependent plasticity precisely determines behaviorally relevant synaptic loci based on top-down inputs to update their weight in a hierarchical multi-layer network. ...
... First, abnormal connections through S1 were disproportionally identified in the communication subspace analysis (Fig. 5g-i; Supplementary Fig. 6). Second, neurons in this region are known to integrate motor and touch signals required for perception 47,72,73 . Third, within S1, Syngap1 regulates dendritic morphogenesis in deep neurons 74 and developmental synaptic connectivity of feed-forward excitation in upper lamina neurons 23 , which could lead to circuit connectivity alterations capable of influencing neuronal dynamics within this cortical area. ...
... Statistics in Supplementary Table 7. Source data are provided as a Source Data file. strong input from M1/M2, a connection that relays whisker motor signals 30,72 , but relatively weak afferent thalamocortical connectivity, an important connection that transmits whisker-touch signals into cortex. These circuit-specific impairments are consistent with abnormal dynamics within the somatomotor network as animals explore the environment using whiskers (Fig. 5g-i). ...
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Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, Syngap1, in cortical excitatory neurons is required for the formation of somatomotor networks that promote SMI-mediated perception. Cortical Syngap1 expression was necessary and sufficient for setting tactile sensitivity, sustaining tactile object exploration, and promoting tactile learning. Mice with deficient Syngap1 expression exhibited impaired neural dynamics induced by exploratory touches within a cortical-thalamic network that promotes attention and perception. Disrupted neuronal dynamics were associated with circuit-specific long-range synaptic connectivity abnormalities. Our data support a model where autonomous Syngap1 expression in cortical excitatory neurons promotes cognitive abilities through the assembly of long-range circuits that integrate temporally-overlapping sensory and motor signals, a process that promotes perception and attention. These data provide systems-level insights into the robust association between Syngap1 expression and cognitive ability.
... We previously reported that the secondary motor cortex (M2) projects top-down cortical inputs to the primary somatosensory cortex (S1). These projections play a crucial role in accurate somatosensory perception (Manita et al., 2015) and perceptual memory consolidation (Miyamoto et al., 2016). Herein, we report the laminar profiles and neuron subtypes of top-down recipient inhibitory S1 neurons. ...
... Three weeks after the injection, we confirmed tdTomato expression at the M2 injection site (Figures 2B, C) and M2 axons in S1 in coronal sections of the brain slices (Figures 2C, D). These axons were preferentially distributed in the superficial and deep layers of S1, which is the typical top-down cortical projection pattern (Felleman and Van Essen, 1991), as previously reported (Figures 2E, F; Manita et al., 2015). ...
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Despite the importance of postsynaptic inhibitory circuitry targeted by mid/long-range projections (e.g., top-down projections) in cognitive functions, its anatomical properties, such as laminar profile and neuron type, are poorly understood owing to the lack of efficient tracing methods. To this end, we developed a method that combines conventional adeno-associated virus (AAV)-mediated transsynaptic tracing with a distal-less homeobox (Dlx) enhancer-restricted expression system to label postsynaptic inhibitory neurons. We called this method “Dlx enhancer-restricted Interneuron-SpECific transsynaptic Tracing” (DISECT). We applied DISECT to a top-down corticocortical circuit from the secondary motor cortex (M2) to the primary somatosensory cortex (S1) in wild-type mice. First, we injected AAV1-Cre into the M2, which enabled Cre recombinase expression in M2-input recipient S1 neurons. Second, we injected AAV1-hDlx-flex-green fluorescent protein (GFP) into the S1 to transduce GFP into the postsynaptic inhibitory neurons in a Cre-dependent manner. We succeeded in exclusively labeling the recipient inhibitory neurons in the S1. Laminar profile analysis of the neurons labeled via DISECT indicated that the M2-input recipient inhibitory neurons were distributed in the superficial and deep layers of the S1. This laminar distribution was aligned with the laminar density of axons projecting from the M2. We further classified the labeled neuron types using immunohistochemistry and in situ hybridization. This post hoc classification revealed that the dominant top-down M2-input recipient neuron types were somatostatin-expressing neurons in the superficial layers and parvalbumin-expressing neurons in the deep layers. These results demonstrate that DISECT enables the investigation of multiple anatomical properties of the postsynaptic inhibitory circuitry.
... Additionally, building on the rapidly growing knowledge about cellular connectivity and behavior-related dynamics in "top-down" corticocortical circuits; e.g. (Petreanu et al., 2009;Petreanu et al., 2012;Xu et al., 2012;Lee et al., 2013;Zagha et al., 2013;Kinnischtzke et al., 2014;Manita et al., 2015), the stimulation and 405 recording paradigms developed here could be adapted to investigate how inputs from higher-order motor areas such as secondary motor cortex (M2, or rostral forelimb area) interact with ascending somatosensory activity to modulate M1 output during goal-directed behaviors. ...
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Spiking activity along synaptic circuits linking primary somatosensory (S1) and motor (M1) areas is fundamental for sensorimotor integration in cortex. Circuits along the ascending somatosensory pathway through mouse hand/forelimb S1 and M1 were recently described in detail (Yamawaki et al., 2021). Here, we characterize the peripherally evoked spiking dynamics in these two cortical areas in the same system. Brief (5 ms) optogenetic photostimulation of the hand generated short (~25 ms) barrages of activity first in S1 (onset latency 15 ms) then M1 (10 ms later). The estimated propagation speed was 20-fold faster from hand to S1 than from S1 to M1. Response amplitudes in M1 were strongly attenuated to approximately a third of those in S1. Responses were typically triphasic, with suppression and rebound following the initial peak. Parvalbumin (PV) inhibitory interneurons were involved in each phase, accounting for three-quarters of the initial spikes generated in S1, and their selective photostimulation sufficed to evoke suppression and rebound in both S1 and M1. Partial silencing of S1 by PV activation during hand stimulation reduced the M1 sensory responses. These results provide quantitative measures of spiking dynamics of cortical activity along the hand/forelimb-related transcortical loop; demonstrate a prominent and mechanistic role for PV neurons in each phase of the response; and, support a conceptual model in which somatosensory signals reach S1 via high-speed subcortical circuits to generate characteristic barrages of cortical activity, then reach M1 via densely polysynaptic corticocortical circuits to generate a similar but delayed and attenuated profile of activity.
... L5 pyramidal neurons have distinct dendritic structures-tufted dendrites in the upper cortical layers and basal dendrites in the deeper cortical layerseach compartmentalized for different types of synaptic integration [30][31][32][33][34] . Tuft dendrites integrate inputs from higher cortical areas, influencing complex cognitive functions such as attention and perception 7,35 . On the other hand, basal dendrites primarily integrate local cortical and subcortical inputs, contributing to sensory and motor information processing 9,36,37 . ...
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Focal cooling is a powerful technique to temporally scale neural dynamics. However, the underlying cellular mechanisms causing this scaling remain unresolved. Here, using targeted focal cooling (with a spatial resolution of 100 micrometers), dual somato-dendritic patch clamp recordings, two-photon calcium imaging, transmitter uncaging, and modeling we reveal that a 5 deg C drop can enhance synaptic transmission, plasticity, and input-output transformations in the distal apical tuft, but not in the basal dendrites of intrinsically bursting L5 pyramidal neurons. This enhancement depends on N-methyl-D-aspartate (NMDA) and Kv4.2, suggesting electrical structure modulation. Paradoxically, and despite the increase in tuft excitability, we observe a reduced rate of recovery from inactivation for apical Na+ channels, thereby regulating back-propagating action potential invasion, coincidence detection, and overall burst probability, resulting in an apparent slowing of somatic spike output. Our findings reveal a differential temperature sensitivity along the basal-tuft axis of L5 neurons analog modulates cortical output.
... It's known to suppress neural responses to predictable inputs (Nassi et al., 2013;Rao & Ballard, 1999)-an observation that forms the core of the predictive coding framework Friston and Kiebel, 2009;Mumford, 1992;Rao and Ballard, 1999. In addition to its predictive function, it's crucial for modulating attention (Debes & Dragoi, 2023), shaping perception (Manita et al., 2015), and conveying task-specific context (Li et al., 2004;Liu et al., 2021). Long-range feedback from the motor (Jordan & Keller, 2020;Leinweber et al., 2017) and auditory cortex (Garner & Keller, 2021) carry important contextual information to the early visual cortex. ...
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Artificial neural networks (ANNs) can generate useful hypotheses about neural computation, but many features of the brain are not captured by standard ANNs. Top-down feedback is a particularly notable missing feature. Its role in the brain is often debated, and it's unclear whether top-down feedback would improve an ANN's ability to model the brain. Here we develop a deep neural network model that captures the core functional properties of top down feedback in the neocortex. This feedback allows identically connected recurrent models to have different processing hierarchies based on the direction of feedforward and feedback connectivity. We then explored the functional impact of different hierarchies on audiovisual categorization tasks. We find that certain hierarchies, such as the one seen in the human brain, impart ANN models with a light visual bias similar to that seen in humans while maintaining excellent performance on all audio-visual tasks. The results further suggest that different configurations of top-down feedback make otherwise identically connected models functionally distinct from each other and from traditional feedforward only recurrent models. Altogether our findings demonstrate that top-down feedback is a relevant feature of biological brains that improves the explanatory power of ANN models in computational neuroscience.
... The neocortex's outermost layer, L1, is highly conserved across species and cortical areas and serves as the primary input layer for top-down information flow [37,[63][64][65][66]. Dysregulation of L1 circuitry can disrupt the dynamics of excitation and inhibition, leading to aberrant processing of emotional, cognitive, and social information observed in SCZ [11,67]. ...
Article
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Neuroimmune interactions play a significant role in regulating synaptic plasticity in both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent synaptic elimination via the complement receptor 3 (CR3). Current models of pathological complement activity in the brain propose that accelerated synaptic loss resulting from overexpression of C4 (C4-OE), a gene associated with schizophrenia, follows this pathway. Here, we report that C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, resulting in pathological synaptic loss. Moreover, C4 circuit alterations in the prefrontal cortex, a brain region associated with neuropsychiatric disorders, were rescued by increasing neuronal levels of SNX27, which we identify as an interacting partner of this neuroimmune protein. Our results link excessive complement activity to an intracellular endo-lysosomal trafficking pathway altering synaptic plasticity.
... 6,7,9 LI additionally receives corticocortical inputs relaying both cross-modal sensory and higher-order associative information into the cortical column. 10,11 sensory inputs, demonstrating that whisker plucking results in significantly reduced Cxcl14 expression and impaired morphological development of SBC interneurons. In addition, Cxcl14 loss of function leads to increased excitability in SBC, but not NGFC, interneurons. ...
Article
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Spontaneous and sensory-evoked activity sculpts developing circuits. Yet, how these activity patterns intersect with cellular programs regulating the differentiation of neuronal subtypes is not well understood. Through electrophysiological and in vivo longitudinal analyses, we show that C-X-C motif chemokine ligand 14 (Cxcl14), a gene previously characterized for its association with tumor invasion, is expressed by single-bouquet cells (SBCs) in layer I (LI) of the somatosensory cortex during development. Sensory deprivation at neonatal stages markedly decreases Cxcl14 expression. Additionally, we report that loss of function of this gene leads to increased intrinsic excitability of SBCs—but not LI neurogliaform cells—and augments neuronal complexity. Furthermore, Cxcl14 loss impairs sensory map formation and compromises the in vivo recruitment of superficial interneurons by sensory inputs. These results indicate that Cxcl14 is required for LI differentiation and demonstrate the emergent role of chemokines as key players in cortical network development.
... In contrast, isometric motor contraction leads to an attenuation of the N20 but not of HFO (Klostermann et al., 2001). Such motor gating of the somatosensory domain has been proposed to emerge via efference copies (Holst, 1954;Wolpert & Ghahramani, 2000;Palmer et al., 2016;Kilteni et al., 2020;Job & Kilteni, 2023) and may act via layer 1 top-down projections (Manita et al., 2015;Manita et al., 2017), thus potentially reflecting a mechanism in line with Dendritic Integration Theory. Last but not least, transcranial alternating current stimulation (tACS) at alpha frequencies has been reported to up-regulate N20 amplitudes but not HFO (Fabbrini et al., 2022). ...
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Neural states shape perception at earliest cortical processing levels. Previously we showed a relationship between the N20 component of the somatosensory evoked potential (SEP), pre-stimulus alpha oscillations, and the perceived intensity in a somatosensory discrimination paradigm (Stephani et al., 2021, eLife). Here we address the follow-up question whether these excitability dynamics reflect changes in feedforward or feedback signals. Re-examining the previous EEG data, we leveraged high-frequency oscillations (HFO) as a metric for neuronal population spiking activity of the first excitatory feedforward volley in the cortex. Using Bayesian statistics, we found evidence against the involvement of HFO in moment-to-moment variability of perceived stimulus intensity, in contrast to previously observed pre-stimulus alpha and N20 effects. Given that the N20 component presumably reflects backpropagating membrane potentials towards the apical dendrites, we argue that top-down feedback processes (e.g., related to alpha oscillations) may thus rely on modulations at distal sites of involved pyramidal cells rather than on output firing changes at basal compartments.
... Distinct top-down and bottom-up brain connectivity has also been illustrated in humans [83], suggesting it is a powerful connectivity paradigm for optimized brain function within the mammalian brain, including humans. Dynamic changes in these different input pathways can rapidly modify neural responses to incoming information, enabling neurons to quickly alter the processing of sensory inputs [12,84] and learnt behaviour [3]. Take, for example, synaptic input from higher-order thalamic nuclei to cortical neurons. ...
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Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the in vitro brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the in vivo intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons, with a specific focus on the latest developments from in vivo studies. This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on'.
... The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region that is associated with spatial attention (Harvey et al. 2012;Carandini and Churchland 2013;Erlich et al. 2015). The AGm has been reported to integrate various sensory information, including somatosensory, visual, and auditory information (Manita et al. 2015(Manita et al. , 2017Luo et al. 2019), together with motor actions and decisionmaking (Sul et al. 2011;Murakami et al. 2014;Barthas and Kwan 2017). In a role of AGm in spatial attention function, our and previous studies have reported that damage to the AGm results in USN-like symptoms in visual, auditory, and somatosensory modalities (King and Corwin 1990b;Erlich et al. 2015;Ishii et al. 2021). ...
Article
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Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among various positions of the lesions, the recovery from USN during recovery periods (postoperative day; POD 10–18) tended to be slower in cases with more rostral lesions in the AGm (r = − 0.302; p = 0.028). Moreover, the total number of arm entries and maximum moving speed did not significantly differ between before and after AGm infarction. According to these results, the anterior lesions may slowly recover from USN-like behavior, and there may be a weak association between the AGm infarct site and recovery rate. In addition, all unilateral focal infarctions in the AGm induced USN-like behavior without motor deficits.
... Previous studies have demonstrated that the late activity phase is critical for perception, as silencing or blocking it interferes with stimulus perception or detection. 17,18,55 Therefore, our results suggest that the perception of the stimulus could still be present under anesthesia and can disappear only at very deep anesthesia levels. ...
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Sensory information must be integrated across a distributed brain network for stimulus processing and perception. Recent studies have revealed specific spatiotemporal patterns of cortical activation for the early and late components of sensory-evoked responses, which are associated with stimulus features and perception, respectively. Here, we investigated how the brain state influences the sensory-evoked activation across the mouse cortex. We utilized isoflurane to modulate the brain state and conducted wide-field calcium imaging of Thy1-GCaMP6f mice to monitor distributed activation evoked by multi-whisker stimulation. Our findings reveal that the level of anesthesia strongly shapes the spatiotemporal features and the functional connectivity of the sensory-activated network. As anesthesia levels decrease, we observe increasingly complex responses, accompanied by the emergence of the late component within the sensory-evoked response. The persistence of the late component under anesthesia raises new questions regarding the potential existence of perception during unconscious states.
... In terms of visuo-tactile responses, the M2 is reciprocally connected with the somatosensory cortex as well as the visual cortical areas 38,39 . Accordingly, M2 has been found to respond to tactile stimulations in rodents 40 , while lesioning the structure evokes somatosensory neglect 41 . Interestingly, optogenetic inactivation of M2 fibres projecting to S1 during NREM sleep caused impairments in a novel object recognition task requiring discrimination of tactile textures 42 . ...
Article
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Episodic memories comprise diverse attributes of experience distributed across neocortical areas. The hippocampus is integral to rapidly binding these diffuse representations, as they occur, to be later reinstated. However, the nature of the information exchanged during this hippocampal-cortical dialogue remains poorly understood. A recent study has shown that the secondary motor cortex carries two types of representations: place cell-like activity, which were impaired by hippocampal lesions, and responses tied to visuo-tactile cues, which became more pronounced following hippocampal lesions. Using two-photon Ca²⁺ imaging to record neuronal activities in the secondary motor cortex of male Thy1-GCaMP6s mice, we assessed the cortical retrieval of spatial and non-spatial attributes from previous explorations in a virtual environment. We show that, following navigation, spontaneous resting state reactivations convey varying degrees of spatial (trajectory sequences) and non-spatial (visuo-tactile attributes) information, while reactivations of non-spatial attributes tend to precede reactivations of spatial representations surrounding hippocampal sharp-wave ripples.
... The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region that is associated with spatial attention (Harvey et al. 2012;Carandini and Churchland 2013;Erlich et al. 2015). The AGm has been reported to integrate various sensory information, including somatosensory, visual, and auditory information (Manita et al. 2015(Manita et al. , 2017Luo et al. 2019), together with motor actions and decisionmaking (Sul et al. 2011;Murakami et al. 2014;Barthas and Kwan 2017). In a role of AGm in spatial attention function, our and previous studies have reported that damage to the AGm results in USN-like symptoms in visual, auditory, and somatosensory modalities (King and Corwin 1990b;Erlich et al. 2015;Ishii et al. 2021). ...
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Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among the various lesion positions, acute severity was higher with the lesion in the intermediate rostrocaudal position. On the other hand, the recovery from USN-like behavior after this phase tended to be slower in cases with more rostral lesions in the AGm. Additionally, no motor paralysis was observed in any of the mice with lesions in each AGm. These results suggest that the intermediate rostrocaudal position of the AGm may significantly influence selection of the direction, regardless of the areas to which it is connected. On the contrary, recovery from USN-like behavior may be dependent on the areas to which it is connected. Highlights Lesion of the rodent medial agranular cortex (AGm) results in unilateral spatial neglect (USN). In the acute phase, the severity was higher with lesions in the intermediate AGm position. Recovery from somatosensory USN tended to be slower with rostral AGm lesions. Recovery from USN may depend on sensory modalities associated with the connected areas. Our results revealed location-dependent differences in attentional functions within the AGm.
... Using an AAV-SynTetOff vector injected into VIP-Cre mice, we showed that L2/3 VIP + neurons in S1BF resemble pyramidal cells in somatodendritic morphology (Sohn et al. 2016(Sohn et al. , 2017. The dendritic morphologies of pyramidal cells and L2/3 VIP + neurons in S1BF indicate that they are strongly affected by afferents in L1, where top-down feedback signals from the frontal cortices abundantly terminate (Veinante and Deschênes 2003;Lee et al. 2013;Manita et al. 2015). Thus, we can suppose the synaptic connectivity to some extent from the information of the axonal ramification and somatodendritic morphology. ...
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Brain computation relies on the neural networks. Neurons extend the neurites such as dendrites and axons, and the contacts of these neurites that form chemical synapses are the biological basis of signal transmissions in the central nervous system. Individual neuronal outputs can influence the other neurons within the range of the axonal spread, while the activities of single neurons can be affected by the afferents in their somatodendritic fields. The morphological profile, therefore, binds the functional role each neuron can play. In addition, synaptic connectivity among neurons displays preference based on the characteristics of presynaptic and postsynaptic neurons. Here, the author reviews the “spatial” and “temporal” connection selectivity in the neocortex. The histological description of the neocortical circuitry depends primarily on the classification of cell types, and the development of gene engineering techniques allows the cell type-specific visualization of dendrites and axons as well as somata. Using genetic labeling of particular cell populations combined with immunohistochemistry and imaging at a subcellular spatial resolution, we revealed the “spatial selectivity” of cortical wirings in which synapses are non-uniformly distributed on the subcellular somatodendritic domains in a presynaptic cell type-specific manner. In addition, cortical synaptic dynamics in learning exhibit presynaptic cell type-dependent “temporal selectivity”: corticocortical synapses appear only transiently during the learning phase, while learning-induced new thalamocortical synapses persist, indicating that distinct circuits may supervise learning-specific ephemeral synapse and memory-specific immortal synapse formation. The selectivity of spatial configuration and temporal reconfiguration in the neural circuitry may govern diverse functions in the neocortex.
... On the other hand, the latter viewpoint posits that cortical information processing is highly distributed; that is, the brain is not as neatly parceled into localized regions, as shown in the brain atlas. For example, we have previously reported that accurate somatosensory perception [63], perceptual memory consolidation [64], and memory enhancement [65] require coordinated activity in the primary somatosensory and secondary motor cortices. It has also been reported that behavior-related signals are represented brain-wide across species [66], including mice [67][68][69], flies [70], and worms [71]. ...
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The neural mechanisms responsible for the reduction of consciousness during sleep remain elusive. Previous studies investigating macro/mesoscale neural data have suggested that functional networks are segregated into spatially localized modules, and that these modules are more segregated during sleep than during wakefulness. However, large-scale single-cell resolution functional networks remain largely unexplored. Here, we simultaneously recorded the activities of up to 10,000 cortical neurons from multiple brain regions in mice during wakefulness and sleep using a fast, single-cell resolution, and wide-field-of-view two-photon calcium imaging technique. We examined how networks were integrated or segregated between brain states in terms of modularity and spatial distribution in the cortex. We found that modularity during non-rapid eye movement sleep was higher than that during wakefulness, indicating a more segregated network. However, these modules were not spatially localized but rather intermixed across regions in both states. Our results provide novel insights into differences in the cellular-scale organization of functional networks during altered states of consciousness.
... It is possible that both locomotion and arousing auditory stimuli affect similar local circuit motifs in V1, and by doing so similarly tune up the gain of the visual system or sharpen visual representations through disinhibition [38,65]. However, it is an open question whether different non-visual inputs tap into similar local circuit motifs-such as L1-mediated control of L2/3 [38,139,140], VIP-mediated disinhibition [65,117,141,142] and L6-mediated gain modulation [54,143]as only a few studies have investigated the intersection of vision with more than one other modality (e.g. motor, auditory and reward) in the same study. ...
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The definition of the visual cortex is primarily based on the evidence that lesions of this area impair visual perception. However, this does not exclude that the visual cortex may process more information than of retinal origin alone, or that other brain structures contribute to vision. Indeed, research across the past decades has shown that non-visual information, such as neural activity related to reward expectation and value, locomotion, working memory and other sensory modalities, can modulate primary visual cortical responses to retinal inputs. Nevertheless, the function of this non-visual information is poorly understood. Here we review recent evidence, coming primarily from studies in rodents, arguing that non-visual and motor effects in visual cortex play a role in visual processing itself, for instance disentangling direct auditory effects on visual cortex from effects of sound-evoked orofacial movement. These findings are placed in a broader framework casting vision in terms of predictive processing under control of frontal, reward- and motor-related systems. In contrast to the prevalent notion that vision is exclusively constructed by the visual cortical system, we propose that visual percepts are generated by a larger network—the extended visual system—spanning other sensory cortices, supramodal areas and frontal systems. This article is part of the theme issue ‘Decision and control processes in multisensory perception’.
... Recent research has shown that task engagement and attention to relevant sensory information can also enhance sensory responses in lower sensory cortices. This response enhancement can be mediated by direct projections from the higher-level cortex areas to the sensory cortices [48][49][50] . ...
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Multiple types of sensory information are detected and integrated to improve perceptual accuracy and sensitivity in biological cognition. However, current studies on electronic skin (e-skin) systems have mainly focused on the optimization of the modality-specific data acquisition and processing. Endowing e-skins with the abilities of multimodal sensing and even perception that can achieve high-level perception behaviors has been insufficiently explored. Moreover, the perception progress of multisensory e-skin systems is faced with challenges at both device and software levels. Here, we provide a perspective on the multisensory fusion of e-skins. The recent progress in e-skins realizing multimodal sensing is reviewed, followed by bottom-up and top-down multimodal perception. With the deepening understanding of neuroscience and the rapid advance of novel algorithms and devices, multimodal perception function becomes possible and will promote the development of highly intelligent e-skin systems.
... Furthermore, responses to stimuli are different due to various brain states. Therefore, when BIM is applied to highly non-stationary activity data with frequent changes of brain states [12,13], the inference result by MCMC may be unstable due to the dependence on initial condition in MCMC, and accuracy of the inference may worsen. Additionally, such disadvantages are also due to hard clustering in BIM, where each neuron must belong to a particular ensemble at any time of experiment. ...
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Various brain functions that are necessary to maintain life activities materialize through the interaction of countless neurons. Therefore, it is important to analyze functional neuronal network. To elucidate the mechanism of brain function, many studies are being actively conducted on functional neuronal ensemble and hub, including all areas of neuroscience. In addition, recent study suggests that the existence of functional neuronal ensembles and hubs contributes to the efficiency of information processing. For these reasons, there is a demand for methods to infer functional neuronal ensembles from neuronal activity data, and methods based on Bayesian inference have been proposed. However, there is a problem in modeling the activity in Bayesian inference. The features of each neuron’s activity have non-stationarity depending on physiological experimental conditions. As a result, the assumption of stationarity in Bayesian inference model impedes inference, which leads to destabilization of inference results and degradation of inference accuracy. In this study, we extend the range of the variable for expressing the neuronal state, and generalize the likelihood of the model for extended variables. By comparing with the previous study, our model can express the neuronal state in larger space. This generalization without restriction of the binary input enables us to perform soft clustering and apply the method to non-stationary neuroactivity data. In addition, for the effectiveness of the method, we apply the developed method to multiple synthetic fluorescence data generated from the electrical potential data in leaky integrated-and-fire model.
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Linking sensory-evoked traveling waves to underlying circuit patterns is critical to understanding the neural basis of sensory perception. To form this link, we performed simultaneous electrophysiology and two-photon calcium imaging through transparent NeuroGrids and mapped touch-evoked traveling waves and underlying microcircuit dynamics. In awake mice, both passive and active whisker touch elicited traveling waves within and across barrels, with a fast early component followed by a late wave that lasted hundreds of milliseconds poststimulus. Notably, late waves were modulated by perceived value and predicted behavioral choice in a two-whisker discrimination task. We found that the late wave feature was (i) modulated by motor feedback, (ii) differentially engaged a sparse ensemble reactivation pattern across layer 2/3, which a balanced-state network model reconciled via feedback-induced inhibitory stabilization, and (iii) aligned to regenerative layer 5 apical dendritic Ca ²⁺ events. Our results reveal that translaminar spacetime patterns organized by cortical feedback support sparse touch-evoked traveling waves.
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A fundamental question in the field of consciousness is how and why physical processes in the brain give rise to consciousness, a problem named the ‘hard problem of consciousness’ by David Chalmers. Despite numerous studies, neuroscience has yet to agree on a single account that addresses the hard problem of consciousness. Here, I introduce the energy-information generation (EIG) theory to answer this problem. The EIG theory posits that consciousness emerges when a neuron generates an EM field which represents the information encoded in the neuron through its energy via numerous neural mechanisms. This paper explains how the mechanisms that allow neurons to store information about the environment can control the energy of the electromagnetic field of neurons through their impact on dendritic spikes during rhythmic synchronized activity. This theory proposes an answer to the hard problem of consciousness and could serve as a framework for future neuroscience research.
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Visual landmarks provide powerful reference signals for efficient navigation by altering the activity of spatially tuned neurons, such as place cells, head direction cells, and grid cells. To understand the neural mechanism by which landmarks exert such strong influence, it is necessary to identify how these visual features gain spatial meaning. In this study, we characterized visual landmark representations in mouse retrosplenial cortex (RSC) using chronic two-photon imaging of the same neuronal ensembles over the course of spatial learning. We found a pronounced increase in landmark-referenced activity in RSC neurons that, once established, remained stable across days. Changing behavioral context by uncoupling treadmill motion from visual feedback systematically altered neuronal responses associated with the coherence between visual scene flow speed and self-motion. To explore potential underlying mechanisms, we modeled how burst firing, mediated by supralinear somatodendritic interactions, could efficiently mediate context- and coherence-dependent integration of landmark information. Our results show that visual encoding shifts to landmark-referenced and context-dependent codes as these cues take on spatial meaning during learning.
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Hypnosis is an effective intervention with proven efficacy that is employed in clinical settings and for investigating various cognitive processes. Despite their practical success, no consensus exists regarding the mechanisms underlying well-established hypnotic phenomena. Here, we suggest a new framework called the Simulation-Adaptation Theory of Hypnosis (SATH). SATH expands the predictive coding framework by focusing on (a) redundancy elimination in generative models using intrinsically generated prediction errors, (b) adaptation due to amplified or prolonged neural activity, and (c) using internally generated predictions as a venue for learning new associations. The core of our treatise is that simulating proprioceptive, interoceptive, and exteroceptive signals, along with the top-down attenuation of the precision of sensory prediction errors due to neural adaptation, can explain objective and subjective hypnotic phenomena. Based on these postulations, we offer mechanistic explanations for critical categories of direct verbal suggestions, including (1) direct-ideomotor, (2) challenge-ideomotor, (3) perceptual, and (4) cognitive suggestions. Notably, we argue that besides explaining objective responses, SATH accounts for the subjective effects of suggestions, i.e., the change in the sense of agency and reality. Finally, we discuss individual differences in hypnotizability and how SATH accommodates them. We believe that SATH is exhaustive and parsimonious in its scope, can explain a wide range of hypnotic phenomena without contradiction, and provides a host of testable predictions for future research.
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Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher and lower level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA-mediated recurrent processing and human perception has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively affected decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings demonstrate that NMDA inhibition selectively affects recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
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Learning alters cortical representations and improves perception. Apical tuft dendrites in Layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of Layer 5 pyramidal neurons as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task.
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In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs.
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The prioritisation and selective processing of information is imperative to survival. One form of prioritisation, known as spatial attention, allows an animal to selectively process sensory input based on its location. While spatial attention is known to produce changes in neuronal representation, it is unclear whether these changes occur as early as the primary sensory cortex. It is also not clear whether changes induced by selective spatial attention differ from those observed with non-selective fluctuations in arousal. To study attention, the rodent whisker system represents a structurally elegant, and functionally efficient alternative to the often-studied primate visual system. Here, we implemented a novel, ecologically relevant paradigm to incorporate spatial attention in a whisker vibration detection task in mice. We demonstrated that mice (n = 11) exhibit spatially selective evidence accumulation behaviour within their responses to single vibration stimuli, across their responses to tens of stimuli, and throughout each day of training. To dissociate the neuronal signatures of spatial attention from those of spatially non-specific behavioural state, we recorded 1461 responsive neurons in the primary vibrissal cortex (vS1) as mice engaged in the detection task. The strength of neuronal responses to vibrissal stimulation correlated significantly with spatial attention, but not with spatially non-specific behavioural state. We found that spatial attention elevates both baseline neuronal activity and a later (200–600 ms) component of evoked responses to whisker vibrations. These results have implications for the microcircuitry of spatial attention in vS1 and value-driven attentional capture in mice.
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In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time-dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs. SIGNIFICANCE STATEMENT Normal sensorimotor integration depends in part on the dynamic interactions between the primary motor cortex and the somatosensory cortex, but the functional properties of the excitatory synapses interconnecting the motor cortex with the somatosensory cortex are poorly understood. Our results show that the short-term dynamics of excitatory motor cortex synapses and the nature of the postsynaptic response they generate onto layer 5 pyramidal neurons in the somatosensory cortex depend on the postsynaptic cell type and if their axons project to other cortical areas or subcortical regions. These two parallel but dynamically distinct channels of synaptic excitation constitute previously unknown synaptic circuits by which different temporal patterns of motor cortex activity can shape how signals propagate out of the somatosensory cortex.
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The cerebral cortex is vital for the processing and perception of sensory stimuli. In the somatosensory axis, information is received primarily by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming from S1 can modulate mechanical and cooling but not heat stimuli such that circuit inhibition causes blunted perception. This suggests that responsiveness to particular somatosensory stimuli occurs in a modality specific fashion and we sought to determine additional cortical substrates. In this work, we identify in a mouse model that inhibition of S2 output increases mechanical and heat, but not cooling sensitivity, in contrast to S1. Combining 2-photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we discover that S2 projections to the secondary motor cortex (M2) govern mechanical and heat sensitivity without affecting motor performance or anxiety. Taken together, we show that S2 is an essential cortical structure that governs mechanical and heat sensitivity.
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Motor cortex plays a key role in controlling voluntary arm movements towards spatial targets. The cortical representation of spatial information has been extensively studied and was found to range from combinations of muscle synergies to cognitive maps of locations in space. How such abstract representations of target space evolve during a behavior, how they integrate with other behavioral features and what role they play in movement control is less clear. Here we addressed these questions by recording the activity of layer 2/3 (L2/3) neurons in the motor cortex using two-photon calcium imaging in head-restrained mice, while they reached for water droplets presented at different spatial locations around their snout. Our results reveal that a majority (>80%) of L2/3 neurons with task-related activity are target-space selective and their activity is contingent on a single target position in an ego-centric reference frame. This spatial framework is preferentially organized along three cardinal directions (Center, Left and Right). Surprisingly, the coding of target space is not limited to the activity during movement planning or execution, but is also predominant during preceding and subsequent phases of the task, and even persists beyond water consumption. More importantly, target specificity is independent of the movement kinematics and is immediately updated when the target is moved to a new position. Our findings suggest that, rather than descending motor commands, the ensemble of L2/3 neurons in the motor cortex conjointly encode internal (behavioral) and external (spatial) aspects of the task, playing a role in higher-order representations related to estimation processes of the ongoing actions.
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Backpropagation of error is the most widely used learning algorithm in artificial neural networks, forming the backbone of modern machine learning and artificial intelligence1,2. Backpropagation provides a solution to the credit assignment problem by vectorizing an error signal tailored to individual neurons. Recent theoretical models have suggested that neural circuits could implement backpropagation like learning by semi independently processing feedforward and feedback information streams in separate dendritic compartments3,4,5,6,7. This presents a compelling, but untested, hypothesis for how cortical circuits could solve credit assignment in the brain. We designed a neurofeedback brain computer interface (BCI) task with an experimenter defined reward function to evaluate the key requirements for dendrites to implement backpropagation like learning. We trained mice to modulate the activity of two spatially intermingled populations (4 or 5 neurons each) of layer 5 pyramidal neurons in the retrosplenial cortex to rotate a visual grating towards a target orientation while we recorded GCaMP activity from somas and corresponding distal apical dendrites. We observed that the relative magnitudes of somatic versus dendritic signals could be predicted using the activity of the surrounding network and contained information about task related variables that could serve as instructive signals, including reward and error. The signs of these putative teaching signals both depended on the causal role of individual neurons in the task and predicted changes in overall activity over the course of learning. These results provide the first biological evidence of a backpropagation-like solution to the credit assignment problem in the brain.
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Our rich behavioural repertoire is supported by complicated synaptic connectivity in the central nervous system, which must be modulated to prevent behavioural control from being overwhelmed. For this modulation, presynaptic inhibition is an efficient mechanism because it can gate specific synaptic input without interfering with main circuit operations. Previously, we reported the task-dependent presynaptic inhibition of the cutaneous afferent input to the spinal cord in behaving monkeys. Here, we report presynaptic inhibition of the proprioceptive afferent input. We found that the input from shortened muscles is transiently facilitated, whereas that from lengthened muscles is persistently reduced. This presynaptic inhibition could be generated by cortical signals because it started before movement onset, and its size was correlated with the performance of stable motor output. Our findings demonstrate that presynaptic inhibition acts as a dynamic filter of proprioceptive signals, enabling the integration of task-relevant signals into spinal circuits.
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Sensory information must be integrated across a distributed brain network for stimulus processing and perception. Recent studies have revealed specific spatiotemporal patterns of cortical activation for the early and late components of sensory-evoked responses, which are associated with stimulus features and perception, respectively. However, our understanding of how the brain state influences the sensory-evoked activation across the mouse cortex remains limited. In this study, we utilized isoflurane to modulate the brain state and conducted wide-field calcium imaging of Thy1-GCaMP6f mice to monitor the distributed activation evoked by multi-whisker stimulation. Our findings reveal that the level of anesthesia strongly shapes the spatiotemporal features and the functional connectivity of the sensory-activated network. As anesthesia levels decrease, we observe increasingly complex responses, accompanied by the emergence of the late component within the sensory-evoked response. The persistence of the late component under anesthesia raises new questions regarding the potential existence of perception during unconscious states.
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Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The molecular and cellular mechanisms that shape SMI within circuits that promote cognition are poorly understood. Here, we demonstrate that expression of the autism/intellectual disability gene, Syngap1, in mouse cortical excitatory neurons promotes touch sensitivity required to elicit perceptual behaviors. Cortical Syngap1 expression enabled touch-induced feedback signals within sensorimotor loops by assembling circuits that support tactile sensitivity. These circuits also encoded correlates of attention that promoted self-generated whisker movements underlying purposeful and sustained object exploration. As Syngap1 deficient animals explored objects with whiskers, relatively weak touch signals were integrated with relatively strong motor signals. This produced a signal-to-noise deficit consistent with impaired tactile sensitivity, reduced tactile exploration, and weak tactile learning. Thus, Syngap1 expression in cortex promotes tactile perception by assembling circuits that integrate touch and whisker motor signals. Deficient Syngap1 expression likely contributes to cognitive impairment through abnormal top-down SMI.
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Biologically plausible learning with neuronal dendrites is a promising perspective to improve the spike-driven learning capability by introducing dendritic processing as an additional hyperparameter. Neuromorphic computing is an effective and essential solution towards spike-based machine intelligence and neural learning systems. However, on-line learning capability for neuromorphic models is still an open challenge. In this study a novel neuromorphic architecture with dendritic on-line learning (NADOL) is presented, which is a novel efficient methodology for brain-inspired intelligence on embedded hardware. With the feature of distributed processing using spiking neural network, NADOL can cut down the power consumption and enhance the learning efficiency and convergence speed. A detailed analysis for NADOL is presented, which demonstrates the effects of different conditions on learning capabilities, including neuron number in hidden layer, dendritic segregation parameters, feedback connection, and connection sparseness with various levels of amplification. Piecewise linear approximation approach is used to cut down the computational resource cost. The experimental results demonstrate a remarkable learning capability that surpasses other solutions, with NADOL exhibiting superior performance over the GPU platform in dendritic learning. This study's applicability extends across diverse domains, including the Internet of Things, robotic control, and brain-machine interfaces. Moreover, it signifies a pivotal step in bridging the gap between artificial intelligence and neuroscience through the introduction of an innovative neuromorphic paradigm.
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The posterior parietal cortex (PPC) in mice has various functions including multisensory integration, vision-guided behaviors, working memory, and posture control. However, an integrated understanding of these functions and their cortical localizations in and around the PPC and higher visual areas (HVAs), has not been completely elucidated. Here we simultaneously imaged the activity of thousands of neurons within a 3 mm x 3 mm field-of-view, including eight cortical areas around the PPC, during behavior. Mice performed both a vision-guided task and a choice history-dependent task, and the imaging results revealed distinct, localized, behavior-related functions of two medial PPC areas. Neurons in the anteromedial (AM) HVA responded to both vision and choice information, and thus AM is a locus of association between these channels. By contrast, the anterior (A) HVA stores choice history with rotational dynamics and represents posture. Mesoscale correlation analysis on the intertrial variability of neuronal activity demonstrated that neurons in area A shared fluctuations with S1t (trunk primary somatosensory area), while neurons in AM exhibited diverse, area-dependent interactions. Pairwise interarea interactions among neurons were precisely predicted by the anatomical input correlations, with the exception of some global interactions. Thus, the medial PPC has two distinct modules, areas A and AM, which each have distinctive modes of cortical communication. These medial PPC modules can serve separate higher-order functions: area A for transmission of information including posture, movement, and working memory; and area AM for multisensory and cognitive integration with locally processed signals.
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The cerebral cortex is vital for the perception and processing of sensory stimuli. In the somatosensory axis, information is received by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming from S1 can modulate mechanical and cooling but not heat stimuli such that circuit inhibition causes blunted mechanical and cooling perception. Using optogenetics and chemogenetics, we find that in contrast to S1, an inhibition of S2 output increases mechanical and heat, but not cooling sensitivity. Combining 2-photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we discover that S2 projections to the secondary motor cortex (M2) govern mechanical and thermal sensitivity without affecting motor or cognitive function. This suggests that while S2, like S1, encodes specific sensory information, that S2 operates through quite distinct neural substrates to modulate responsiveness to particular somatosensory stimuli and that somatosensory cortical encoding occurs in a largely parallel fashion.
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The neural origins of spontaneous or self-initiated actions are not well understood and their interpretation is controversial. To address these issues, we used a task in which rats decide when to abort waiting for a delayed tone. We recorded neurons in the secondary motor cortex (M2) and interpreted our findings in light of an integration-to-bound decision model. A first population of M2 neurons ramped to a constant threshold at rates proportional to waiting time, strongly resembling integrator output. A second population, which we propose provide input to the integrator, fired in sequences and showed trial-to-trial rate fluctuations correlated with waiting times. An integration model fit to these data also quantitatively predicted the observed inter-neuronal correlations. Together, these results reinforce the generality of the integration-to-bound model of decision-making. These models identify the initial intention to act as the moment of threshold crossing while explaining how antecedent subthreshold neural activity can influence an action without implying a decision.
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Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory.
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Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50-400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.
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A Direct Line in the Brain For decades, neuroscientists have assumed that there is a “canonical microcircuit” in the neo cortex, in which information is transformed as excitation spreads serially along connections from thalamus, to cortical layer 4, then to layers 2/3, to layers 5/6, and finally to other brain regions. Each cortical layer is thought to transform sensory signals to extract behaviorally relevant information. Now, Constantinople and Bruno (p. 1591 ) challenge this dogma. In vivo whole-cell recordings revealed that sensory stimuli activate neurons in deep cortical layers simultaneously to those in layer 4 and that a large number of thalamic neurons converge onto deep pyramidal neurons, possibly allowing sensory information to completely bypass upper layers. Temporary blockade of layer 4 revealed that synaptic input to deep cortical layers derived entirely from the thalamus and not at all from upper cortical layers. This thalamically derived synaptic input reliably drove pyramidal neurons in layer 5 to discharge action potentials in the living animal. These deep layer neurons project to numerous higher-order brain regions and could directly mediate behavior.
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Higher-order motor cortices, such as the secondary motor area (M2) in rodents, select future action patterns and transmit them to the primary motor cortex (M1). To better understand motor processing, we characterized "top-down" and "bottom-up" connectivities between M1 and M2 in the rat cortex. Somata of pyramidal cells (PCs) in M2 projecting to M1 were distributed in lower layer 2/3 (L2/3) and upper layer 5 (L5), whereas PCs projecting from M1 to M2 had somata distributed throughout L2/3 and L5. M2 afferents terminated preferentially in upper layer 1 of M1, which also receives indirect basal ganglia output through afferents from the ventral anterior and ventromedial thalamic nuclei. On the other hand, M1 afferents terminated preferentially in L2/3 of M2, a zone receiving indirect cerebellar output through thalamic afferents from the ventrolateral nucleus. While L5 corticopontine (CPn) cells with collaterals to the spinal cord did not participate in corticocortical projections, CPn cells with collaterals to the thalamus contributed preferentially to connections from M2 to M1. L5 callosal projection (commissural) cells participated in connectivity between M1 and M2 bidirectionally. We conclude that the connectivity between M1 and M2 is directionally specialized, involving specific PC subtypes that selectively target lamina receiving distinct thalamocortical inputs.
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Imaging the activities of individual neurons with genetically encoded Ca(2+) indicators (GECIs) is a promising method for understanding neuronal network functions. Here, we report GECIs with improved neuronal Ca(2+) signal detectability, termed G-CaMP6 and G-CaMP8. Compared to a series of existing G-CaMPs, G-CaMP6 showed fairly high sensitivity and rapid kinetics, both of which are suitable properties for detecting subtle and fast neuronal activities. G-CaMP8 showed a greater signal (F(max)/F(min) = 38) than G-CaMP6 and demonstrated kinetics similar to those of G-CaMP6. Both GECIs could detect individual spikes from pyramidal neurons of cultured hippocampal slices or acute cortical slices with 100% detection rates, demonstrating their superior performance to existing GECIs. Because G-CaMP6 showed a higher sensitivity and brighter baseline fluorescence than G-CaMP8 in a cellular environment, we applied G-CaMP6 for Ca(2+) imaging of dendritic spines, the putative postsynaptic sites. By expressing a G-CaMP6-actin fusion protein for the spines in hippocampal CA3 pyramidal neurons and electrically stimulating the granule cells of the dentate gyrus, which innervate CA3 pyramidal neurons, we found that sub-threshold stimulation triggered small Ca(2+) responses in a limited number of spines with a low response rate in active spines, whereas supra-threshold stimulation triggered large fluorescence responses in virtually all of the spines with a 100% activity rate.
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A striking example of the constructive nature of visual perception is how the human visual system completes contours of occluded objects. To date, it is unclear whether perceptual completion emerges during early stages of visual processing or whether higher-level mechanisms are necessary. To answer this question, we used transcranial magnetic stimulation to disrupt signaling in V1/V2 and in the lateral occipital (LO) area at different moments in time while participants performed a discrimination task involving a Kanizsa-type illusory figure. Results show that both V1/V2 and higher-level visual area LO are critically involved in perceptual completion. However, these areas seem to be involved in an inverse hierarchical fashion, in which the critical time window for V1/V2 follows that for LO. These results are in line with the growing evidence that feedback to V1/V2 contributes to perceptual completion.
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Active dendrites provide neurons with powerful processing capabilities. However, little is known about the role of neuronal dendrites in behaviourally related circuit computations. Here we report that a novel global dendritic nonlinearity is involved in the integration of sensory and motor information within layer 5 pyramidal neurons during an active sensing behaviour. Layer 5 pyramidal neurons possess elaborate dendritic arborizations that receive functionally distinct inputs, each targeted to spatially separate regions. At the cellular level, coincident input from these segregated pathways initiates regenerative dendritic electrical events that produce bursts of action potential output and circuits featuring this powerful dendritic nonlinearity can implement computations based on input correlation. To examine this in vivo we recorded dendritic activity in layer 5 pyramidal neurons in the barrel cortex using two-photon calcium imaging in mice performing an object-localization task. Large-amplitude, global calcium signals were observed throughout the apical tuft dendrites when active touch occurred at particular object locations or whisker angles. Such global calcium signals are produced by dendritic plateau potentials that require both vibrissal sensory input and primary motor cortex activity. These data provide direct evidence of nonlinear dendritic processing of correlated sensory and motor information in the mammalian neocortex during active sensation.
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The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons.
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The axonal arborization of single motor thalamic neurons was examined in rat brain using a viral vector expressing membrane-targeted palmitoylation site-attached green fluorescent protein (palGFP). We first divided the ventral anterior-ventral lateral motor thalamic nuclei into 1) the rostromedial portion, which was designated inhibitory afferent-dominant zone (IZ) with intense glutamate decarboxylase immunoreactivity and weak vesicular glutamate transporter 2 immunoreactivity, and 2) the caudolateral portion, named excitatory subcortical afferent-dominant zone (EZ) with the reversed immunoreactivity profile. We then labeled 38 motor thalamic neurons in 29 hemispheres by injecting a diluted palGFP-Sindbis virus solution and isolated 10 IZ and EZ neurons for reconstruction. All the reconstructed IZ neurons widely projected not only to the cerebral cortex but also to the neostriatum, whereas the EZ neurons sent axons almost exclusively to the cortex. More interestingly, 47-66% of axon varicosities of IZ neurons were observed in layer I of cortical areas. In contrast, only 2-15% of varicosities of EZ neurons were found in layer I, most varicosities being located in middle layers. These results suggest that 2 forms of information from the basal ganglia and cerebellum are differentially supplied to apical and basal dendrites, respectively, of cortical pyramidal neurons and integrated to produce a motor execution command
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Despite widespread neural activity related to reward values, signals related to upcoming choice have not been clearly identified in the rodent brain. Here we examined neuronal activity in the lateral (AGl) and medial (AGm) agranular cortex, corresponding to the primary and secondary motor cortex, respectively, in rats performing a dynamic foraging task. Choice signals, before behavioral manifestation of the rat's choice, arose in the AGm earlier than in any other areas of the rat brain previously studied under free-choice conditions. The AGm also conveyed neural signals for decision value and chosen value. By contrast, upcoming choice signals arose later, and value signals were weaker, in the AGl. We also found that AGm lesions made the rats' choices less dependent on dynamically updated values. These results suggest that rodent secondary motor cortex might be uniquely involved in both representing and reading out value signals for flexible action selection.
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Technologies for silencing the electrical activity of genetically targeted neurons in the brain are important for assessing the contribution of specific cell types and pathways toward behaviors and pathologies. Recently we found that archaerhodopsin-3 from Halorubrum sodomense (Arch), a light-driven outward proton pump, when genetically expressed in neurons, enables them to be powerfully, transiently, and repeatedly silenced in response to pulses of light. Because of the impressive characteristics of Arch, we explored the optogenetic utility of opsins with high sequence homology to Arch, from archaea of the Halorubrum genus. We found that the archaerhodopsin from Halorubrum strain TP009, which we named ArchT, could mediate photocurrents of similar maximum amplitude to those of Arch (∼900 pA in vitro), but with a >3-fold improvement in light sensitivity over Arch, most notably in the optogenetic range of 1-10 mW/mm(2), equating to >2× increase in brain tissue volume addressed by a typical single optical fiber. Upon expression in mouse or rhesus macaque cortical neurons, ArchT expressed well on neuronal membranes, including excellent trafficking for long distances down neuronal axons. The high light sensitivity prompted us to explore ArchT use in the cortex of the rhesus macaque. Optical perturbation of ArchT-expressing neurons in the brain of an awake rhesus macaque resulted in a rapid and complete (∼100%) silencing of most recorded cells, with suppressed cells achieving a median firing rate of 0 spikes/s upon illumination. A small population of neurons showed increased firing rates at long latencies following the onset of light stimulation, suggesting the existence of a mechanism of network-level neural activity balancing. The powerful net suppression of activity suggests that ArchT silencing technology might be of great use not only in the causal analysis of neural circuits, but may have therapeutic applications.
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Selective attention filters information to limit what is encoded and maintained in working memory. Although the prefrontal cortex (PFC) is central to both selective attention and working memory, the underlying neural processes that link these cognitive abilities remain elusive. Using functional magnetic resonance imaging to guide repetitive transcranial magnetic stimulation with electroencephalographic recordings in humans, we perturbed PFC function at the inferior frontal junction in participants before they performed a selective-attention, delayed-recognition task. This resulted in diminished top-down modulation of activity in posterior cortex during early encoding stages, which predicted a subsequent decrement in working memory accuracy. Participants with stronger fronto-posterior functional connectivity displayed greater disruptive effects. Our data further suggests that broad alpha-band (7-14 Hz) phase coherence subserved this long-distance top-down modulation. These results suggest that top-down modulation mediated by the prefrontal cortex is a causal link between early attentional processes and subsequent memory performance.
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By a Whisker Every student learns that the sensory cortex is used for processing sensation and the motor cortex is used for perceiving movement. However, in the real world, this may not always be so neatly arranged. Matyas et al. (p. 1240 ) have found that sensory and motor fields are specialized for different types of movement, such that in mice the motor cortex controlled the forward movement (protraction) of their whiskers and the sensory cortex controlled backwards movements (retraction) of whiskers. So if a whisker hits an object, then a reasonable first reaction might be a motor command for retraction. Similarly, the motor cortex stimulates protraction for more active exploration. Hence, the sensory cortex is also motor and the motor cortex is also sensory. In an ecological context, these combined reactions offer a repertoire useful for a mouse seeking food and shelter in a complex environment.
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Kernel smoother and a time-histogram are classical tools for estimating an instantaneous rate of spike occurrences. We recently established a method for selecting the bin width of the time-histogram, based on the principle of minimizing the mean integrated square error (MISE) between the estimated rate and unknown underlying rate. Here we apply the same optimization principle to the kernel density estimation in selecting the width or "bandwidth" of the kernel, and further extend the algorithm to allow a variable bandwidth, in conformity with data. The variable kernel has the potential to accurately grasp non-stationary phenomena, such as abrupt changes in the firing rate, which we often encounter in neuroscience. In order to avoid possible overfitting that may take place due to excessive freedom, we introduced a stiffness constant for bandwidth variability. Our method automatically adjusts the stiffness constant, thereby adapting to the entire set of spike data. It is revealed that the classical kernel smoother may exhibit goodness-of-fit comparable to, or even better than, that of modern sophisticated rate estimation methods, provided that the bandwidth is selected properly for a given set of spike data, according to the optimization methods presented here.
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Traditionally, mapping the motor cortex requires electrodes to stimulate the brain and define motor output pathways. Although effective, electrode-based methods are labor-intensive, potentially damaging to the cortex and can have off-target effects. As an alternative method of motor mapping, we photostimulated transgenic mice expressing the light-sensitive ion channel channelrhodopsin-2 in predominantly layer-5 output cortical neurons. We report that optical stimulation of these neurons in vivo using a stage scanning laser system resulted in muscle excitation within 10-20 ms, which can be recorded using implanted electromyogram electrodes or by a noninvasive motion sensor. This approach allowed us to make highly reproducible automated maps of the mouse forelimb and hindlimb motor cortex much faster than with previous methods. We anticipate that the approach will facilitate the study of changes in the location and properties of motor maps after skilled training or damage to the nervous system.
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Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and similar "feedback" interactions in the cerebral cortex. Excitatory input to apical tufts in neocortical layer 1 has been traditionally assumed to be predominantly cortical, as thalamic pathways directed to this layer were regarded relatively scant and diffuse. However, the sensitive tracing methods used in the present study show that, throughout the rat neocortex, large numbers (mean approximately 4500/mm(2)) of thalamocortical neurons converge in layer 1 and that this convergence gives rise to a very high local density of thalamic terminals. Moreover, we show that the layer 1-projecting neurons are present in large numbers in most, but not all, motor, association, limbic, and sensory nuclei of the rodent thalamus. Some layer 1-projecting axons branch to innervate large swaths of the cerebral hemisphere, whereas others arborize within only a single cortical area. Present data imply that realistic modeling of cortical circuitry should factor in a dense axonal canopy carrying highly convergent thalamocortical input to pyramidal cell apical tufts. In addition, they are consistent with the notion that layer 1-projecting axons may be a robust anatomical substrate for extensive "feedback" interactions between cortical areas via the thalamus.
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The computational power of single neurons is greatly enhanced by active dendritic conductances that have a large influence on their spike activity. In cortical output neurons such as the large pyramidal cells of layer 5 (L5), activation of apical dendritic calcium channels leads to plateau potentials that increase the gain of the input/output function and switch the cell to burst-firing mode. The apical dendrites are innervated by local excitatory and inhibitory inputs as well as thalamic and corticocortical projections, which makes it a formidable task to predict how these inputs influence active dendritic properties in vivo. Here we investigate activity in populations of L5 pyramidal dendrites of the somatosensory cortex in awake and anaesthetized rats following sensory stimulation using a new fibre-optic method for recording dendritic calcium changes. We show that the strength of sensory stimulation is encoded in the combined dendritic calcium response of a local population of L5 pyramidal cells in a graded manner. The slope of the stimulus-response function was under the control of a particular subset of inhibitory neurons activated by synaptic inputs predominantly in L5. Recordings from single apical tuft dendrites in vitro showed that activity in L5 pyramidal neurons disynaptically coupled via interneurons directly blocks the initiation of dendritic calcium spikes in neighbouring pyramidal neurons. The results constitute a functional description of a cortical microcircuit in awake animals that relies on the active properties of L5 pyramidal dendrites and their very high sensitivity to inhibition. The microcircuit is organized so that local populations of apical dendrites can adaptively encode bottom-up sensory stimuli linearly across their full dynamic range.
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In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patches of cortex devoted to particular movements. The location of major subdivisions such as the forelimb or hindlimb areas is somatotopic and is consistent from animal to animal, but the internal organization of the pattern of movements represented within major subdivisions varies significantly between animals. The motor cortex includes both agranular primary motor cortex (AgL) and, in addition, a significant amount of the bordering granular somatic sensory cortex (Gr(SI)), as well as the rostral portion of the taste sensory insular or claustrocortex (Cl). The rat frontal cortex also contains a second, rostral motor representation of the forelimb, trunk and hindlimb, which is somatotopically organized and may be the rat's supplementary motor area. Both of these motor representations give rise to direct corticospinal projections, some of which may make monosynaptic connections with cervical enlargement motoneurons. Medial to the primary motor cortex, in cytoarchitectonic field AgM, is what appears to be part of the rat's frontal eye fields, a region which also includes the vibrissae motor representation. The somatic motor cortical output organization pattern in the rat is remarkably similar to that seen in the primate, whose primary, supplementary and frontal eye field cortical motor regions have been extensively studied.
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Tactile information is actively acquired and processed in the brain through concerted interactions between movement and sensation. Somatosensory input is often the result of self-generated movement during the active touch of objects, and conversely, sensory information is used to refine motor control. There must therefore be important interactions between sensory and motor pathways, which we chose to investigate in the mouse whisker sensorimotor system. Voltage-sensitive dye was applied to the neocortex of mice to directly image the membrane potential dynamics of sensorimotor cortex with subcolumnar spatial resolution and millisecond temporal precision. Single brief whisker deflections evoked highly distributed depolarizing cortical sensory responses, which began in the primary somatosensory barrel cortex and subsequently excited the whisker motor cortex. The spread of sensory information to motor cortex was dynamically regulated by behavior and correlated with the generation of sensory-evoked whisker movement. Sensory processing in motor cortex may therefore contribute significantly to active tactile sensory perception.
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In recent years, many new cortical areas have been identified in the macaque monkey. The number of identified connections between areas has increased even more dramatically. We report here on (1) a summary of the layout of cortical areas associated with vision and with other modalities, (2) a computerized database for storing and representing large amounts of information on connectivity patterns, and (3) the application of these data to the analysis of hierarchical organization of the cerebral cortex. Our analysis concentrates on the visual system, which includes 25 neocortical areas that are predominantly or exclusively visual in function, plus an additional 7 areas that we regard as visual-association areas on the basis of their extensive visual inputs. A total of 305 connections among these 32 visual and visual-association areas have been reported. This represents 31% of the possible number of pathways it each area were connected with all others. The actual degree of connectivity is likely to be closer to 40%. The great majority of pathways involve reciprocal connections between areas. There are also extensive connections with cortical areas outside the visual system proper, including the somatosensory cortex, as well as neocortical, transitional, and archicortical regions in the temporal and frontal lobes. In the somatosensory/motor system, there are 62 identified pathways linking 13 cortical areas, suggesting an overall connectivity of about 40%. Based on the laminar patterns of connections between areas, we propose a hierarchy of visual areas and of somato sensory/motor areas that is more comprehensive than those suggested in other recent studies. The current version of the visual hierarchy includes 10 levels of cortical processing. Altogether, it contains 14 levels if one includes the retina and lateral geniculate nucleus at the bottom as well as the entorhinal cortex and hippocampus at the top. Within this hierarchy, there are multiple, intertwined processing streams, which, at a low level, are related to the compartmental organization of areas V1 and V2 and, at a high level, are related to the distinction between processing centers in the temporal and parietal lobes. However, there are some pathways and relationships (about 10% of the total) whose descriptions do not fit cleanly into this hierarchical scheme for one reason or another. In most instances, though, it is unclear whether these represent genuine exceptions to a strict hierarchy rather than inaccuracies or uncertainties in the reported assignment.
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We review evidence for partially segregated networks of brain areas that carry out different attentional functions. One system, which includes parts of the intraparietal cortex and superior frontal cortex, is involved in preparing and applying goal-directed (top-down) selection for stimuli and responses. This system is also modulated by the detection of stimuli. The other system, which includes the temporoparietal cortex and inferior frontal cortex, and is largely lateralized to the right hemisphere, is not involved in top-down selection. Instead, this system is specialized for the detection of behaviourally relevant stimuli, particularly when they are salient or unexpected. This ventral frontoparietal network works as a 'circuit breaker' for the dorsal system, directing attention to salient events. Both attentional systems interact during normal vision, and both are disrupted in unilateral spatial neglect.
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We investigated attentional guidance in early visual areas in the brain by recording event-related potentials directly from the surface of visual cortex. Patients performed a contextual cueing task in which attentive search to targets was guided by implicitly learned spatial context information. The earliest activity in striate cortex (area V1) was not modulated by contextual cueing, whereas later activity beginning at ~200 ms was enhanced by contextual cueing in V1, V2 and other portions of extrastriate cortex. These results suggest that context can enhance visual processing by temporally late top-down modulation of activity in anatomically early areas of visual cortex. Together with anatomical and neurophysiological studies in animals, these results suggest an excitatory feedback mechanism acting on apical dendrites of pyramidal cells in V1 and other areas of visual cortex.
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Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.
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Neuronal oscillations have been hypothesized to play an important role in cognition and its ensuing behavior, but evidence that links a specific neuronal oscillation to a discrete cognitive event is largely lacking. We measured neuronal activity in the entorhinal-hippocampal circuit while mice performed a reward-based spatial working memory task. During the memory retention period, a transient burst of high gamma synchronization preceded an animal's correct choice in both prospective planning and retrospective mistake correction, but not an animal's incorrect choice. Optogenetic inhibition of the circuit targeted to the choice point area resulted in a coordinated reduction in both high gamma synchrony and correct execution of a working-memory-guided behavior. These findings suggest that transient high gamma synchrony contributes to the successful execution of spatial working memory. Furthermore, our data are consistent with an association between transient high gamma synchrony and explicit awareness of the working memory content.
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Gamma-aminobutyric acid (GABA)ergic neurons in the central nervous system regulate the activity of other neurons and play a crucial role in information processing. To assist an advance in the research of GABAergic neurons, here we produced two lines of glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mouse. The distribution pattern of GFP-positive somata was the same as that of the GAD67 in situ hybridization signal in the central nervous system. We encountered neither any apparent ectopic GFP expression in GAD67-negative cells nor any apparent lack of GFP expression in GAD67-positive neurons in the two GAD67-GFP knock-in mouse lines. The timing of GFP expression also paralleled that of GAD67 expression. Hence, we constructed a map of GFP distribution in the knock-in mouse brain. Moreover, we used the knock-in mice to investigate the colocalization of GFP with NeuN, calretinin (CR), parvalbumin (PV), and somatostatin (SS) in the frontal motor cortex. The proportion of GFP-positive cells among NeuN-positive cells (neocortical neurons) was approximately 19.5%. All the CR-, PV-, and SS-positive cells appeared positive for GFP. The CR-, PV, and SS-positive cells emitted GFP fluorescence at various intensities characteristics to them. The proportions of CR-, PV-, and SS-positive cells among GFP-positive cells were 13.9%, 40.1%, and 23.4%, respectively. Thus, the three subtypes of GABAergic neurons accounted for 77.4% of the GFP-positive cells. They accounted for 6.5% in layer I. In accord with unidentified GFP-positive cells, many medium-sized spherical somata emitting intense GFP fluorescence were observed in layer I.
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The phenomenon whereby the relative timing between presynaptic and postsynaptic spiking determines the direction and extent of synaptic changes in a critical temporal window is known as spike timing-dependent synaptic plasticity (STDP). We have previously reported that STDP profiles can be classified into two types depending on their layer-specific location along CA1 pyramidal neuron dendrites in the rat hippocampus, suggesting that there are differences in information processing between the proximal dendrite (PD) and distal dendrite (DD). However, how the different types of information processing interact at different dendritic locations remains unclear. To investigate how the temporal information of inputs to PD influences information processing at DD, PD stimulation was applied while the STDP protocol was simultaneously applied at DDs of CA1 pyramidal neurons. Synaptic plasticity induced by the STDP protocol at DDs was enhanced or depressed depending on the timing of the back-propagating action potentials (bAPs) and the excitatory and inhibitory postsynaptic potentials elicited by PD stimulation. These results suggested that bAPs function as carriers of temporal information of PD inputs to DD. Next, the influence of DD on PD was investigated using the same protocol. Synaptic plasticity at PD was modulated only if the pairing stimuli were applied to elicit coincidental timing of bAP and the excitatory postsynaptic potential. Such coding modulations could provide the basis for a novel learning rule and may be important factors in the integration of spatiotemporal input information in neural networks in the brain.
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A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at the cellular level to the basic cortical neuronal unit: the pyramidal cell. The mechanism is robustly triggered by coincident input to opposite poles of the neuron, is exquisitely matched to the large- and fine-scale architecture of the cortex, and is tightly controlled by local microcircuits of inhibitory neurons targeting subcellular compartments. This article explores the experimental evidence and the implications for how the cortex operates.
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Rhesus monkeys were trained to respond to constant-current electrical pulse stimuli to the hand which are known to elicit touch sensation in man. Simultaneously, recordings of somatosensory evoked potentials (SEPs) were made from postcentral gyrus of the performing monkeys. The prominent features of the SEP at most recording sites were a negative (N1) component peaking at 50-65 msec followed by a positive wave (P2) peaking at 105-130 msec. Primary evoked activity (P1) was minimal or absent at most sites at the intensities employed. Differences in N1 peak latency ranging from 4 to 9 msec were observed between the central member of a cluster of recording sites and those surrounding it. These differences are thought to reflect the propagation of evoked activity from some unidentified focus in postcentral gyrus to surrounding regions. N1 and P2 amplitude was found to decrease as a function of behavioral response latency at both the center and surrounding sites of the electrode clusters. The signal detection theoretical model, which provided the interpretative framework for neurophysiologic and psychophysical responses, suggested that N1 and P2 peak amplitude may reflect somatosensory information processing events necessary for psychophysical performance of the monkey. The propagation of evoked activity to different sites on postcentral gyrus could therefore signify the transmission of this sensory information to surrounding cortical regions. Since the psychophysical model is equally applicable to monkey or man, it is suggested that evidence presented here and in similar studies may be relevant to the question of the neural coding of conscious somatic sensory experiences of man.