Dorsolateral Striatum is a Bottleneck for Responding to Task-Relevant Stimuli in a Learned Whisker Detection Task in Mice.

A learned sensory-motor behavior engages multiple brain regions, including the neocortex and the basal ganglia. How a target stimulus is detected by these regions and converted to a motor response remains poorly understood. Here, we performed electrophysiological recordings and pharmacological inactivations of whisker motor cortex and dorsolateral striatum to determine the representations within, and functions of, each region during performance in a selective whisker detection task in male and female mice. From the recording experiments, we observed robust, lateralized sensory responses in both structures. We also observed bilateral choice probability and preresponse activity in both structures, with these features emerging earlier in whisker motor cortex than dorsolateral striatum. These findings establish both whisker motor cortex and dorsolateral striatum as potential contributors to the sensory-to-motor (sensorimotor) transformation. We performed pharmacological inactivation studies to determine the necessity of these brain regions for this task. We found that suppressing the dorsolateral striatum severely disrupts responding to task-relevant stimuli, without disrupting the ability to respond, whereas suppressing whisker motor cortex resulted in more subtle changes in sensory detection and response criterion. Together these data support the dorsolateral striatum as an essential node in the sensorimotor transformation of this whisker detection task.SIGNIFICANCE STATEMENT Selecting an item in a grocery store, hailing a cab - these daily practices require us to transform sensory stimuli into motor responses. Many decades of previous research have studied goal-directed sensory-to-motor transformations within various brain structures, including the neocortex and the basal ganglia. Yet, our understanding of how these regions coordinate to perform sensory-to-motor transformations is limited because these brain structures are often studied by different researchers and through different behavioral tasks. Here, we record and perturb specific regions of the neocortex and the basal ganglia and compare their contributions during performance of a goal-directed somatosensory detection task. We find notable differences in the activities and functions of these regions, which suggests specific contributions to the sensory-to-motor transformation process.

The Importance of Accounting for Movement When Relating Neuronal Activity to Sensory and Cognitive Processes.

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we (1) review task designs for separating task-related and movement-related activity, (2) review three "case studies" in which not considering movement would have resulted in critically different interpretations of neuronal function, and (3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

Global, Low-Amplitude Cortical State Predicts Response Outcomes in a Selective Detection Task in Mice.

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support low amplitude and low variability as an optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli.

Functional Localization of an Attenuating Filter within Cortex for a Selective Detection Task in Mice.

An essential feature of goal-directed behavior is the ability to selectively respond to the diverse stimuli in one's environment. However, the neural mechanisms that enable us to respond to target stimuli while ignoring distractor stimuli are poorly understood. To study this sensory selection process, we trained male and female mice in a selective detection task in which mice learn to respond to rapid stimuli in the target whisker field and ignore identical stimuli in the opposite, distractor whisker field. In expert mice, we used widefield Ca2+ imaging to analyze target-related and distractor-related neural responses throughout dorsal cortex. For target stimuli, we observed strong signal activation in primary somatosensory cortex (S1) and frontal cortices, including both the whisker region of primary motor cortex (wMC) and anterior lateral motor cortex (ALM). For distractor stimuli, we observed strong signal activation in S1, with minimal propagation to frontal cortex. Our data support only modest subcortical filtering, with robust, step-like attenuation in distractor processing between mono-synaptically coupled regions of S1 and wMC. This study establishes a highly robust model system for studying the neural mechanisms of sensory selection and places important constraints on its implementation.SIGNIFICANCE STATEMENT Responding to task-relevant stimuli while ignoring task-irrelevant stimuli is critical for goal-directed behavior. However, the neural mechanisms involved in this selection process are poorly understood. We trained mice in a detection task with both target and distractor stimuli. During expert performance, we measured neural activity throughout cortex using widefield imaging. We observed responses to target stimuli in multiple sensory and motor cortical regions. In contrast, responses to distractor stimuli were abruptly suppressed beyond sensory cortex. Our findings localize the sites of attenuation when successfully ignoring a distractor stimulus and provide essential foundations for further revealing the neural mechanism of sensory selection and distractor suppression.

Movement and Performance Explain Widespread Cortical Activity in a Visual Detection Task.

Recent studies in mice reveal widespread cortical signals during task performance; however, the various task-related and task-independent processes underlying this activity are incompletely understood. Here, we recorded wide-field neural activity, as revealed by GCaMP6s, from dorsal cortex while simultaneously monitoring orofacial movements, walking, and arousal (pupil diameter) of head-fixed mice performing a Go/NoGo visual detection task and examined the ability of task performance and spontaneous or task-related movements to predict cortical activity. A linear model was able to explain a significant fraction (33-55% of variance) of widefield dorsal cortical activity, with the largest factors being movements (facial, walk, eye), response choice (hit, miss, false alarm), and arousal and indicate that a significant fraction of trial-to-trial variability arises from both spontaneous and task-related changes in state (e.g., movements, arousal). Importantly, secondary motor cortex was highly correlated with lick rate, critical for optimal task performance (high d'), and was the first region to significantly predict the lick response on target trials. These findings suggest that secondary motor cortex is critically involved in the decision and performance of learned movements and indicate that a significant fraction of trial-to-trial variation in cortical activity results from spontaneous and task-related movements and variations in behavioral/arousal state.

Distinct Functional Groups Emerge from the Intrinsic Properties of Molecularly Identified Entorhinal Interneurons and Principal Cells.

Inhibitory interneurons are an important source of synaptic inputs that may contribute to network mechanisms for coding of spatial location by entorhinal cortex (EC). The intrinsic properties of inhibitory interneurons in the EC of the mouse are mostly undescribed. Intrinsic properties were recorded from known cell types, such as, stellate and pyramidal cells and 6 classes of molecularly identified interneurons (regulator of calcineurin 2, somatostatin, serotonin receptor 3a, neuropeptide Y neurogliaform (NGF), neuropeptide Y non-NGF, and vasoactive intestinal protein) in acute brain slices. We report a broad physiological diversity between and within cell classes. We also found differences in the ability to produce postinhibitory rebound spikes and in the frequency and amplitude of incoming EPSPs. To understand the source of this intrinsic variability we applied hierarchical cluster analysis to functionally classify neurons. These analyses revealed physiologically derived cell types in EC that mostly corresponded to the lines identified by biomarkers with a few unexpected and important differences. Finally, we reduced the complex multidimensional space of intrinsic properties to the most salient five that predicted the cellular biomolecular identity with 81.4% accuracy. These results provide a framework for the classification of functional subtypes of cortical neurons by their intrinsic membrane properties.

Synaptic Mechanisms of Tight Spike Synchrony at Gamma Frequency in Cerebral Cortex.

During the generation of higher-frequency (e.g., gamma) oscillations, cortical neurons can exhibit pairwise tight (<10 ms) spike synchrony. To understand how synaptic currents contribute to rhythmic activity and spike synchrony, we performed dual whole-cell recordings in mouse entorhinal cortical slices generating periodic activity (the slow oscillation). This preparation exhibited a significant amount of gamma-coherent spike synchrony during the active phase of the slow oscillation (Up state), particularly among fast-spiking inhibitory interneurons. IPSCs arriving in pairs of either pyramidal or fast-spiking neurons during the Up state were highly synchronized and exhibited significant coherence at frequencies from 10 to 100 Hz, peaking at ∼40 Hz, suggesting both synchronous discharge of, and synaptic divergence from, nearby inhibitory neurons. By inferring synaptic currents related to spike generation in simultaneously recorded pyramidal or fast-spiking neurons, we detected a decay of inhibition ∼20 ms before spiking. In fast-spiking interneurons, this was followed by an even larger excitatory input immediately before spike generation. Consistent with an important role for phasic excitation in driving spiking, we found that the correlation of excitatory inputs was highly predictive of spike synchrony in pairs of fast-spiking interneurons. Interestingly, spike synchrony in fast-spiking interneurons was not related to the strength of gap junctional coupling, and was still prevalent in connexin 36 knock-out animals. Our results support the pyramidal-interneuron gamma model of fast rhythmic oscillation in the cerebral cortex and suggest that spike synchrony and phase preference arises from the precise interaction of excitatory-inhibitory postsynaptic currents. SIGNIFICANCE STATEMENT: We dissected the cellular and synaptic basis of spike synchrony occurring at gamma frequency (30-80 Hz). We used simultaneous targeted whole-cell recordings in an active slice preparation and analyzed the relationships between synaptic inputs and spike generation. We found that both pyramidal and fast-spiking neurons receive large, coherent inhibitory synaptic inputs at gamma frequency. In addition, we found that fast-spiking interneurons receive large, phasic excitatory synaptic inputs immediately before spike generation followed shortly by synaptic inhibition. These data support the principal-interneuron gamma generation model, and reveal how the synaptic connectivity between excitatory and inhibitory neurons supports the generation of gamma oscillations and spike synchrony.

The interplay of seven subthreshold conductances controls the resting membrane potential and the oscillatory behavior of thalamocortical neurons.

The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductance mechanisms that underlie their rich membrane behavior at subthreshold potentials. Using patch-clamp recordings of TC neurons in brain slices from mice and a realistic conductance-based computational model, we characterized seven subthreshold ion currents of TC neurons and quantified their individual contributions to the total steady-state conductance at levels below tonic firing threshold. We then used the TC neuron model to show that the resting membrane potential results from the interplay of several inward and outward currents over a background provided by the potassium and sodium leak currents. The steady-state conductances of depolarizing Ih (hyperpolarization-activated cationic current), IT (low-threshold calcium current), and INaP (persistent sodium current) move the membrane potential away from the reversal potential of the leak conductances. This depolarization is counteracted in turn by the hyperpolarizing steady-state current of IA (fast transient A-type potassium current) and IKir (inwardly rectifying potassium current). Using the computational model, we have shown that single parameter variations compatible with physiological or pathological modulation promote burst firing periodicity. The balance between three amplifying variables (activation of IT, activation of INaP, and activation of IKir) and three recovering variables (inactivation of IT, activation of IA, and activation of Ih) determines the propensity, or lack thereof, of repetitive burst firing of TC neurons. We also have determined the specific roles that each of these variables have during the intrinsic oscillation.

Motor cortex gates distractor stimulus encoding in sensory cortex.

Suppressing responses to distractor stimuli is a fundamental cognitive function, essential for performing goal-directed tasks. A common framework for the neuronal implementation of distractor suppression is the attenuation of distractor stimuli from early sensory to higher-order processing. However, details of the localization and mechanisms of attenuation are poorly understood. We trained mice to selectively respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of whisker motor cortex increased the overall tendency to respond and the detection of distractor whisker stimuli. Within sensory cortex, optogenetic inhibition of whisker motor cortex enhanced the propagation of distractor stimuli into target-preferring neurons. Single unit analyses revealed that whisker motor cortex (wMC) decorrelates target and distractor stimulus encoding in target-preferring primary somatosensory cortex (S1) neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from wMC to S1, through the differential activation of putative excitatory and inhibitory neurons before stimulus onset. Overall, our studies support a contribution of motor cortex to sensory selection, in suppressing behavioral responses to distractor stimuli by gating distractor stimulus propagation within sensory cortex.

Multiple Temporal and Object-Based Strategies Across Learning for a Selective Detection Task in Mice.

Goal-directed behavior paradigms inevitably involve temporal processes, such as anticipation, expectation, timing, waiting, and withholding. And yet, amongst the vast use of object-based task paradigms, characterizations of temporal features are often neglected. Here, we longitudinally analyzed mice from naïve to expert performance in a somatosensory selective detection task. In addition to tracking standard measures from signal detection theory, we also characterized learning of temporal features. We find that mice transition from general sampling strategies to stimulus detection and stimulus discrimination. During these transitions, mice learn to wait as they anticipate an expected stimulus presentation and to time their response after a stimulus presentation. By establishing and implementing standardized measures, we show that the development of waiting and timing in the task overlaps with learning of stimulus detection and discrimination. We also investigated sex differences in temporal and object-based trajectories of learning, finding that males learn strategies idiosyncratically and that females learn strategies more sequentially and stereotypically. Overall, our findings emphasize multiple temporal strategies in learning for an object-based task and highlight the importance of considering diverse temporal and object-based features when characterizing behavioral and neuronal aspects of learning.

The locus coeruleus mediates behavioral flexibility.

Behavioral flexibility is the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a tactile-based rule-shift detection task in which mice responded to left and right whisker deflections in a context-dependent manner and exhibited varying degrees of switching behavior. Recording spiking activity from optogenetically tagged neurons in the LC at millisecond precision during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation accelerated task switching and improved task performance. Overall, our study provides important evidence to reveal the link between LC activity and behavioral flexibility.

The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors.

A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT(3A)) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT(3A)R-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT(3A)Rs, acetylcholine also depolarizes 5-HT(3A)R-expressing neurons via nicotinic receptors. 5-HT(3A)R-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT(3A)R neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT(3A)R-expressing neurons during sensory process depending on different behavioral states.

Cortical Localization of the Sensory-Motor Transformation in a Whisker Detection Task in Mice.

Responding to a stimulus requires transforming an internal sensory representation into an internal motor representation. Where and how this sensory-motor transformation occurs is a matter of vigorous debate. Here, we trained male and female mice in a whisker detection go/no-go task in which they learned to respond (lick) following a transient whisker deflection. Using single unit recordings, we quantified sensory-related, motor-related, and choice-related activities in whisker primary somatosensory cortex (S1), whisker region of primary motor cortex (wMC), and anterior lateral motor cortex (ALM), three regions that have been proposed to be critical for the sensory-motor transformation in whisker detection. We observed strong sensory encoding in S1 and wMC, with enhanced encoding in wMC, and a lack of sensory encoding in ALM. We observed strong motor encoding in all three regions, yet largest in wMC and ALM. We observed the earliest choice probability in wMC, despite earliest sensory responses in S1. Based on the criteria of having both strong sensory and motor representations and early choice probability, we identify whisker motor cortex as the cortical region most directly related to the sensory-motor transformation. Our data support a model of sensory encoding originating in S1, sensory amplification and sensory-motor transformation occurring within wMC, and motor signals emerging in ALM after the sensory-motor transformation.

Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes.

Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca(2+) spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca(2+) spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca(2+)](i) changes throughout the dendritic tree in response to climbing fiber activation. Ca(2+) signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca(2+) influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease.

Erratum: Addendum: Shaping the Cortical Landscape: Functions and Mechanisms of Top-Down Cortical Feedback Pathways.

[This corrects the article DOI: 10.3389/fnsys.2020.00033.].

Shaping the Cortical Landscape: Functions and Mechanisms of Top-Down Cortical Feedback Pathways.

Cortical feedback pathways are proposed to guide cognition and behavior according to context and goal-direction. At the cellular level, cortical feedback pathways target multiple excitatory and inhibitory populations. However, we currently lack frameworks that link how the cellular mechanisms of cortical feedback pathways underlie their cognitive/behavioral functions. To establish this link, we expand on the framework of signal routing, the ability of cortical feedback pathways to proactively modulate how feedforward signals are propagated throughout the cortex. We propose that cortical feedback modulates routing through multiple mechanisms: preparing intended motor representations, setting the trigger conditions for evoking cortical outputs, altering coupling strengths between cortical regions, and suppressing expected sensory representations. In developing this framework, we first define the anatomy of cortical feedback pathways and identify recent advances in studying their functions at high specificity and resolution. Second, we review the diverse functions of cortical feedback pathways throughout the cortical hierarchy and evaluate these functions from the framework of signal routing. Third, we review the conserved cellular targets and circuit impacts of cortical feedback. Fourth, we introduce the concept of the "cortical landscape," a graphical depiction of the routes through cortex that are favored at a specific moment in time. We propose that the cortical landscape, analogous to energy landscapes in physics and chemistry, can capture important features of signal routing including coupling strength, trigger conditions, and preparatory states. By resolving the cortical landscape, we may be able to quantify how the cellular processes of cortical feedback ultimately shape cognition and behavior.

Kv3.3 channels at the Purkinje cell soma are necessary for generation of the classical complex spike waveform.

Voltage-gated potassium channel subunit Kv3.3 is prominently expressed in cerebellar Purkinje cells and is known to be important for cerebellar function, as human and mouse movement disorders result from mutations in Kv3.3. To understand these behavioral deficits, it is necessary to know the role of Kv3.3 channels on the physiological responses of Purkinje cells. We studied the function of Kv3.3 channels in regulating the synaptically evoked Purkinje cell complex spike, the massive postsynaptic response to the activation of climbing fiber afferents, believed to be fundamental to cerebellar physiology. Acute slice recordings revealed that Kv3.3 channels are required for generation of the repetitive spikelets of the complex spike. We found that spikelet expression is regulated by somatic, and not by dendritic, Kv3 activity, which is consistent with dual somatic-dendritic recordings that demonstrate spikelet generation at axosomatic membranes. Simulations of Purkinje cell Na+ currents show that the unique electrical properties of Kv3 and resurgent Na+ channels are coordinated to limit accumulation of Na+ channel inactivation and enable rapid, repetitive firing. We additionally show that Kv3.3 knock-out mice produce altered complex spikes in vitro and in vivo, which is likely a cellular substrate of the cerebellar phenotypes observed in these mice. This characterization presents new tools to study complex spike function, cerebellar signaling, and Kv3.3-dependent human and mouse phenotypes.

Modulation of cortical circuits by top-down processing and arousal state in health and disease.

In this review, we explore how contextual modulations of sensory processing are implemented within the local cortical circuit. We focus on contextual influences of global arousal state (e.g. how alert am I?), sensory predictions (e.g. which stimuli do I expect?), and top-down attention (what is relevant to me?). We review recent literature suggesting that these operations are implemented throughout sensory cortices, and are mediated by excitatory and inhibitory local circuits. By focusing on the circuit mechanisms of contextual modulation operations, we may begin to understand how mutations in GABAergic interneurons and alterations in neuromodulatory signaling lead to specific deficits of information processing in neuropsychiatric disease.

Distribution of Kv3.3 potassium channel subunits in distinct neuronal populations of mouse brain.

Kv3.3 proteins are pore-forming subunits of voltage-dependent potassium channels, and mutations in the gene encoding for Kv3.3 have recently been linked to human disease, spinocerebellar ataxia 13, with cerebellar and extracerebellar symptoms. To understand better the functions of Kv3.3 subunits in brain, we developed highly specific antibodies to Kv3.3 and analyzed immunoreactivity throughout mouse brain. We found that Kv3.3 subunits are widely expressed, present in important forebrain structures but particularly prominent in brainstem and cerebellum. In forebrain and midbrain, Kv3.3 expression was often found colocalized with parvalbumin and other Kv3 subunits in inhibitory neurons. In brainstem, Kv3.3 was strongly expressed in auditory and other sensory nuclei. In cerebellar cortex, Kv3.3 expression was found in Purkinje and granule cells. Kv3.3 proteins were observed in axons, terminals, somas, and, unlike other Kv3 proteins, also in distal dendrites, although precise subcellular localization depended on cell type. For example, hippocampal dentate granule cells expressed Kv3.3 subunits specifically in their mossy fiber axons, whereas Purkinje cells of the cerebellar cortex strongly expressed Kv3.3 subunits in axons, somas, and proximal and distal, but not second- and third-order, dendrites. Expression in Purkinje cell dendrites was confirmed by immunoelectron microscopy. Kv3 channels have been demonstrated to rapidly repolarize action potentials and support high-frequency firing in various neuronal populations. In this study, we identified additional populations and subcellular compartments that are likely to sustain high-frequency firing because of the expression of Kv3.3 and other Kv3 subunits.

Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model.

Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input-output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation.