Cortical Networks Relating to Arousal Are Differentially Coupled to Neural Activity and Hemodynamics.

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25, respectively, at a time lag of 0 s. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in the prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies >1 Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity.

Layer 1 of somatosensory cortex: an important site for input to a tiny cortical compartment.

Neocortical layer 1 has been proposed to be at the center for top-down and bottom-up integration. It is a locus for interactions between long-range inputs, layer 1 interneurons, and apical tuft dendrites of pyramidal neurons. While input to layer 1 has been studied intensively, the level and effect of input to this layer has still not been completely characterized. Here we examined the input to layer 1 of mouse somatosensory cortex with retrograde tracing and optogenetics. Our assays reveal that local input to layer 1 is predominantly from layers 2/3 and 5 pyramidal neurons and interneurons, and that subtypes of local layers 5 and 6b neurons project to layer 1 with different probabilities. Long-range input from sensory-motor cortices to layer 1 of somatosensory cortex arose predominantly from layers 2/3 neurons. Our optogenetic experiments showed that intra-telencephalic layer 5 pyramidal neurons drive layer 1 interneurons but have no effect locally on layer 5 apical tuft dendrites. Dual retrograde tracing revealed that a fraction of local and long-range neurons was both presynaptic to layer 5 neurons and projected to layer 1. Our work highlights the prominent role of local inputs to layer 1 and shows the potential for complex interactions between long-range and local inputs, which are both in position to modify the output of somatosensory cortex.

Premotor Ramping of Thalamic Neuronal Activity Is Modulated by Nigral Inputs and Contributes to Control the Timing of Action Release.

The ventromedial (VM)/ventro-anterior-lateral (VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathologic motor control functions and decision-making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and, on the other hand, motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal-directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct (corr) and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action) and weaker for trials with no licks [omission (omi)] compared with correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led to a reduced probability of impulsive action and an increased amount of omissions trials. We propose a parsimonious model explaining our data and conclude that a thalamic ramping mechanism contributes to the control of proper timing of action release and that inhibitory nigral inputs are sufficient to interrupt this mechanism and modulate the amount of motor impulsivity in this task.SIGNIFICANCE STATEMENT Coordinated neural activity in motor circuits is essential for correct movement preparation and execution, and even slight imbalances in neural processing can lead to failure in behavioral tasks or motor disorders. Here we focused on how failure to regulate the control of activity balance in the motor thalamus can be implicated in impulsive action release or omissions to act, through an activity ramping mechanism that is required for proper action release. Using optogenetic activation of inhibitory basal ganglia terminals in motor thalamus we show that basal ganglia input is well positioned to control this ramping activity and determine the timing of action initiation.

A general method to generate artificial spike train populations matching recorded neurons.

We developed a general method to generate populations of artificial spike trains (ASTs) that match the statistics of recorded neurons. The method is based on computing a Gaussian local rate function of the recorded spike trains, which results in rate templates from which ASTs are drawn as gamma distributed processes with a refractory period. Multiple instances of spike trains can be sampled from the same rate templates. Importantly, we can manipulate rate-covariances between spike trains by performing simple algorithmic transformations on the rate templates, such as filtering or amplifying specific frequency bands, and adding behavior related rate modulations. The method was examined for accuracy and limitations using surrogate data such as sine wave rate templates, and was then verified for recorded spike trains from cerebellum and cerebral cortex. We found that ASTs generated with this method can closely follow the firing rate and local as well as global spike time variance and power spectrum. The method is primarily intended to generate well-controlled spike train populations as inputs for dynamic clamp studies or biophysically realistic multicompartmental models. Such inputs are essential to study detailed properties of synaptic integration with well-controlled input patterns that mimic the in vivo situation while allowing manipulation of input rate covariances at different time scales.

Robust transmission of rate coding in the inhibitory Purkinje cell to cerebellar nuclei pathway in awake mice.

Neural coding through inhibitory projection pathways remains poorly understood. We analyze the transmission properties of the Purkinje cell (PC) to cerebellar nucleus (CN) pathway in a modeling study using a data set recorded in awake mice containing respiratory rate modulation. We find that inhibitory transmission from tonically active PCs can transmit a behavioral rate code with high fidelity. We parameterized the required population code in PC activity and determined that 20% of PC inputs to a full compartmental CN neuron model need to be rate-comodulated for transmission of a rate code. Rate covariance in PC inputs also accounts for the high coefficient of variation in CN spike trains, while the balance between excitation and inhibition determines spike rate and local spike train variability. Overall, our modeling study can fully account for observed spike train properties of cerebellar output in awake mice, and strongly supports rate coding in the cerebellum.

The Roles of the Olivocerebellar Pathway in Motor Learning and Motor Control. A Consensus Paper.

For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less suitable for one or the other of these functions, and why having multiple functions makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest that it has the potential to act in both the motor learning and motor control functions of the cerebellum.

Optogenetic stimulation of cortico-subthalamic projections is sufficient to ameliorate bradykinesia in 6-ohda lesioned mice.

Electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for ameliorating the motor symptoms of Parkinson's disease (PD) including bradykinesia. The STN receives its main excitatory input from cortex; however, the contribution of cortico-subthalamic projection neurons to the effects of DBS remains unclear. To isolate the consequences of stimulating layer 5 primary motor cortex (M1) projections to the STN, we used a dual virus transfection technique to selectively express opsins in these neurons in mice made parkinsonian by unilateral nigrostriatal 6-OHDA lesioning. AAVs containing WGA-Cre constructs were injected in the STN to retrogradely place Cre in STN afferents, while AAVs containing Cre-dependent ultrafast hChR2(E123T/T159C)-EYFP opsin constructs were injected in M1 layer 5, producing specific opsin expression in M1-STN projections. Under unstimulated conditions, lesioned mice showed bradykinesia and hypokinesia (decreased movement), along with electrophysiological changes similar to those observed in PD patients. Specifically, low frequency power (theta, alpha, low beta) was increased and gamma power was decreased, while M1/STN coherence and STN phase-amplitude-coupling (PAC) were increased. Optogenetic stimulation (100-130Hz) of STN afferents in these mice ameliorated bradykinesia and hypokinesia and brought the neural dynamics closer to the non-parkinsonian state by reducing theta and alpha and increasing gamma power in M1, decreasing STN PAC, and reducing theta band coherence. Histological examination of the EYFP expression revealed that, in addition to orthodromic and antidromic effects, stimulation of cortico-subthalamic neurons may cause wide-spread increased glutamatergic activity due to collaterals that project to areas of the thalamus and other brain regions.

The neuronal code(s) of the cerebellum.

Understanding how neurons encode information in sequences of action potentials is of fundamental importance to neuroscience. The cerebellum is widely recognized for its involvement in the coordination of movements, which requires muscle activation patterns to be controlled with millisecond precision. Understanding how cerebellar neurons accomplish such high temporal precision is critical to understanding cerebellar function. Inhibitory Purkinje cells, the only output neurons of the cerebellar cortex, and their postsynaptic target neurons in the cerebellar nuclei, fire action potentials at high, sustained frequencies, suggesting spike rate modulation as a possible code. Yet, millisecond precise spatiotemporal spike activity patterns in Purkinje cells and inferior olivary neurons have also been observed. These results and ongoing studies suggest that the neuronal code used by cerebellar neurons may span a wide time scale from millisecond precision to slow rate modulations, likely depending on the behavioral context.

Quasi-periodic patterns (QPP): large-scale dynamics in resting state fMRI that correlate with local infraslow electrical activity.

Functional connectivity measurements from resting state blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) are proving a powerful tool to probe both normal brain function and neuropsychiatric disorders. However, the neural mechanisms that coordinate these large networks are poorly understood, particularly in the context of the growing interest in network dynamics. Recent work in anesthetized rats has shown that the spontaneous BOLD fluctuations are tightly linked to infraslow local field potentials (LFPs) that are seldom recorded but comparable in frequency to the slow BOLD fluctuations. These findings support the hypothesis that long-range coordination involves low frequency neural oscillations and establishes infraslow LFPs as an excellent candidate for probing the neural underpinnings of the BOLD spatiotemporal patterns observed in both rats and humans. To further examine the link between large-scale network dynamics and infraslow LFPs, simultaneous fMRI and microelectrode recording were performed in anesthetized rats. Using an optimized filter to isolate shared components of the signals, we found that time-lagged correlation between infraslow LFPs and BOLD is comparable in spatial extent and timing to a quasi-periodic pattern (QPP) found from BOLD alone, suggesting that fMRI-measured QPPs and the infraslow LFPs share a common mechanism. As fMRI allows spatial resolution and whole brain coverage not available with electroencephalography, QPPs can be used to better understand the role of infraslow oscillations in normal brain function and neurological or psychiatric disorders.

Behavior-related pauses in simple-spike activity of mouse Purkinje cells are linked to spike rate modulation.

Purkinje cells (PCs) in the mammalian cerebellum express high-frequency spontaneous activity with average spike rates between 30 and 200 Hz. Cerebellar nuclear (CN) neurons receive converging input from many PCs, resulting in a continuous barrage of inhibitory inputs. It has been hypothesized that pauses in PC activity trigger increases in CN spiking activity. A prediction derived from this hypothesis is that pauses in PC simple-spike activity represent relevant behavioral or sensory events. Here, we asked whether pauses in the simple-spike activity of PCs related to either fluid licking or respiration, play a special role in representing information about behavior. Both behaviors are widely represented in cerebellar PC simple-spike activity. We recorded PC activity in the vermis and lobus simplex of head-fixed mice while monitoring licking and respiratory behavior. Using cross-correlation and Granger causality analysis, we examined whether short interspike intervals (ISIs) had a different temporal relationship to behavior than long ISIs or pauses. Behavior-related simple-spike pauses occurred during low-rate simple-spike activity in both licking- and breathing-related PCs. Granger causality analysis revealed causal relationships between simple-spike pauses and behavior. However, the same results were obtained from an analysis of surrogate spike trains with gamma ISI distributions constructed to match rate modulations of behavior-related Purkinje cells. Our results therefore suggest that the occurrence of pauses in simple-spike activity does not represent additional information about behavioral or sensory events that goes beyond the simple-spike rate modulations.

Infraslow LFP correlates to resting-state fMRI BOLD signals.

The slow fluctuations of the blood-oxygenation-level dependent (BOLD) signal in resting-state fMRI are widely utilized as a surrogate marker of ongoing neural activity. Spontaneous neural activity includes a broad range of frequencies, from infraslow (<0.5 Hz) fluctuations to fast action potentials. Recent studies have demonstrated a correlative relationship between the BOLD fluctuations and power modulations of the local field potential (LFP), particularly in the gamma band. However, the relationship between the BOLD signal and the infraslow components of the LFP, which are directly comparable in frequency to the BOLD fluctuations, has not been directly investigated. Here we report a first examination of the temporal relation between the resting-state BOLD signal and infraslow LFPs using simultaneous fMRI and full-band LFP recording in rat. The spontaneous BOLD signal at the recording sites exhibited significant localized correlation with the infraslow LFP signals as well as with the slow power modulations of higher-frequency LFPs (1-100 Hz) at a delay comparable to the hemodynamic response time under anesthesia. Infraslow electrical activity has been postulated to play a role in attentional processes, and the findings reported here suggest that infraslow LFP coordination may share a mechanism with the large-scale BOLD-based networks previously implicated in task performance, providing new insight into the mechanisms contributing to the resting state fMRI signal.

Neural correlates of time-varying functional connectivity in the rat.

Functional connectivity between brain regions, measured with resting state functional magnetic resonance imaging, holds great potential for understanding the basis of behavior and neuropsychiatric diseases. Recently it has become clear that correlations between the blood oxygenation level dependent (BOLD) signals from different areas vary over the course of a typical scan (6-10 min in length), though the changes are obscured by standard methods of analysis that assume the relationships are stationary. Unfortunately, because similar variability is observed in signals that share no temporal information, it is unclear which dynamic changes are related to underlying neural events. To examine this question, BOLD data were recorded simultaneously with local field potentials (LFP) from interhemispheric primary somatosensory cortex (SI) in anesthetized rats. LFP signals were converted into band-limited power (BLP) signals including delta, theta, alpha, beta and gamma. Correlation between signals from interhemispheric SI was performed in sliding windows to produce signals of correlation over time for BOLD and each BLP band. Both BOLD and BLP signals showed large changes in correlation over time and the changes in BOLD were significantly correlated to the changes in BLP. The strongest relationship was seen when using the theta, beta and gamma bands. Interestingly, while steady-state BOLD and BLP correlate with the global fMRI signal, dynamic BOLD becomes more like dynamic BLP after the global signal is regressed. As BOLD sliding window connectivity is partially reflecting underlying LFP changes, the present study suggests it may be a valuable method of studying dynamic changes in brain states.

Gain control of synaptic response function in cerebellar nuclear neurons by a calcium-activated potassium conductance.

Small conductance Ca(2+)-activated potassium (SK) current provides an important modulator of excitatory synaptic transmission, which undergoes plastic regulation via multiple mechanisms. We examined whether inhibitory input processing is also dependent on SK current in the cerebellar nuclei (CN) where inhibition provides the only route of information transfer from the cerebellar cortical Purkinje cells. We employed dynamic clamping in conjunction with computer simulations to address this question. We found that SK current plays a critical role in the inhibitory synaptic control of spiking output. Specifically, regulation of SK current density resulted in a gain control of spiking output, such that low SK current promoted large output signaling for large inhibitory cell input fluctuations due to Purkinje cell synchronization. In contrast, smaller nonsynchronized Purkinje cell input fluctuations were not amplified. Regulation of SK density in the CN therefore would likely lead to important consequences for the transmission of synchronized Purkinje cell activity to the motor system.

Modeling Synaptic Integration of Bursty and ß Oscillatory Inputs in Ventromedial Motor Thalamic Neurons in Normal and Parkinsonian States.

The ventromedial motor thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous in vitro experiments performed in mice showed that dopamine depletion enhances the excitability of thalamocortical (TC) neurons in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo, we constructed biophysically detailed mouse VM TC model neurons fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo We found that VM neuron models in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursting in inhibitory input from the substantia nigra pars reticulata (SNR), as observed in parkinsonian conditions, evoked a postinhibitory firing rate increase with a longer duration in dopamine-depleted than control conditions, due to different M-type potassium channel densities. With ß oscillations in the inhibitory inputs from SNR and the excitatory inputs from cortex, we observed spike-phase locking in the activity of the models in normal and dopamine-depleted states, which relayed and amplified the oscillations of the inputs, suggesting that the increased ß oscillations observed in VM of parkinsonian animals are predominantly a consequence of changes in the presynaptic activity rather than changes in intrinsic properties.

Widefield imaging of rapid pan-cortical voltage dynamics with an indicator evolved for one-photon microscopy.

Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the limited performance of current GEVIs restricts their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator with enhanced performance across all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in mice. We also developed an approach to correct optical measurements from hemodynamic and motion artifacts effectively. Finally, we achieved stable brain-wide voltage imaging and successfully tracked gamma-frequency whisker and visual stimulations in awake mice in single trials, opening the door to investigating the role of high-frequency signals in brain computations.

Brain rhythms control microglial response and cytokine expression via NF-κB signaling.

Microglia transform in response to changes in sensory or neural activity, such as sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, affect microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at 40 hertz, within the gamma band, and 20 hertz, within the beta band, we found that these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. Flicker induced expression of certain cytokines independently of microglia, including interleukin-10 and macrophage colony-stimulating factor. We hypothesized that nuclear factor κB (NF-κB) plays a causal role in frequency-specific cytokine and microglial responses because this pathway is activated by synaptic activity and regulates cytokines. After flicker, phospho-NF-κB colabeled with neurons more than microglia. Inhibition of NF-κB signaling down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglial morphology. These results reveal a mechanism through which brain rhythms affect brain function by altering microglial morphology and cytokines via NF-κB.

Dendritic sodium channels promote active decorrelation and reduce phase locking to parkinsonian input oscillations in model globus pallidus neurons.

Correlated firing among populations of neurons is present throughout the brain and is often rhythmic in nature, observable as an oscillatory fluctuation in the local field potential. Although rhythmic population activity is believed to be critical for normal function in many brain areas, synchronized neural oscillations are associated with disease states in other cases. In the globus pallidus (GP in rodents, homolog of the primate GPe), pairs of neurons generally have uncorrelated firing in normal animals despite an anatomical organization suggesting that they should receive substantial common input. In contrast, correlated and rhythmic GP firing is observed in animal models of Parkinson's disease (PD). Based in part on these findings, it has been proposed that an important part of basal ganglia function is active decorrelation, whereby redundant information is compressed. Mechanisms that implement active decorrelation, and changes that cause it to fail in PD, are subjects of great interest. Rat GP neurons express fast, transient voltage-dependent sodium channels (NaF channels) in their dendrites, with the expression level being highest near asymmetric synapses. We recently showed that the dendritic NaF density strongly influences the responsiveness of model GP neurons to synchronous excitatory inputs. In the present study, we use rat GP neuron models to show that dendritic NaF channel expression is a potential cellular mechanism of active decorrelation. We further show that model neurons with lower dendritic NaF channel expression have a greater tendency to phase lock with oscillatory synaptic input patterns like those observed in PD.

Thalamic bursting and the role of timing and synchrony in thalamocortical signaling in the awake mouse.

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.

Phase response curve analysis of a full morphological globus pallidus neuron model reveals distinct perisomatic and dendritic modes of synaptic integration.

Synchronization of globus pallidus (GP) neurons and cortically entrained oscillations between GP and other basal ganglia nuclei are key features of the pathophysiology of Parkinson's disease. Phase response curves (PRCs), which tabulate the effects of phasic inputs within a neuron's spike cycle on output spike timing, are efficient tools for predicting the emergence of synchronization in neuronal networks and entrainment to periodic input. In this study we apply physiologically realistic synaptic conductance inputs to a full morphological GP neuron model to determine the phase response properties of the soma and different regions of the dendritic tree. We find that perisomatic excitatory inputs delivered throughout the interspike interval advance the phase of the spontaneous spike cycle yielding a type I PRC. In contrast, we demonstrate that distal dendritic excitatory inputs can either delay or advance the next spike depending on whether they occur early or late in the spike cycle. We find this latter pattern of responses, summarized by a biphasic (type II) PRC, was a consequence of dendritic activation of the small conductance calcium-activated potassium current, SK. We also evaluate the spike-frequency dependence of somatic and dendritic PRC shapes, and we demonstrate the robustness of our results to variations of conductance densities, distributions, and kinetic parameters. We conclude that the distal dendrite of GP neurons embodies a distinct dynamical subsystem that could promote synchronization of pallidal networks to excitatory inputs. These results highlight the need to consider different effects of perisomatic and dendritic inputs in the control of network behavior.

Dendritic sodium channels regulate network integration in globus pallidus neurons: a modeling study.

The globus pallidus (GP) predominantly contains GABAergic projection neurons that occupy a central position in the indirect pathway of the basal ganglia. They have long dendrites that can extend through one-half the diameter of the GP in rats, potentially enabling convergence and interaction between segregated basal ganglia circuits. Because of the length and fine diameter of GP dendrites, however, it is unclear how much influence distal synapses have on spiking activity. Dendritic expression of fast voltage-dependent Na(+) channels (NaF channels) can enhance the importance of distal excitatory synapses by allowing for dendritic spike initiation and by subthreshold boosting of EPSPs. Antibody labeling has demonstrated the presence of NaF channel proteins in GP dendrites, but the quantitative expression density of the channels remains unknown. We built a series of nine GP neuron models that differed only in their dendritic NaF channel expression level to assess the functional impact of this parameter. The models were all similar in their basic electrophysiological features; however, higher expression levels of dendritic NaF channels increased the relative effectiveness of distal inputs for both excitatory and inhibitory synapses, broadening the effective extent of the dendritic tree. Higher dendritic NaF channel expression also made the neurons more resistant to tonic inhibition and highly sensitive to clustered synchronous excitation. The dendritic NaF channel expression pattern may therefore be a critical determinant of convergence for both the striatopallidal and subthalamopallidal projections, while also dictating which spatiotemporal input patterns are most effective at driving GP neuron output.