Shawn D. Burton

Intrinsic heterogeneity in oscillatory dynamics limits correlation-induced neural synchronization

Synchronous neural oscillations are found throughout the brain and are thought to contribute to neural coding and the propagation of activity. Several proposed mechanisms of synchronization have gained support through combined theoretical and experimental investigation, including mechanisms based on coupling and correlated input. Here, we ask how correlation-induced synchrony is affected by physiological heterogeneity across neurons. To address this question, we examined cell-to-cell differences in phase-response curves (PRCs), which characterize the response of periodically firing neurons to weak perturbations. Using acute slice electrophysiology, we measured PRCs across a single class of principal neurons capable of sensory-evoked oscillations in vivo: the olfactory bulb mitral cells (MCs). Periodically firing MCs displayed a broad range of PRCs, each of which was well fit by a simple three-parameter model. MCs also displayed differences in firing rate-current relationships and in preferred firing rate ranges. Both the observed PRC heterogeneity and moderate firing rate differences (∼10 Hz) separately reduced the maximum correlation-induced synchrony between MCs by up to 25-30%. Simulations further demonstrated that these components of heterogeneity alone were sufficient to account for the difference in synchronization among heterogeneous vs. homogeneous populations in vitro. Within this simulation framework, independent modulation of specific PRC features additionally revealed which aspects of PRC heterogeneity most strongly impact correlation-induced synchronization. Finally, we demonstrated good agreement of novel mathematical theory with our experimental and simulation results, providing a theoretical basis for the influence of heterogeneity on correlation-induced neural synchronization.

Greater excitability and firing irregularity of tufted cells underlies distinct afferent‐evoked activity of olfactory bulb mitral and tufted cells

The two classes of principal neurons in the mammalian main olfactory bulb, mitral and tufted cells, respond with different firing latencies and rates to afferent‐evoked input; how these differences in activity arise is incompletely understood. Tufted cells receive stronger afferent‐evoked excitation than mitral cells, but this difference alone is insufficient to account for the greater afferent‐evoked firing in tufted versus mitral cells. Mitral and tufted cells exhibit significant intrinsic functional differences; compared to mitral cells, tufted cells fire action potentials with shorter durations and faster afterhyperpolarizations and exhibit twofold greater firing rate–current curve gains and peak rates. Tufted cells exhibit diverse firing modes, including tonic firing and irregular stuttering, and on average fire more irregularly than mitral cells. Collectively, stronger afferent excitation, greater intrinsic excitability and more irregular firing in tufted cells combine to drive distinct responses of mitral and tufted cells to sensory input.

Brain-wide analysis of electrophysiological diversity yields novel categorization of mammalian neuron types

For decades, neurophysiologists have characterized the biophysical properties of a rich diversity of neuron types. However, identifying common features and computational roles shared across neuron types is made more difficult by inconsistent conventions for collecting and reporting biophysical data. Here, we leverage NeuroElectro, a literature-based database of electrophysiological properties (www.neuroelectro.org), to better understand neuronal diversity, both within and across neuron types, and the confounding influences of methodological variability. We show that experimental conditions (e.g., electrode types, recording temperatures, or animal age) can explain a substantial degree of the literature-reported biophysical variability observed within a neuron type. Critically, accounting for experimental metadata enables massive cross-study data normalization and reveals that electrophysiological data are far more reproducible across laboratories than previously appreciated. Using this normalized dataset, we find that neuron types throughout the brain cluster by biophysical properties into six to nine superclasses. These classes include intuitive clusters, such as fast-spiking basket cells, as well as previously unrecognized clusters, including a novel class of cortical and olfactory bulb interneurons that exhibit persistent activity at theta-band frequencies.

Targeting the Tcf4 G13ANDE17 binding site to selectively disrupt β-Catenin/T-Cell factor protein?protein interactions

Selective disruption of protein-protein interactions by small molecules is important for probing the structure and dynamic aspects of cellular network. It can also provide new therapeutic targets. β-Catenin of the canonical Wnt signaling pathway uses the same positively charged groove to bind with T-cell factor (Tcf), cadherin, and adenomatous polysis coli (APC). The extravagant formation of β-catenin/Tcf interactions drives the initiation and progression of many cancers and fibroses, while β-catenin/cadherin and β-catenin/APC interactions are essential for cell-cell adhesion and β-catenin degradation. In this study, a selective binding site that can differentiate β-catenin/Tcf, β-catenin/cadherin, and β-catenin/APC interactions was identified by alanine scanning and biochemical assays. A new peptidomimetic strategy that incorporates SiteMap and multiple-copy simultaneous search was used to design selective small-molecule inhibitors for β-catenin/Tcf interactions. A potent inhibitor was discovered to bind with β-catenin and completely disrupt β-catenin/Tcf interactions. It also exhibits dual selectivity for β-catenin/Tcf over β-catenin/cadherin and β-catenin/APC interactions in both biochemical and cell-based assays. This study provides a proof of concept for designing selective inhibitors for β-catenin/Tcf interactions.

Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb

Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell-mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity. SIGNIFICANCE STATEMENT Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates.

Impact of neuronal heterogeneity on correlated colored noise-induced synchronization

Synchronization plays an important role in neural signal processing and transmission. Many hypotheses have been proposed to explain the origin of neural synchronization. In recent years, correlated noise-induced synchronization has received support from many theoretical and experimental studies. However, many of these prior studies have assumed that neurons have identical biophysical properties and that their inputs are well modeled by white noise. In this context, we use colored noise to induce synchronization between oscillators with heterogeneity in both phase-response curves and frequencies. In the low noise limit, we derive novel analytical theory showing that the time constant of colored noise influences correlated noise-induced synchronization and that oscillator heterogeneity can limit synchronization. Surprisingly, however, heterogeneous oscillators may synchronize better than homogeneous oscillators given low input correlations. We also find resonance of oscillator synchronization to colored noise inputs when firing frequencies diverge. Collectively, these results prove robust for both relatively high noise regimes and when applied to biophysically realistic spiking neuron models, and further match experimental recordings from acute brain slices.

Distinct lateral inhibitory circuits drive parallel processing of sensory information in the mammalian olfactory bulb

Splitting sensory information into parallel pathways is a common strategy in sensory systems. Yet, how circuits in these parallel pathways are composed to maintain or even enhance the encoding of specific stimulus features is poorly understood. Here, we have investigated the parallel pathways formed by mitral and tufted cells of the olfactory system in mice and characterized the emergence of feature selectivity in these cell types via distinct lateral inhibitory circuits. We find differences in activity-dependent lateral inhibition between mitral and tufted cells that likely reflect newly described differences in the activation of deep and superficial granule cells. Simulations show that these circuit-level differences allow mitral and tufted cells to best discriminate odors in separate concentration ranges, indicating that segregating information about different ranges of stimulus intensity may be an important function of these parallel sensory pathways. DOI: http://dx.doi.org/10.7554/eLife.16039.001

Olfactory Bulb Deep Short-Axon Cells Mediate Widespread Inhibition of Tufted Cell Apical Dendrites

In the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system, GABAergic interneuron signaling shapes principal neuron activity to regulate olfaction. However, a lack of known selective markers for MOB interneurons has strongly impeded cell-type-selective investigation of interneuron function. Here, we identify the first selective marker of glomerular layer-projecting deep short-axon cells (GL-dSACs) and investigate systematically the structure, abundance, intrinsic physiology, feedforward sensory input, neuromodulation, synaptic output, and functional role of GL-dSACs in the mouse MOB circuit. GL-dSACs are located in the internal plexiform layer, where they integrate centrifugal cholinergic input with highly convergent feedforward sensory input. GL-dSAC axons arborize extensively across the glomerular layer to provide highly divergent yet selective output onto interneurons and principal tufted cells. GL-dSACs are thus capable of shifting the balance of principal tufted versus mitral cell activity across large expanses of the MOB in response to diverse sensory and top-down neuromodulatory input. SIGNIFICANCE STATEMENT The identification of cell-type-selective molecular markers has fostered tremendous insight into how distinct interneurons shape sensory processing and behavior. In the main olfactory bulb (MOB), inhibitory circuits regulate the activity of principal cells precisely to drive olfactory-guided behavior. However, selective markers for MOB interneurons remain largely unknown, limiting mechanistic understanding of olfaction. Here, we identify the first selective marker of a novel population of deep short-axon cell interneurons with superficial axonal projections to the sensory input layer of the MOB. Using this marker, together with immunohistochemistry, acute slice electrophysiology, and optogenetic circuit mapping, we reveal that this novel interneuron population integrates centrifugal cholinergic input with broadly tuned feedforward sensory input to modulate principal cell activity selectively.

Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures.

Neuroligins are a family of cell adhesion molecules critical in establishing proper central nervous system connectivity; disruption of neuroligin signaling in vivo precipitates a broad range of cognitive deficits. Despite considerable recent progress, the specific synaptic function of neuroligin-1 (NL1) remains unclear. A current model proposes that NL1 acts exclusively to mature pre-existent synaptic connections in an activity-dependent manner. A second element of this activity-dependent maturation model is that an alternate molecule acts upstream of NL1 to initiate synaptic connections. SynCAM1 (SC1) is hypothesized to function in this capacity, though several uncertainties remain regarding SC1 function. Using overexpression and chronic pharmacological blockade of synaptic activity, we now demonstrate that NL1 is capable of robustly recruiting synapsin-positive terminals independent of synaptic maturation and activity in 2-week old primary hippocampal neuronal cultures. We further report that neither SC1 overexpression nor knockdown of endogenous SC1 impacts synapsin punctum densities, suggesting that SC1 is not a limiting factor of synapse initiation in maturing hippocampal neurons in vitro. Consistent with these findings, we observed profoundly greater recruitment of synapsin-positive presynaptic terminals by NL1 than SC1 in a mixed-culture assay of artificial synaptogenesis between primary neurons and heterologous cells. Collectively, our results contend multiple aspects of the proposed model of NL1 and SC1 function and motivate an alternative model whereby SC1 may mature synaptic connections forged by NL1. Supporting this model, we present evidence that combined NL1 and SC1 overexpression triggers excitotoxic neurodegeneration through SC1 signaling at synaptic connections initiated by NL1.

Stimulus features, resetting curves, and the dependence on adaptation

We derive a formula that relates the spike-triggered covariance (STC) to the phase resetting curve (PRC) of a neural oscillator. We use this to show how changes in the shape of the PRC alter the sensitivity of the neuron to different stimulus features, which are the eigenvectors of the STC. We compute the PRC and STC for some biophysical models. We compare the STCs and their spectral properties for a two-parameter family of PRCs. Surprisingly, the skew of the PRC has a larger effect on the spectrum and shape of the STC than does the bimodality of the PRC (which plays a large role in synchronization properties). Finally, we relate the STC directly to the spike-triggered average and apply this theory to an olfactory bulb mitral cell recording.