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The feedback projections from cortical layer 6 (L6CT) to the sensory thalamus have long been implicated in playing a primary role in gating sensory signaling but remain poorly understood. To causally elucidate the full range of effects of these projections, we targeted silicon probe recordings to the whisker thalamocortical circuit of awake mice selectively expressing Channelrhodopsin-2 in L6CT neurons. Through optogenetic manipulation of L6CT neurons, multi-site electrophysiological recordings, and modeling of L6CT circuitry, we establish L6CT neurons as dynamic modulators of ongoing spiking in the ventral posteromedial nucleus of the thalamus (VPm), either suppressing or enhancing VPm spiking depending on L6CT neurons' firing rate and synchrony. Differential effects across the cortical excitatory and inhibitory sub-populations point to an overall influence of L6CT feedback on cortical excitability that could have profound implications for regulating sensory signaling across a range of ethologically relevant conditions., (© 2024. The Author(s).)

Rapid sensory adaptation is observed across all sensory systems, and strongly shapes sensory percepts in complex sensory environments. Yet despite its ubiquity and likely necessity for survival, the mechanistic basis is poorly understood. A wide range of primarily in vitro and anesthetized studies have demonstrated the emergence of adaptation at the level of primary sensory cortex, with only modest signatures in earlier stages of processing. The nature of rapid adaptation and how it shapes sensory representations during wakefulness, and thus the potential role in perceptual adaptation, is underexplored, as are the mechanisms that underlie this phenomenon. To address these knowledge gaps, we recorded spiking activity in primary somatosensory cortex (S1) and the upstream ventral posteromedial (VPm) thalamic nucleus in the vibrissa pathway of awake male and female mice, and quantified responses to whisker stimuli delivered in isolation and embedded in an adapting sensory background. We found that cortical sensory responses were indeed adapted by persistent sensory stimulation; putative excitatory neurons were profoundly adapted, and inhibitory neurons only modestly so. Further optogenetic manipulation experiments and network modeling suggest this largely reflects adaptive changes in synchronous thalamic firing combined with robust engagement of feedforward inhibition, with little contribution from synaptic depression. Taken together, these results suggest that cortical adaptation in the regime explored here results from changes in the timing of thalamic input, and the way in which this differentially impacts cortical excitation and feedforward inhibition, pointing to a prominent role of thalamic gating in rapid adaptation of primary sensory cortex. SIGNIFICANCE STATEMENT Rapid adaptation of sensory activity strongly shapes representations of sensory inputs across all sensory pathways over the timescale of seconds, and has profound effects on sensory perception. Despite its ubiquity and theoretical role in the efficient encoding of complex sensory environments, the mechanistic basis is poorly understood, particularly during wakefulness. In this study in the vibrissa pathway of awake mice, we show that cortical representations of sensory inputs are strongly shaped by rapid adaptation, and that this is mediated primarily by adaptive gating of the thalamic inputs to primary sensory cortex and the differential way in which these inputs engage cortical subpopulations of neurons., (Copyright © 2021 the authors.)

As the tools to simultaneously record electrophysiological signals from large numbers of neurons within and across brain regions become increasingly available, this opens up for the first time the possibility of establishing the details of causal relationships between monosynaptically connected neurons and the patterns of neural activation that underlie perception and behavior. Although recorded activity across synaptically connected neurons has served as the cornerstone for much of what we know about synaptic transmission and plasticity, this has largely been relegated to ex vivo preparations that enable precise targeting under relatively well-controlled conditions. Analogous studies in vivo, where image-guided targeting is often not yet possible, rely on indirect, data-driven measures, and as a result such studies have been sparse and the dependence upon important experimental parameters has not been well studied. Here, using in vivo extracellular single-unit recordings in the topographically aligned rodent thalamocortical pathway, we sought to establish a general experimental and computational framework for inferring synaptic connectivity. Specifically, attacking this problem within a statistical signal detection framework utilizing experimentally recorded data in the ventral-posterior medial (VPm) region of the thalamus and the homologous region in layer 4 of primary somatosensory cortex (S1) revealed a trade-off between network activity levels needed for the data-driven inference and synchronization of nearby neurons within the population that results in masking of synaptic relationships. Here, we provide a framework for establishing connectivity in multisite, multielectrode recordings based on statistical inference, setting the stage for large-scale assessment of synaptic connectivity within and across brain structures. NEW & NOTEWORTHY Despite the fact that all brain function relies on the long-range transfer of information across different regions, the tools enabling us to measure connectivity across brain structures are lacking. Here, we provide a statistical framework for identifying and assessing potential monosynaptic connectivity across neuronal circuits from population spiking activity that generalizes to large-scale recording technologies that will help us to better understand the signaling within networks that underlies perception and behavior.

Sensory signals from the outside world are transduced at the periphery, passing through thalamus before reaching cortex, ultimately giving rise to the sensory representations that enable us to perceive the world. The thalamocortical circuit is particularly sensitive to the temporal precision of thalamic spiking due to highly convergent synaptic connectivity. Thalamic neurons can exhibit burst and tonic modes of firing that strongly influence timing within the thalamus. The impact of these changes in thalamic state on sensory encoding in the cortex, however, remains unclear. Here, we investigated the role of thalamic state on timing in the thalamocortical circuit of the vibrissa pathway in the anesthetized rat. We optogenetically hyperpolarized thalamus while recording single unit activity in both thalamus and cortex. Tonic spike-triggered analysis revealed temporally precise thalamic spiking that was locked to weak white-noise sensory stimuli, whereas thalamic burst spiking was associated with a loss in stimulus-locked temporal precision. These thalamic state-dependent changes propagated to cortex such that the cortical timing precision was diminished during the hyperpolarized (burst biased) thalamic state. Although still sensory driven, the cortical neurons became significantly less precisely locked to the weak white-noise stimulus. The results here suggests a state-dependent differential regulation of spike timing precision in the thalamus that could gate what signals are ultimately propagated to cortex. NEW & NOTEWORTHY The majority of sensory signals are transmitted through the thalamus. There is growing evidence of complex thalamic gating through coordinated firing modes that have a strong impact on cortical sensory representations. Optogenetic hyperpolarization of thalamus pushed it into burst firing that disrupted precise time-locked sensory signaling, with a direct impact on the downstream cortical encoding, setting the stage for a timing-based thalamic gate of sensory signaling.

Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling. SIGNIFICANCE STATEMENT It is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first-order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected., (Copyright © 2018 the authors 0270-6474/18/384870-16$15.00/0.)

Sensory stimulation drives complex interactions across neural circuits as information is encoded and then transmitted from one brain region to the next. In the highly interconnected thalamocortical circuit, these complex interactions elicit repeatable neural dynamics in response to temporal patterns of stimuli that provide insight into the circuit properties that generated them. Here, using a combination of in vivo voltage-sensitive dye (VSD) imaging of cortex, single-unit recording in thalamus, and optogenetics to manipulate thalamic state in the rodent vibrissa pathway, we probed the thalamocortical circuit with simple temporal patterns of stimuli delivered either to the whiskers on the face (sensory stimulation) or to the thalamus directly via electrical or optogenetic inputs (artificial stimulation). VSD imaging of cortex in response to whisker stimulation revealed classical suppressive dynamics, while artificial stimulation of thalamus produced an additional facilitation dynamic in cortex not observed with sensory stimulation. Thalamic neurons showed enhanced bursting activity in response to artificial stimulation, suggesting that bursting dynamics may underlie the facilitation mechanism we observed in cortex. To test this experimentally, we directly depolarized the thalamus, using optogenetic modulation of the firing activity to shift from a burst to a tonic mode. In the optogenetically depolarized thalamic state, the cortical facilitation dynamic was completely abolished. Together, the results obtained here from simple probes suggest that thalamic state, and ultimately thalamic bursting, may play a key role in shaping more complex stimulus-evoked dynamics in the thalamocortical pathway., New & Noteworthy: For the first time, we have been able to utilize optogenetic modulation of thalamic firing modes combined with optical imaging of cortex in the rat vibrissa system to directly test the role of thalamic state in shaping cortical response properties., (Copyright © 2017 the American Physiological Society.)

It has been posited that the regulation of burst/tonic firing in the thalamus could function as a mechanism for controlling not only how much but what kind of information is conveyed to downstream cortical targets. Yet how this gating mechanism is adaptively modulated on fast timescales by ongoing sensory inputs in rich sensory environments remains unknown. Using single-unit recordings in the rat vibrissa thalamus (VPm), we found that the degree of bottom-up adaptation modulated thalamic burst/tonic firing as well as the synchronization of bursting across the thalamic population along a continuum for which the extremes facilitate detection or discrimination of sensory inputs. Optogenetic control of baseline membrane potential in thalamus further suggests that this regulation may result from an interplay between adaptive changes in thalamic membrane potential and synaptic drive from inputs to thalamus, setting the stage for an intricate control strategy upon which cortical computation is built., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. Here, we used voltage-sensitive dye imaging of primary somatosensory cortex in the anesthetized rat in response to deflections of the facial vibrissae and electrical or optogenetic stimulation of thalamic neurons that project directly to the somatosensory cortex. Although the different inputs produced responses that were similar in terms of the average cortical activation, the variability of the cortical response was strikingly different for artificial versus sensory inputs. Furthermore, electrical microstimulation resulted in highly unnatural spatial activation of cortex, whereas optical input resulted in spatial cortical activation that was similar to that induced by sensory inputs. A thalamocortical network model suggested that observed differences could be explained by differences in the way in which artificial and natural inputs modulate the magnitude and synchrony of population activity. Finally, the variability structure in the response for each case strongly influenced the optimal inputs for driving the pathway from the perspective of an ideal observer of cortical activation when considered in the context of information transmission., Significance Statement: Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery and clinical translation. However, neural activity generated by these artificial means differs dramatically from normal circuit function, both locally and in the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. The significance of this work is in quantifying the differences, elucidating likely mechanisms underlying the differences, and determining the implications for information processing., (Copyright © 2015 the authors 0270-6474/15/3515702-14$15.00/0.)

It has long been posited that detectability of sensory inputs can be sacrificed in favor of improved discriminability and that sensory adaptation may mediate this trade-off. The extent to which this trade-off exists behaviorally and the complete picture of the underlying neural representations that likely subserve the phenomenon remain unclear. In the rodent vibrissa system, an ideal observer analysis of cortical activity measured using voltage-sensitive dye imaging in anesthetized animals was combined with behavioral detection and discrimination tasks, thalamic recordings from awake animals, and computational modeling to show that spatial discrimination performance was improved following adaptation, but at the expense of the ability to detect weak stimuli. Together, these results provide direct behavioral evidence for the trade-off between detectability and discriminability, that this trade-off can be modulated through bottom-up sensory adaptation, and that these effects correspond to important changes in thalamocortical coding properties., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In a wide range of studies, the emergence of orientation selectivity in primary visual cortex has been attributed to a complex interaction between feed-forward thalamic input and inhibitory mechanisms at the level of cortex. Although it is well known that layer 4 cortical neurons are highly sensitive to the timing of thalamic inputs, the role of the stimulus-driven timing of thalamic inputs in cortical orientation selectivity is not well understood. Here we show that the synchronization of thalamic firing contributes directly to the orientation tuned responses of primary visual cortex in a way that optimizes the stimulus information per cortical spike. From the recorded responses of geniculate X-cells in the anesthetized cat, we synthesized thalamic sub-populations that would likely serve as the synaptic input to a common layer 4 cortical neuron based on anatomical constraints. We used this synchronized input as the driving input to an integrate-and-fire model of cortical responses and demonstrated that the tuning properties match closely to those measured in primary visual cortex. By modulating the overall level of synchronization at the preferred orientation, we show that efficiency of information transmission in the cortex is maximized for levels of synchronization which match those reported in thalamic recordings in response to naturalistic stimuli, a property which is relatively invariant to the orientation tuning width. These findings indicate evidence for a more prominent role of the feed-forward thalamic input in cortical feature selectivity based on thalamic synchronization.

Objective: Nonlinear system identification approaches were used to develop a dynamical model of the network level response to patterns of microstimulation in vivo., Approach: The thalamocortical circuit of the rodent vibrissa pathway was the model system, with voltage sensitive dye imaging capturing the cortical response to patterns of stimulation delivered from a single electrode in the ventral posteromedial thalamus. The results of simple paired stimulus experiments formed the basis for the development of a phenomenological model explicitly containing nonlinear elements observed experimentally. The phenomenological model was fit using datasets obtained with impulse train inputs, Poisson-distributed in time and uniformly varying in amplitude., Main Results: The phenomenological model explained 58% of the variance in the cortical response to out of sample patterns of thalamic microstimulation. Furthermore, while fit on trial-averaged data, the phenomenological model reproduced single trial response properties when simulated with noise added into the system during stimulus presentation. The simulations indicate that the single trial response properties were dependent on the relative sensitivity of the static nonlinearities in the two stages of the model, and ultimately suggest that electrical stimulation activates local circuitry through linear recruitment, but that this activity propagates in a highly nonlinear fashion to downstream targets., Significance: The development of nonlinear dynamical models of neural circuitry will guide information delivery for sensory prosthesis applications, and more generally reveal properties of population coding within neural circuits.

Voltage-sensitive dye imaging was used to quantify in vivo, network level spatiotemporal cortical activation in response to electrical microstimulation of the thalamus in the rat vibrissa pathway. Thalamic microstimulation evoked a distinctly different cortical response than natural sensory stimulation, with response to microstimulation spreading over a larger area of cortex and being topographically misaligned with the cortical column to which the stimulated thalamic region projects. Electrical stimulation with cathode-leading asymmetric waveforms reduced this topographic misalignment while simultaneously increasing the spatial specificity of the cortical activation. Systematically increasing the asymmetry of the microstimulation pulses revealed a continuum between symmetric and asymmetric stimulation that gradually reduced the topographic bias. These data strongly support the hypothesis that manipulation of the electrical stimulation waveform can be used to selectively activate specific neural elements. Specifically, our results are consistent with the prediction that cathode-leading asymmetric waveforms preferentially stimulate cell bodies over axons, while symmetric waveforms preferentially activate axons over cell bodies. The findings here provide some initial steps toward the design and optimization of microstimulation of neural circuitry, and open the door to more sophisticated engineering tools, such as nonlinear system identification techniques, to develop technologies for more effective control of activity in the nervous system.

Although it has long been posited that sensory adaptation serves to enhance information flow in sensory pathways, the neural basis remains elusive. Simultaneous single-unit recordings in the thalamus and cortex in anesthetized rats showed that adaptation differentially influenced thalamus and cortex in a manner that fundamentally changed the nature of information conveyed about vibrissa motion. Using an ideal observer of cortical activity, we found that performance in detecting vibrissal deflections degraded with adaptation while performance in discriminating among vibrissal deflections of different velocities was enhanced, a trend not observed in thalamus. Analysis of simultaneously recorded thalamic neurons did reveal, however, an analogous adaptive change in thalamic synchrony that mirrored the cortical response. An integrate-and-fire model using experimentally measured thalamic input reproduced the observed transformations. The results here suggest a shift in coding strategy with adaptation that directly controls information relayed to cortex, which could have implications for encoding velocity signatures of textures.

Although adaptation is a ubiquitous property of neurons in the early visual pathway, the functional consequences in the natural visual environment are unknown. In this issue of Neuron, Mante et al. show, through a comprehensive set of in vivo experiments in the visual thalamus, that the basic functional mechanisms of adaptation that have been well studied with artificial probes capture the neuronal response in the natural environment and are predictable from properties of the visual scene that may be represented by local neural ensembles.

Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling. [ABSTRACT FROM AUTHOR]

Although it has long been posited that sensory adaptation serves to enhance information flow in sensory pathways, the neural basis remains elusive. Simultaneous single-unit recordings in the thalamus and cortex in anesthetized rats showed that adaptation differentially influenced thalamus and cortex in a manner that fundamentally changed the nature of information conveyed about vibrissa motion. Using an ideal observer of cortical activity, we found that performance in detecting vibrissal deflections degraded with adaptation while performance in discriminating among vibrissal deflections of different velocities was enhanced, a trend not observed in thalamus. Analysis of simultaneously recorded thalamic neurons did reveal, however, an analogous adaptive change in thalamic synchrony that mirrored the cortical response. An integrate-and-fire model using experimentally measured thalamic input reproduced the observed transformations. The results here suggest a shift in coding strategy with adaptation that directly controls information relayed to cortex, which could have implications for encoding velocity signatures of textures. [ABSTRACT FROM AUTHOR]

In the lateral geniculate nucleus (LGN) of the thalamus, visual stimulation produces two distinct types of responses known as tonic and burst. Due to the dynamics of the T-type Ca2+ channels involved in burst generation, the type of response evoked by a particular stimulus depends on the resting membrane potential, which is controlled by a network of modulatory connections from other brain areas. In this study, we use simulated responses to natural scene movies to describe how modulatory and stimulus-driven changes in LGN membrane potential interact to determine the luminance sequences that trigger burst responses. We find that at low resting potentials, when the T channels are de-inactivated and bursts are relatively frequent, an excitatory stimulus transient alone is sufficient to evoke a burst. However, to evoke a burst at high resting potentials, when the T channels are inactivated and bursts are relatively rare, prolonged inhibitory stimulation followed by an excitatory transient is required. We also observe evidence of these effects in vivo, where analysis of experimental recordings demonstrates that the luminance sequences that trigger bursts can vary dramatically with the overall burst percentage of the response. To characterize the functional consequences of the effects of resting potential on burst generation, we simulate LGN responses to different luminance sequences at a range of resting potentials with and without a mechanism for generating bursts. Using analysis based on signal detection theory, we show that bursts enhance detection of specific luminance sequences, ranging from the onset of excitatory sequences at low resting potentials to the offset of inhibitory sequences at high resting potentials. These results suggest a dynamic role for burst responses during visual processing that may change according to behavioral state. [ABSTRACT FROM AUTHOR]

The role of the lateral geniculate nucleus (LGN) of the thalamus in visual encoding remains an open question. Here, we characterize the function of tonic and burst spikes in cat LGN X-cells in signaling features of natural stimuli. A significant increase in bursting was observed during natural stimulation (relative to white noise stimulation) and was linked to the strong correlation structure of the natural scene movies. Burst responses were triggered by specific stimulus events consisting of a prolonged inhibitory stimulus, followed by an excitatory stimulus, such as the movement of an object into the receptive field. LGN responses to natural scene movies were predicted using an integrate-and-fire (IF) framework and compared with experimentally observed responses. The standard IF model successfully predicted LGN responses to natural scene movies during tonic firing, indicating a linear relationship between stimulus and response. However, the IF model typically underpredicted the LGN response during periods of bursting, indicating a nonlinear amplification of the stimulus in the actual response. The addition of a burst mechanism to the IF model was necessary to accurately predict the entire LGN response. These results suggest that LGN bursts are an important part of the neural code, providing a nonlinear amplification of stimulus features that are typical of the natural environment. [ABSTRACT FROM AUTHOR]

An abstract of the article "Dynamic feature selectivity in the thalamus of the rat whisker system" by Clarissa J. Shephard and colleagues is presented.

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior-medial thalamus in the vibrissa pathway of the awake mouse and measured spiking activity in the thalamus and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting; however, surprisingly, the S1 cortical response was not amplified, but instead, timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to the cortex. • Optogenetic thalamic hyperpolarization enhances thalamic sensory-evoked bursting • S1 cortical responses are not amplified • Thalamic bursting increases S1 timing precision and synchrony • A highly sensitive, timing-based gating of sensory signaling to cortex It has long been proposed that the thalamus serves as a dynamic gate for control of sensory signaling to cortex through switching between tonic and burst firing modes. Using optogenetic manipulation in the awake mouse, Borden et al. demonstrate a thalamic burst-driven, timing-based gating of sensory signaling to the cortex. [ABSTRACT FROM AUTHOR]

• Gigaseal formation shows a strong dependence on pipette-cell distance. • Tissue motion can be predicted and compensated with a feed-forward control system. • Compensation for tissue motion improves whole-cell success rates in the thalamus. Whole-cell patch-clamp recording in vivo is the gold-standard method for measuring subthreshold electrophysiology from single cells during behavioural tasks, sensory stimulations, and optogenetic manipulation. However, these recordings require a tight, gigaohm resistance, seal between a glass pipette electrode's aperture and a cell's membrane. These seals are difficult to form, especially in vivo , in part because of a strong dependence on the distance between the pipette aperture and cell membrane. We elucidate and utilize this dependency to develop an autonomous method for placement and synchronization of pipette's tip aperture to the membrane of a nearby, moving neuron, which enables high-yield seal formation and subsequent recordings deep in the brain of the living mouse. This synchronization procedure nearly doubles the reported gigaseal yield in the thalamus (>3 mm below the pial surface) from 26 % (n = 17/64) to 48 % (n = 32/66). Whole-cell recording yield improved from 10 % (n = 9/88) to 24 % (n = 18/76) when motion compensation was used during the gigaseal formation. As an example of its application, we utilized this system to investigate the role of the sensory environment and ventral posterior medial region (VPM) projection synchrony on intracellular dynamics in the barrel cortex. Current methods of in vivo whole-cell patch clamping do not synchronize the position of the pipette to motion of the cell. This method results in substantially greater subcortical whole-cell recording yield than previously reported and thus makes pan-brain whole-cell electrophysiology practical in the living mouse brain. [ABSTRACT FROM AUTHOR]