@article {69841, title = {DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning.}, journal = {Nat Neurosci}, year = {2025}, month = {2025 Mar 31}, abstract = {

Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.

}, issn = {1546-1726}, doi = {10.1038/s41593-025-01923-4}, url = {https://doi.org/10.1038/s41593-025-01923-4}, author = {Mohar, Boaz and Michel, Gabriela and Wang, Yi-Zhi and Hernandez, Veronica and Grimm, Jonathan B and Park, Jin-Yong and Patel, Ronak and Clarke, Morgan and Brown, Timothy A and Bergmann, Cornelius and Gebis, Kamil K and Wilen, Anika P and Liu, Bian and Johnson, Richard and Graves, Austin and Tchumatchenko, Tatjana and Savas, Jeffrey N and Fornasiero, Eugenio F and Huganir, Richard L and Tillberg, Paul W and Lavis, Luke D and Svoboda, Karel and Spruston, Nelson} } @article {68938, title = {Learning produces an orthogonalized state machine in the hippocampus.}, journal = {Nature}, year = {2025}, month = {2025 Feb 12}, abstract = {

Cognitive maps confer animals with flexible intelligence by representing spatial, temporal and abstract relationships that can be used to shape thought, planning and behaviour. Cognitive maps have been observed in the hippocampus1, but their algorithmic form and learning mechanisms remain obscure. Here we used large-scale, longitudinal two-photon calcium imaging to record activity from thousands of neurons in the CA1 region of the hippocampus while mice learned to efficiently collect rewards from two subtly different linear tracks in virtual reality. Throughout learning, both animal behaviour and hippocampal neural activity progressed through multiple stages, gradually revealing improved task representation that mirrored improved behavioural efficiency. The learning process involved progressive decorrelations in initially similar hippocampal neural activity within and across tracks, ultimately resulting in orthogonalized representations resembling a state machine capturing the inherent structure of the task. This decorrelation process was driven by individual neurons acquiring task-state-specific responses (that is, {\textquoteright}state cells{\textquoteright}). Although various standard artificial neural networks did not naturally capture these dynamics, the clone-structured causal graph, a hidden Markov model variant, uniquely reproduced both the final orthogonalized states and the learning trajectory seen in animals. The observed cellular and population dynamics constrain the mechanisms underlying cognitive map formation in the hippocampus, pointing to hidden state inference as a fundamental computational principle, with implications for both biological and artificial intelligence.

}, doi = {10.1038/s41586-024-08548-w}, url = {https://doi.org/10.1038/s41586-024-08548-w}, author = {Sun, Weinan and Winnubst, Johan and Natrajan, Maanasa and Lai, Chongxi and Kajikawa, Koichiro and Michaelos, Michalis and Gattoni, Rachel and Stringer, Carsen and Flickinger, Daniel and Fitzgerald, James E and Spruston, Nelson} } @article {69710, title = {Discovery of neuronal cell types by pairing whole cell reconstructions with RNA expression profiles}, journal = {bioRxiv}, year = {2024}, month = {12/2024}, abstract = {

Effective classification of neuronal cell types requires both molecular and morphological descriptors to be collected in situ at single cell resolution. However, current spatial transcriptomics techniques are not compatible with imaging workflows that successfully reconstruct the morphology of complete axonal projections. Here, we introduce a new methodology that combines tissue clearing, submicron whole-brain two photon imaging, and Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to assign molecular identities to fully reconstructed neurons in the mouse brain, which we call morphoFISH. We used morphoFISH to molecularly identify a previously unknown population of cingulate neurons projecting ipsilaterally to the dorsal striatum and contralaterally to higher-order thalamus. By pairing whole-brain morphometry, improved techniques for nucleic acid preservation and spatial gene expression, morphoFISH offers a quantitative solution for discovery of multimodal cell types and complements existing techniques for characterization of increasingly fine-grained cellular heterogeneity in brain circuits.Competing Interest StatementThe authors have declared no competing interest.

}, doi = {10.1101/2024.12.30.630829}, url = {https://www.biorxiv.org/content/early/2024/12/31/2024.12.30.630829}, author = {The MouseLight Project Team and Ferreira, Tiago A. and Eddison, Mark and Copeland, Monique and Lay, Mary and Tenshaw, Emily and Weldon, Monet and Schauder, David and Olbris, Donald J. and Rokicki, Konrad and Spruston, Nelson and Tillberg, Paul W. and Korff, Wyatt and Dudman, Joshua T.} } @article {67847, title = {Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus.}, journal = {Neuron}, volume = {110}, year = {2022}, month = {2022 Jan 05}, pages = {96-108.e4}, abstract = {

To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2021.10.003}, author = {Zhao, Xinyu and Hsu, Ching-Lung and Spruston, Nelson} } @article {67270, title = {Bursting potentiates the neuro-AI connection.}, journal = {Nature Neuroscience}, volume = {24}, year = {2021}, month = {2021 Jul 01}, pages = {905-6}, issn = {1546-1726}, doi = {10.1038/s41593-021-00844-2}, author = {Sun, Weinan and Zhao, Xinyu and Spruston, Nelson} } @article {65824, title = {Linking axon morphology to gene expression: a strategy for neuronal cell-type classification.}, journal = {Current Opinion in Neurobiology}, volume = {65}, year = {2020}, month = {2020 Dec 01}, pages = {70-76}, abstract = {

To study how the brain drives cognition and behavior we need to understand its cellular composition. Advances in single-cell transcriptomics have revolutionized our ability to characterize neuronal diversity. To arrive at meaningful descriptions of cell types, however, gene expression must be linked to structural and functional properties. Axonal projection patterns are an appropriate measure, as they are diverse, change only gradually over time, and they influence and constrain circuit function. Here, we consider how efforts to map transcriptional and morphological diversity in the mouse brain could be linked to generate a modern taxonomy of the mouse brain.

}, issn = {1873-6882}, doi = {10.1016/j.conb.2020.10.006}, author = {Winnubst, Johan and Spruston, Nelson and Harris, Julie A} } @article {65908, title = {Linking axon morphology to gene expression: a strategy for neuronal cell-type classification.}, journal = {Current Opinion in Neurobiology}, volume = {65}, year = {2020}, month = {2020 Dec 01}, pages = {70-76}, abstract = {

To study how the brain drives cognition and behavior we need to understand its cellular composition. Advances in single-cell transcriptomics have revolutionized our ability to characterize neuronal diversity. To arrive at meaningful descriptions of cell types, however, gene expression must be linked to structural and functional properties. Axonal projection patterns are an appropriate measure, as they are diverse, change only gradually over time, and they influence and constrain circuit function. Here, we consider how efforts to map transcriptional and morphological diversity in the mouse brain could be linked to generate a modern taxonomy of the mouse brain.

}, issn = {1873-6882}, doi = {10.1016/j.conb.2020.10.006}, author = {Winnubst, Johan and Spruston, Nelson and Harris, Julie A} } @article {65617, title = {Membrane potential dynamics underlying context-dependent sensory responses in the hippocampus.}, journal = {Nature Neuroscience}, volume = {23}, year = {2020}, month = {2020 Jul 1}, pages = {881-91}, abstract = {

As animals navigate, they must identify features within context. In the mammalian brain, the hippocampus has the ability to separately encode different environmental contexts, even when they share some prominent features. To do so, neurons respond to sensory features in a context-dependent manner; however, it is not known how this encoding emerges. To examine this, we performed electrical recordings in the hippocampus as mice navigated in two distinct virtual environments. In CA1, both synaptic input to single neurons and population activity strongly tracked visual cues in one environment, whereas responses were almost completely absent when the same cue was presented in a second environment. A very similar, highly context-dependent pattern of cue-driven spiking was also observed in CA3. These results indicate that CA1 inherits a complex spatial code from upstream regions, including CA3, that have already computed a context-dependent representation of environmental features.

}, issn = {1546-1726}, doi = {10.1038/s41593-020-0646-2}, author = {Zhao, Xinyu and Wang, Yingxue and Spruston, Nelson and Magee, Jeffrey C} } @article {65584, title = {A Sparse, Spatially Biased Subtype of Mature Granule Cell Dominates Recruitment in Hippocampal-Associated Behaviors.}, journal = {Cell Reports}, volume = {31}, year = {2020}, month = {2020 Apr 28}, pages = {107551}, abstract = {

Animals can store information about experiences by activating specific neuronal populations, and subsequent reactivation of these neural ensembles can lead to recall of salient experiences. In the hippocampus, granule cells of the dentate gyrus participate in such memory engrams; however, whether there is an underlying logic to granule cell participation has not been examined. Here, we find that a range of novel experiences preferentially activates granule cells of the suprapyramidal blade relative to the infrapyramidal blade. Motivated by this, we identify a suprapyramidal-blade-enriched population of granule cells with distinct spatial, morphological, physiological, and developmental properties. Via transcriptomics, we map these traits onto a sparse and discrete granule cell subtype that is recruited at a 10-fold greater frequency than expected by subtype prevalence, constituting the majority of all recruited granule cells. Thus, in behaviors known to involve hippocampal-dependent memory formation, a rare and spatially localized subtype dominates overall granule cell recruitment.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2020.107551}, author = {Erwin, Sarah R and Sun, Weinan and Copeland, Monique and Lindo, Sarah and Spruston, Nelson and Cembrowski, Mark S} } @article {65320, title = {Transcriptional co-repressor Sin3a regulates hippocampal synaptic plasticity via Homer1/mGluR5.}, journal = {JCI Insight}, year = {2020}, month = {2020 Feb 18}, abstract = {

Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of two classes of regulatory complexes: permissive co-activators and silencing co-repressors. Much work has focused on co-activator complexes, but little is known about the co-repressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the co-repressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the post-synaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the mGluR1α- and mGluR5-dependence of long-term potentiation, and increases activation of extracellular signal regulated kinase (ERK) in the hippocampus after learning. Our studies define a critical role for co-repressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.

}, issn = {2379-3708}, doi = {10.1172/jci.insight.92385}, author = {Bridi, Morgan S and Schoch, Hannah and Florian, C{\'e}drick and Poplawski, Shane G and Banerjee, Anamika and Hawk, Joshua D and Banks, Giulia S and Lejards, Camille and Hahn, Chang-Gyu and Giese, Karl Peter and Havekes, Robbert and Spruston, Nelson and Abel, Ted} } @article {65205, title = {Functional clustering of dendritic activity during decision-making.}, journal = {Elife}, volume = {8}, year = {2019}, month = {2019 Oct 30}, abstract = {

The active properties of dendrites can support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence and selectivity of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large learning capacity in individual neurons.

}, issn = {2050-084X}, doi = {10.7554/eLife.46966}, author = {Kerlin, Aaron and Boaz, Mohar and Flickinger, Daniel and MacLennan, Bryan J and Dean, Matthew B and Davis, Courtney and Spruston, Nelson and Svoboda, Karel} } @article {64824, title = {Heterogeneity within classical cell types is the rule: lessons from hippocampal pyramidal neurons.}, journal = {Nature Reviews. Neuroscience}, volume = {20}, year = {2019}, month = {2019 Feb 18}, pages = {193-204}, abstract = {

The mechanistic operation of brain regions is often interpreted by partitioning constituent neurons into {\textquoteright}cell types{\textquoteright}. Historically, such cell types were broadly defined by their correspondence to gross features of the nervous system (such as cytoarchitecture). Modern-day neuroscientific techniques, enabling a more nuanced examination of neuronal properties, have illustrated a wealth of heterogeneity within these classical cell types. Here, we review the extent of this within-cell-type heterogeneity in one of the simplest cortical regions of the mammalian brain, the rodent hippocampus. We focus on the mounting evidence\ that the classical CA3, CA1 and subiculum pyramidal cell types all exhibit prominent\ and spatially patterned within-cell-type heterogeneity, and suggest these cell\ types\ provide a model system for exploring the organization and function of such heterogeneity. Given that the hippocampus is structurally simple and evolutionarily ancient,\ within-cell-type heterogeneity is likely to be a general and crucial feature of the\ mammalian brain.

}, issn = {1471-0048}, doi = {10.1038/s41583-019-0125-5}, author = {Cembrowski, Mark S and Spruston, Nelson} } @article {64874, title = {Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain.}, journal = {Elife}, volume = {8}, year = {2019}, month = {2019 Apr 12}, abstract = {

Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases we provide an extensive resource for further investigation of mouse neuronal cell types.

}, issn = {2050-084X}, doi = {10.7554/eLife.38619}, author = {Sugino, Ken and Clark, Erin and Schulmann, Anton and Shima, Yasuyuki and Wang, Lihua and Hunt, David L and Hooks, Bryan M and Traenkner, Dimitri and Chandrashekar, Jayaram and Picard, Serge and Lemire, Andrew L and Spruston, Nelson and Hantman, Adam W and Nelson, Sacha B} } @article {65138, title = {Reconstruction of 1,000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain.}, journal = {Cell}, volume = {179}, year = {2019}, month = {2019 Sep 19}, pages = {268-81}, abstract = {

Neuronal\ cell\ types\ are the nodes of neural circuits that determine the flow of information within the\ brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of\ cell\ type and\ reveals\ how individual\ neurons\ route their output across the\ brain. Despite the importance of morphology, few\ projection\ neurons\ in the\ mouse\ brain\ have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the\ brain. We used this platform to reconstruct more than\ 1,000\ projection\ neurons\ in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed\ neurons\ constitute more than 85\ meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of\ projection\ neurons\ and suggest organizational principles of\ long-range\ connectivity.

}, issn = {00928674}, doi = {10.1016/j.cell.2019.07.042}, author = {Winnubst, Johan and Bas, Erhan and Ferreira, Tiago A. and Wu, Zhuhao and Economo, Michael N. and Edson, Patrick and Arthur, Ben J. and Bruns, Christopher and Rokicki, Konrad and Schauder, David and Olbris, Donald J. and Murphy, Sean D. and Ackerman, David G. and Arshadi, Cameron and Baldwin, Perry and Blake, Regina and Elsayed, Ahmad and Hasan, Mashtura and Ramirez, Daniel and Dos Santos, Bruno and Weldon, Monet and Zafar, Amina and Dudman, Joshua T. and Gerfen, Charles R. and Hantman, Adam W. and Korff, Wyatt and Sternson, Scott M. and Spruston, Nelson and Svoboda, Karel and Chandrashekar, Jayaram} } @article {65225, title = {ShuTu: Open-source software for efficient and accurate reconstruction of dendritic morphology.}, journal = {Frontiers in Neuroinformatics}, volume = {13}, year = {2019}, month = {2019 Oct 31}, pages = {68}, abstract = {

Neurons perform computations by integrating inputs from thousands of synapses-mostly in the dendritic tree-to drive action potential firing in the axon. One fruitful approach to studying this process is to record from neurons using patch-clamp electrodes, fill the recorded neurons with a substance that allows subsequent staining, reconstruct the three-dimensional architectures of the dendrites, and use the resulting functional and structural data to develop computer models of dendritic integration. Accurately producing quantitative reconstructions of dendrites is typically a tedious process taking many hours of manual inspection and measurement. Here we present ShuTu, a new software package that facilitates accurate and efficient reconstruction of dendrites imaged using bright-field microscopy. The program operates in two steps: (1) automated identification of dendritic processes, and (2) manual correction of errors in the automated reconstruction. This approach allows neurons with complex dendritic morphologies to be reconstructed rapidly and efficiently, thus facilitating the use of computer models to study dendritic structure-function relationships and the computations performed by single neurons.

}, issn = {1662-5196}, doi = {10.3389/fninf.2019.00068}, author = {Jin, Dezhe Z and Zhao, Ting and Hunt, David L and Tillage, Rachel P and Hsu, Ching-Lung and Spruston, Nelson} } @article {49475, title = {Astrocytes integrate and drive action potential firing in inhibitory subnetworks.}, journal = {Nature Communications}, volume = {9}, year = {2018}, month = {2018 Oct 18}, pages = {4336}, abstract = {

Many brain functions depend on the ability of neural networks to temporally integrate transient inputs to produce sustained discharges. This can occur through cell-autonomous mechanisms in individual neurons and through reverberating activity in recurrently connected neural networks. We report a third mechanism involving temporal integration of neural activity by a network of astrocytes. Previously, we showed that some types of interneurons can generate long-lasting trains of action potentials (barrage firing) following repeated depolarizing stimuli. Here we show that calcium signaling in an astrocytic network correlates with barrage firing; that active depolarization of astrocyte networks by chemical or optogenetic stimulation enhances; and that chelating internal calcium, inhibiting release from internal stores, or inhibiting GABA transporters or metabotropic glutamate receptors inhibits barrage firing. Thus, networks of astrocytes influence the spatiotemporal dynamics of neural networks by directly integrating neural activity and driving barrages of action potentials in some populations of inhibitory interneurons.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06338-3}, author = {Deemyad, Tara and L{\"u}thi, Joel and Spruston, Nelson} } @article {49174, title = {Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes.}, journal = {Cell}, volume = {173}, year = {2018}, month = {2018 Apr 10}, pages = {1280-92}, abstract = {

The mammalian hippocampus, comprised of serially connected subfields, participates in diverse behavioral and cognitive functions. It has been postulated that parallel circuitry embedded within hippocampal subfields may underlie such functional diversity. We sought to identify, delineate, and manipulate this putatively parallel architecture in the dorsal subiculum, the primary output subfield of the dorsal hippocampus. Population and single-cell RNA-seq revealed that the subiculum can be divided into two spatially adjacent subregions associated with prominent differences in pyramidal cell gene expression. Pyramidal cells occupying these two regions differed in their long-range inputs, local wiring, projection targets, and electrophysiological properties. Leveraging gene-expression differences across these regions, we use genetically restricted neuronal silencing to show that\ these regions differentially contribute to spatial working memory. This work provides a coherent molecular-, cellular-, circuit-, and behavioral-level demonstration that the hippocampus embeds structurally and functionally dissociable streams within its serial architecture.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2018.03.031}, author = {Cembrowski, Mark S and Phillips, Matthew G and DiLisio, Salvatore F and Shields, Brenda C and Winnubst, Johan and Chandrashekar, Jayaram and Bas, Erhan and Spruston, Nelson} } @article {49276, title = {A novel pyramidal cell type promotes sharp-wave synchronization in the hippocampus.}, journal = {Nature Neuroscience}, volume = {21}, year = {2018}, month = {2018 Jun 18}, pages = {985-95}, abstract = {

To support cognitive function, the CA3 region of the hippocampus performs computations involving attractor dynamics. Understanding how cellular and ensemble activities of CA3 neurons enable computation is critical for elucidating the neural correlates of cognition. Here we show that CA3 comprises not only classically described pyramid cells with thorny excrescences, but also includes previously unidentified {\textquoteright}athorny{\textquoteright} pyramid cells that lack mossy-fiber input. Moreover, the two neuron types have distinct morphological and physiological phenotypes and are differentially modulated by acetylcholine. To understand the contribution of these athorny pyramid neurons to circuit function, we measured cell-type-specific firing patterns during sharp-wave synchronization events in vivo and recapitulated these dynamics with an attractor network model comprising two principal cell types. Our data and simulations reveal a key role for athorny cell bursting in the initiation of sharp waves: transient network attractor states that signify the execution of pattern completion computations vital to cognitive function.

}, issn = {1546-1726}, doi = {10.1038/s41593-018-0172-7}, author = {Hunt, David L and Linaro, Daniele and Si, Bailu and Romani, Sandro and Spruston, Nelson} } @article {49274, title = {Persistent sodium current mediates the steep voltage dependence of spatial coding in hippocampal pyramidal neurons.}, journal = {Neuron}, year = {2018}, month = {2018 Jun 05}, abstract = {

The mammalian hippocampus forms a cognitive map using neurons that fire according to an animal{\textquoteright}s position ("place cells") and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses in\ vivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of in\ vitro, in\ vivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2018.05.025}, author = {Hsu, Ching-Lung and Zhao, Xinyu and Milstein, Aaron D and Spruston, Nelson} } @article {49046, title = {Single excitatory axons form clustered synapses onto CA1 pyramidal cell dendrites.}, journal = {Nature Neuroscience}, volume = {21}, year = {2018}, month = {2018 Mar}, pages = {353-63}, abstract = {

CA1 pyramidal neurons are a major output of the hippocampus and encode features of experience that constitute episodic memories. Feature-selective firing of these neurons results from the dendritic integration of inputs from multiple brain regions. While it is known that synchronous activation of spatially clustered inputs can contribute to firing through the generation of dendritic spikes, there is no established mechanism for spatiotemporal synaptic clustering. Here we show that single presynaptic axons form multiple, spatially clustered inputs onto the distal, but not proximal, dendrites of CA1 pyramidal neurons. These compound connections exhibit ultrastructural features indicative of strong synapses and occur much more commonly in entorhinal than in thalamic afferents. Computational simulations revealed that compound connections depolarize dendrites in a biophysically efficient manner, owing to their inherent spatiotemporal clustering. Our results suggest that distinct afferent projections use different connectivity motifs that differentially contribute to dendritic integration.

}, doi = {10.1038/s41593-018-0084-6}, author = {Bloss, Erik B and Cembrowski, Mark S and Karsh, Bill and Colonell, Jennifer and Fetter, Richard D and Spruston, Nelson} } @article {49492, title = {The subiculum is a patchwork of discrete subregions.}, journal = {eLife}, volume = {7}, year = {2018}, month = {2018 Oct 30}, abstract = {

In the hippocampus, the classical pyramidal cell type of the subiculum acts as a primary output, conveying hippocampal signals to a diverse suite of downstream regions. Accumulating evidence suggests that the subiculum pyramidal cell population may actually be comprised of discrete subclasses. Here, we investigated the extent and organizational principles governing pyramidal cell heterogeneity throughout the mouse subiculum. Using single-cell RNA-seq, we find that the subiculum pyramidal cell population can be deconstructed into eight separable subclasses. These subclasses were mapped onto abutting spatial domains, ultimately producing a complex laminar and columnar organization with heterogeneity across classical dorsal-ventral, proximal-distal, and superficial-deep axes. We further show that these transcriptomically defined subclasses correspond to differential protein products and can be associated with specific projection targets. This work deconstructs the complex landscape of subiculum pyramidal cells into spatially segregated subclasses that may be observed, controlled, and interpreted in future experiments.

}, issn = {2050-084X}, doi = {10.7554/eLife.37701}, author = {Cembrowski, Mark S and Wang, Lihua and Lemire, Andrew L and Copeland, Monique and DiLisio, Salvatore F and Clements, Jody and Spruston, Nelson} } @article {48492, title = {Integrating Results across Methodologies Is Essential for Producing Robust Neuronal Taxonomies.}, journal = {Neuron}, volume = {94}, year = {2017}, month = {2017 May 17}, pages = {747-751.e1}, abstract = {

Elucidating the diversity and spatial organization of cell types in the brain is an essential goal of neuroscience, with many emerging technologies helping to advance this endeavor. Using a new in\ situ hybridization method that can measure the expression of hundreds of genes in a given mouse brain section (amplified seqFISH), Shah et\ al. (2016) describe a spatial organization of hippocampal cell types that differs from previous reports. In seeking to understand this discrepancy, we find that many of the barcoded genes used by seqFISH to characterize this spatial organization, when cross-validated by other sensitive methodologies, exhibit negligible expression in the hippocampus. Additionally, the results of Shah et\ al. (2016) do not recapitulate canonical cellular hierarchies and improperly classify major neuronal cell types. We suggest that, when describing the spatial organization of brain regions, cross-validation using multiple techniques should be used to yield robust and informative cellular classification. This Matters Arising paper is in response to Shah et\ al. (2016), published in Neuron. See also the response by Shah et\ al. (2017), published in this issue.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2017.04.023}, author = {Cembrowski, Mark S and Spruston, Nelson} } @article {47463, title = {Brain derived neurotrophic factor differentially modulates excitability of two classes of hippocampal output neurons.}, journal = {Journal of Neurophysiology}, volume = {116}, year = {2016}, month = {2016 May 4}, pages = {466-71}, abstract = {

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampus-dependent learning and memory. Canonically, this has been ascribed to an enhancing effect on neuronal excitability and synaptic plasticity in the CA1 region. However, it is the pyramidal neurons in the subiculum that form the primary efferent pathways conveying hippocampal information to other areas of the brain, and yet the effect of BDNF on these neurons has remained unexplored. We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular pyramidal neurons can be divided into two major classes, which have different electrophysiological and morphological properties, different requirements for the induction of plasticity and different extra-hippocampal projections. We found that BDNF increases excitability in one class of subicular pyramidal neurons, yet decreases excitability of the other class. Further, while endogenous BDNF was necessary for the induction of synaptic plasticity in both cell types, BDNF enhanced intrinsic plasticity in one class of pyramidal neurons, yet suppressed intrinsic plasticity in the other. Taken together, these data suggest a novel role for BDNF signaling, as it appears to dynamically and bidirectionally regulate the output of hippocampal information to different regions of the brain.

}, issn = {1522-1598}, doi = {10.1152/jn.00186.2016}, author = {Graves, Austin R and Moore, Shannon J and Spruston, Nelson and Tryba, Andrew Kieran and Kaczorowski, Catherine C} } @article {47442, title = {Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons.}, journal = {eLife}, volume = {5}, year = {2016}, month = {2016}, abstract = {

Clarifying gene expression in narrowly defined neuronal populations can provide insight into cellular identity, computation, and functionality. Here, we used next-generation RNA sequencing (RNA-seq) to produce a quantitative, whole genome characterization of gene expression for the major excitatory neuronal classes of the hippocampus; namely, granule cells and mossy cells of the dentate gyrus, and pyramidal cells of areas CA3, CA2, and CA1. Moreover, for the canonical cell classes of the trisynaptic loop, we profiled transcriptomes at both dorsal and ventral poles, producing a cell-class- and region-specific transcriptional description for these populations. This dataset clarifies the transcriptional properties and identities of lesser-known cell classes, and moreover reveals unexpected variation in the trisynaptic loop across the dorsal-ventral axis. We have created a public resource, Hipposeq (http://hipposeq.janelia.org), which provides analysis and visualization of these data and will act as a roadmap relating molecules to cells, circuits, and computation in the hippocampus.

}, issn = {2050-084X}, doi = {10.7554/eLife.14997}, author = {Cembrowski, Mark S and Wang, Lihua and Sugino, Ken and Shields, Brenda C and Spruston, Nelson} } @article {47278, title = {Spatial gene-expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons.}, journal = {Neuron}, year = {2016}, month = {2016 Jan 13}, abstract = {

Tissue and organ function has been conventionally understood in terms of the interactions among discrete and homogeneous cell types. This approach has proven difficult in neuroscience due to the marked diversity across different neuron classes, but it may be further hampered by prominent within-class variability. Here, we considered a well-defined canonical neuronal population-hippocampal CA1 pyramidal cells (CA1 PCs)-and systematically examined the extent and spatial rules of transcriptional heterogeneity. Using next-generation RNA sequencing, we identified striking variability in CA1 PCs, such that the differences within CA1 along the dorsal-ventral axis rivaled differences across distinct pyramidal neuron classes. This variability emerged from a spectrum of continuous gene-expression gradients, producing a transcriptional profile consistent with a multifarious continuum of cells. This work reveals an unexpected amount of variability within a canonical and narrowly defined neuronal population and suggests that continuous, within-class heterogeneity may be an important feature of neural circuits.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.12.013}, author = {Cembrowski, Mark S and Bachman, Julia L and Wang, Lihua and Sugino, Ken and Shields, Brenda C and Spruston, Nelson} } @article {47322, title = {Structured dendritic inhibition supports branch-selective integration in CA1 pyramidal cells.}, journal = {Neuron}, year = {2016}, month = {2016 Feb 18}, abstract = {

Neuronal circuit function is governed by precise patterns of connectivity between specialized groups of neurons. The diversity of GABAergic interneurons is a hallmark of cortical circuits, yet little is known about their targeting to individual postsynaptic dendrites. We examined synaptic connectivity between molecularly defined inhibitory interneurons and CA1 pyramidal cell dendrites using correlative light-electron microscopy and large-volume array tomography. We show that interneurons can be highly selective in their connectivity to specific dendritic branch types and, furthermore, exhibit precisely targeted connectivity to the origin or end of individual branches. Computational simulations indicate that the observed subcellular targeting enables control over the nonlinear integration of synaptic input or the initiation and backpropagation of action potentials in a branch-selective manner. Our results demonstrate that connectivity between interneurons and pyramidal cell dendrites is more precise and spatially segregated than previously appreciated, which may be a critical determinant of how inhibition shapes dendritic computation.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2016.01.029}, author = {Bloss, Erik B and Cembrowski, Mark S and Karsh, Bill and Colonell, Jennifer and Fetter, Richard D and Spruston, Nelson} } @article {46525, title = {Age-dependent changes in intrinsic neuronal excitability in subiculum after status epilepticus.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015 Mar 16}, pages = {e0119411}, abstract = {

Kainic acid-induced status epilepticus (KA-SE) in mature rats results in the development of spontaneous recurrent seizures and a pattern of cell death resembling hippocampal sclerosis in patients with temporal lobe epilepsy. In contrast, KA-SE in young animals before postnatal day (P) 18 is less likely to cause cell death or epilepsy. To investigate whether changes in neuronal excitability occur in the subiculum after KA-SE, we examined the age-dependent effects of SE on the bursting neurons of subiculum, the major output region of the hippocampus. Patch-clamp recordings were used to monitor bursting in pyramidal neurons in the subiculum of rat hippocampal slices. Neurons were studied either one or 2-3 weeks following injection of KA or saline (control) in immature (P15) or more mature (P30) rats, which differ in their sensitivity to KA as well as the long-term sequelae of the KA-SE. A significantly greater proportion of subicular pyramidal neurons from P15 rats were strong-bursting neurons and showed increased frequency-dependent bursting compared to P30 animals. Frequency-dependent burst firing was enhanced in P30, but not in P15 rats following KA-SE. The enhancement of bursting induced by KA-SE in more mature rats suggests that the frequency-dependent limitation of repetitive burst firing, which normally occurs in the subiculum, is compromised following SE. These changes could facilitate the initiation of spontaneous recurrent seizures or their spread from the hippocampus to other parts of the brain.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0119411}, author = {Chung, Sungkwon and Spruston, Nelson and Koh, Sookyong} } @article {46901, title = {BigNeuron: Large-scale 3D neuron reconstruction from optical microscopy images.}, journal = {Neuron}, volume = {87}, year = {2015}, month = {2015 Jul 15}, pages = {252-6}, abstract = {

Understanding the structure of single neurons is critical for understanding how they function within neural circuits. BigNeuron is a new community effort that combines modern bioimaging informatics, recent leaps in labeling and microscopy, and the widely recognized need for openness and standardization to provide a community resource for automated reconstruction of dendritic and axonal morphology of single neurons.

Understanding the structure of single neurons is critical for understanding how they function within neural circuits. BigNeuron is a new community effort that combines modern bioimaging informatics, recent leaps in labeling and microscopy, and the widely recognized need for openness and standardization to provide a community resource for automated reconstruction of dendritic and axonal morphology of single neurons.

}, doi = {10.1016/j.neuron.2015.06.036}, author = {Peng, Hanchuan and Hawrylycz, Michael and Roskams, Jane and Hill, Sean and Spruston, Nelson and Meijering, Erik and Ascoli, Giorgio A} } @article {47178, title = {Dendritic integration: 60 years of progress.}, journal = {Nature Neuroscience}, volume = {18}, year = {2015}, month = {2015 Dec}, pages = {1713-21}, abstract = {

Understanding how individual neurons integrate the thousands of synaptic inputs they receive is critical to understanding how the brain works. Modeling studies in silico and experimental work in vitro, dating back more than half a century, have revealed that neurons can perform a variety of different passive and active forms of synaptic integration on their inputs. But how are synaptic inputs integrated in the intact brain? With the development of new techniques, this question has recently received substantial attention, with new findings suggesting that many of the forms of synaptic integration observed in vitro also occur in vivo, including in awake animals. Here we review six decades of progress, which collectively highlights the complex ways that single neurons integrate their inputs, emphasizing the critical role of dendrites in information processing in the brain.

}, issn = {1546-1726}, doi = {10.1038/nn.4157}, author = {Stuart, Greg J and Spruston, Nelson} } @article {47201, title = {Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons.}, journal = {eLife}, volume = {4}, year = {2015}, month = {2015 Aug 06}, abstract = {

Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity.

}, issn = {2050-084X}, doi = {10.7554/eLife.06414}, author = {Kim, Yujin and Hsu, Ching-Lung and Cembrowski, Mark S and Mensh, Brett D and Spruston, Nelson} } @article {45788, title = {Assembling cell ensembles.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Jun 19}, pages = {1502-4}, abstract = {

The way the hippocampus processes information and encodes memories in the form of "cell assemblies" is likely determined in part by how its circuits are wired up during development. In this issue, Xu et\ al. now provide new insight into how neurons arising from a single common precursor migrate to their final destination and form functionally synchronous ensembles.

}, keywords = {Animals, Hippocampus}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.05.032}, author = {Spruston, Nelson} } @article {6715, title = {Balanced synaptic impact via distance-dependent synapse distribution and complementary expression of AMPARs and NMDARs in hippocampal dendrites.}, journal = {Neuron}, volume = {80}, year = {2013}, month = {2013 Dec 18}, pages = {1451-63}, abstract = {

Neuronal computation involves the integration of synaptic inputs that are often distributed over expansive dendritic trees, suggesting the need for compensatory mechanisms that enable spatially disparate synapses to influence neuronal output. In hippocampal CA1 pyramidal neurons, such mechanisms have indeed been reported, which normalize either the ability of distributed synapses to drive action potential initiation in the axon or their ability to drive dendritic spiking locally. Here we report that these mechanisms can coexist, through an elegant combination of distance-dependent regulation of synapse number and synaptic expression of AMPA and NMDA receptors. Together, these complementary gradients allow individual dendrites in both the apical and basal dendritic trees of hippocampal neurons to operate as facile computational subunits capable of supporting both global integration in the soma/axon and local integration in the dendrite.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2013.09.027}, author = {Menon, Vilas and Musial, Timothy F and Liu, Annie and Katz, Yael and Kath, William L and Spruston, Nelson and Nicholson, Daniel A} } @article {6486, title = {Mechanisms of retroaxonal barrage firing in hippocampal interneurons.}, journal = {The Journal of Physiology}, volume = {591}, year = {2013}, month = {2013 Oct 1}, pages = {4793-805}, abstract = {

Abstract We recently described a new form of neural integration and firing in a subset of interneurons, in which evoking hundreds of action potentials over tens of seconds to minutes produces a sudden barrage of action potentials lasting about a minute beyond the inciting stimulation. During this persistent firing, action potentials are generated in the distal axon and propagate retrogradely to the soma. To distinguish this from other forms of persistent firing, we refer to it here as {\textquoteright}retroaxonal barrage firing{\textquoteright}, or {\textquoteright}barrage firing{\textquoteright} for short. Its induction is blocked by chemical inhibitors of gap junctions and curiously, stimulation of one interneuron in some cases triggers barrage firing in a nearby, unstimulated interneuron. Beyond these clues, the mechanisms of barrage firing are unknown. Here we report new results related to these mechanisms. Induction of barrage firing was blocked by lowering extracellular calcium, as long as normal action potential threshold was maintained, and it was inhibited by blocking L-type voltage-gated calcium channels. Despite its calcium dependence, barrage firing was not prevented by inhibiting chemical synaptic transmission. Furthermore, loading the stimulated/recorded interneuron with BAPTA did not block barrage firing, suggesting that the required calcium entry occurs in other cells. Finally, barrage firing was normal in mice with deletion of the primary gene for neuronal gap junctions (connexin36), suggesting that non-neuronal gap junctions may be involved. Together, these findings suggest that barrage firing is probably triggered by a multicellular mechanism involving calcium signalling and gap junctions, but operating independently of chemical synaptic transmission.

}, issn = {1469-7793}, doi = {10.1113/jphysiol.2013.258418}, author = {Sheffield, Mark E J and Edgerton, Gabrielle B and Heuermann, Robert J and Deemyad, Tara and Mensh, Brett D and Spruston, Nelson} } @article {6720, title = {Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors.}, journal = {Neuron}, volume = {76}, year = {2012}, month = {2012 Nov 21}, pages = {776-89}, abstract = {

Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information.

}, keywords = {3-dione, 6-Cyano-7-nitroquinoxaline-2, Analysis of Variance, Animals, Benzylamines, Biophysics, CA1 Region, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Amino Acid Transporter 3, GABA Antagonists, Glutamate Decarboxylase, Hippocampal, Lysine, Male, Membrane Potentials, Metabotropic Glutamate, Neurons, Newborn, Patch-Clamp Techniques, Phosphinic Acids, Pyridazines, Rats, Receptors, Time Factors}, issn = {1097-4199}, doi = {10.1016/j.neuron.2012.09.036}, author = {Graves, Austin R and Moore, Shannon J and Bloss, Erik B and Mensh, Brett D and Kath, William L and Spruston, Nelson} } @article {5922, title = {Synaptic amplification by dendritic spines enhances input cooperativity.}, journal = {Nature}, volume = {491}, year = {2012}, month = {2012 Nov 22}, pages = {599-602}, abstract = {

Dendritic spines are the nearly ubiquitous site of excitatory synaptic input onto neurons and as such are critically positioned to influence diverse aspects of neuronal signalling. Decades of theoretical studies have proposed that spines may function as highly effective and modifiable chemical and electrical compartments that regulate synaptic efficacy, integration and plasticity. Experimental studies have confirmed activity-dependent structural dynamics and biochemical compartmentalization by spines. However, there is a longstanding debate over the influence of spines on the electrical aspects of synaptic transmission and dendritic operation. Here we measure the amplitude ratio of spine head to parent dendrite voltage across a range of dendritic compartments and calculate the associated spine neck resistance (R(neck)) for spines at apical trunk dendrites in rat hippocampal CA1 pyramidal neurons. We find that R(neck) is large enough (\ 500 MΩ) to amplify substantially the spine head depolarization associated with a unitary synaptic input by \ 1.5- to \ 45-fold, depending on parent dendritic impedance. A morphologically realistic compartmental model capable of reproducing the observed spatial profile of the amplitude ratio indicates that spines provide a consistently high-impedance input structure throughout the dendritic arborization. Finally, we demonstrate that the amplification produced by spines encourages electrical interaction among coactive inputs through an R(neck)-dependent increase in spine head voltage-gated conductance activation. We conclude that the electrical properties of spines promote nonlinear dendritic processing and associated forms of plasticity and storage, thus fundamentally enhancing the computational capabilities of neurons.

}, keywords = {Animals, Dendritic Spines, Electric Impedance, Excitatory Postsynaptic Potentials, Male, Models, Neurological, Pyramidal Cells, Rats, Sprague-Dawley, Synapses, Wistar}, issn = {1476-4687}, doi = {10.1038/nature11554}, author = {Harnett, Mark T and Makara, Judit K and Spruston, Nelson and Kath, William L and Magee, Jeffrey C} } @article {5335, title = {Synergistic actions of metabotropic acetylcholine and glutamate receptors on the excitability of hippocampal CA1 pyramidal neurons.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {32}, year = {2012}, month = {2012 May 2}, pages = {6081-91}, abstract = {

A variety of neurotransmitters are responsible for regulating neural activity during different behavioral states. Unique responses to combinations of neurotransmitters provide a powerful mechanism by which neural networks could be differentially activated during a broad range of behaviors. Here, we show, using whole-cell recordings in rat hippocampal slices, that group I metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChRs) synergistically increase the excitability of hippocampal CA1 pyramidal neurons by converting the post-burst afterhyperpolarization to an afterdepolarization via a rapidly reversible upregulation of Ca(v)2.3 R-type calcium channels. Coactivation of mAChRs and mGluRs also induced a long-lasting enhancement of the responses mediated by each receptor type. These results suggest that cooperative signaling via mAChRs and group I mGluRs could provide a mechanism by which cognitive processes may be modulated by conjoint activation of two separate neurotransmitter systems.

}, keywords = {Action Potentials, Animals, Calcium Channels, Cation Transport Proteins, Inbred C57BL, Knockout, Male, Metabotropic Glutamate, Mice, Muscarinic, Pyramidal Cells, R-Type, Rats, Receptors, Wistar}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.6519-11.2012}, author = {Park, Jin-Yong and Spruston, Nelson} } @article {6778, title = {Target-specific output patterns are predicted by the distribution of regular-spiking and bursting pyramidal neurons in the subiculum.}, journal = {Hippocampus}, volume = {22}, year = {2012}, month = {2012 Apr}, pages = {693-706}, abstract = {

Pyramidal neurons in the subiculum project to a variety of cortical and subcortical areas in the brain to convey information processed in the hippocampus. Previous studies have shown that two groups of subicular pyramidal neurons{\textendash}regular-spiking and bursting neurons{\textendash}are distributed in an organized fashion along the proximal-distal axis, with more regular-spiking neurons close to CA1 (proximal) and more bursting neurons close to presubiculum (distal). Anatomically, neurons projecting to some targets are located more proximally along this axis, while others are located more distally. However, the relationship between the firing properties and the targets of subicular pyramidal neurons is not known. To study this relationship, we used in vivo injections of retrogradely transported fluorescent beads into each of nine different regions and conducted whole-cell current-clamp recordings from the bead-containing subicular neurons in acute brain slices. We found that subicular projections to each area were composed of a mixture of regular-spiking and bursting neurons. Neurons projecting to amygdala, lateral entorhinal cortex, nucleus accumbens, and medial/ventral orbitofrontal cortex were located primarily in the proximal subiculum and consisted mostly of regular-spiking neurons (\~{}80\%). By contrast, neurons projecting to medial EC, presubiculum, retrosplenial cortex, and ventromedial hypothalamus were located primarily in the distal subiculum and consisted mostly of bursting neurons (\~{}80\%). Neurons projecting to a thalamic nucleus were located in the middle portion of subiculum, and their probability of bursting was close to 50\%. Thus, the fraction of bursting neurons projecting to each target region was consistent with the known distribution of regular-spiking and bursting neurons along the proximal-distal axis of the subiculum. Variation in the distribution of regular-spiking and bursting neurons suggests that different types of information are conveyed from the subiculum to its various targets.

}, keywords = {Action Potentials, Animals, Biophysical Phenomena, CA1 Region, CA3 Region, Efferent Pathways, Electrophysiological Phenomena, Hippocampal, Hippocampus, Male, Patch-Clamp Techniques, Pyramidal Cells, Rats, Wistar}, issn = {1098-1063}, doi = {10.1002/hipo.20931}, author = {Kim, Yujin and Spruston, Nelson} } @article {6779, title = {Slow integration leads to persistent action potential firing in distal axons of coupled interneurons.}, journal = {Nature Neuroscience}, volume = {14}, year = {2011}, month = {2011 Feb}, pages = {200-7}, abstract = {

The conventional view of neurons is that synaptic inputs are integrated on a timescale of milliseconds to seconds in the dendrites, with action potential initiation occurring in the axon initial segment. We found a much slower form of integration that leads to action potential initiation in the distal axon, well beyond the initial segment. In a subset of rodent hippocampal and neocortical interneurons, hundreds of spikes, evoked over minutes, resulted in persistent firing that lasted for a similar duration. Although axonal action potential firing was required to trigger persistent firing, somatic depolarization was not. In paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell. Thus, these interneurons can slowly integrate spiking, share the output across a coupled network of axons and respond with persistent firing even in the absence of input to the soma or dendrites.

}, keywords = {Action Potentials, Animals, Axons, Cerebral Cortex, Dendrites, Hippocampus, Interneurons, Mice, Nerve Net, Patch-Clamp Techniques, Synapses, Transgenic}, issn = {1546-1726}, doi = {10.1038/nn.2728}, author = {Sheffield, Mark E J and Best, Tyler K and Mensh, Brett D and Kath, William L and Spruston, Nelson} } @article {6780, title = {A post-burst after depolarization is mediated by group i metabotropic glutamate receptor-dependent upregulation of Ca(v)2.3 R-type calcium channels in CA1 pyramidal neurons.}, journal = {PLoS Biology}, volume = {8}, year = {2010}, month = {2010}, pages = {e1000534}, abstract = {

Activation of group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) regulates neural activity in a variety of ways. In CA1 pyramidal neurons, activation of group I mGluRs eliminates the post-burst afterhyperpolarization (AHP) and produces an afterdepolarization (ADP) in its place. Here we show that upregulation of Ca(v)2.3 R-type calcium channels is responsible for a component of the ADP lasting several hundred milliseconds. This medium-duration ADP is rapidly and reversibly induced by activation of mGluR5 and requires activation of phospholipase C (PLC) and release of calcium from internal stores. Effects of mGluR activation on subthreshold membrane potential changes are negligible but are large following action potential firing. Furthermore, the medium ADP exhibits a biphasic activity dependence consisting of short-term facilitation and longer-term inhibition. These findings suggest that mGluRs may dramatically alter the firing of CA1 pyramidal neurons via a complex, activity-dependent modulation of Ca(v)2.3 R-type channels that are activated during spiking at physiologically relevant rates and patterns.

}, keywords = {Action Potentials, Animals, Calcium Channels, Cation Transport Proteins, Female, Inbred C57BL, Ion Channel Gating, Male, Metabotropic Glutamate, Methoxyhydroxyphenylglycol, Mice, Neurons, Patch-Clamp Techniques, Pyramidal Cells, R-Type, Rats, Receptors, Up-Regulation, Wistar, Xenopus}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1000534}, author = {Park, Jin-Yong and Remy, Stefan and Varela, Juan and Cooper, Donald C and Chung, Sungkwon and Kang, Ho-Won and Lee, Jung-Ha and Spruston, Nelson} } @article {6782, title = {Questions about STDP as a general model of synaptic plasticity.}, journal = {Frontiers in Synaptic Neuroscience}, volume = {2}, year = {2010}, month = {2010}, pages = {140}, abstract = {

According to spike-timing-dependent plasticity (STDP), the timing of the Na(+) spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na(+) spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na(+) spikes does not necessarily prevent LTP induction. Thus, Na(+) spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca(2+) spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na(+) spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD.

}, issn = {1663-3563}, doi = {10.3389/fnsyn.2010.00140}, author = {Lisman, John and Spruston, Nelson} } @article {45911, title = {Plasticity of burst firing induced by synergistic activation of metabotropic glutamate and acetylcholine receptors.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {287-300}, abstract = {

Subiculum, the primary efferent pathway of hippocampus, participates in memory for spatial tasks, relapse to drug abuse, and temporal lobe seizures. Subicular pyramidal neurons exhibit low-threshold burst firing driven by a spike afterdepolarization. Here we report that burst firing can be regulated by stimulation of afferent projections to subiculum. Unlike synaptic plasticity, burst plasticity did not require synaptic depolarization, activation of AMPA or NMDA receptors, or action potential firing. Rather, enhancement of burst firing required synergistic activation of group I, subtype 1 metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChR). When either of these receptors was blocked, a suppression of bursting was revealed, which in turn was blocked by antagonists of group I, subtype 5 mGluRs. These results indicate that the output of subiculum can be strongly and bidirectionally regulated by activation of glutamatergic inputs within the hippocampus and cholinergic afferents from the medial septum.

}, keywords = {Acetylcholine, Action Potentials, Afferent Pathways, Animals, Cholinergic Fibers, Electric Stimulation, Excitatory Amino Acid Antagonists, Glutamic Acid, Hippocampus, Male, Neuronal Plasticity, Pyramidal Cells, Rats, Rats, Wistar, Receptors, Cholinergic, Receptors, Metabotropic Glutamate, Receptors, Muscarinic, Septal Nuclei, Synaptic Transmission, Theta Rhythm}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.12.013}, author = {Moore, Shannon J and Cooper, Donald C and Spruston, Nelson} } @article {6783, title = {A state-mutating genetic algorithm to design ion-channel models.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, year = {2009}, month = {2009 Sep 29}, pages = {16829-34}, abstract = {

Realistic computational models of single neurons require component ion channels that reproduce experimental findings. Here, a topology-mutating genetic algorithm that searches for the best state diagram and transition-rate parameters to model macroscopic ion-channel behavior is described. Important features of the algorithm include a topology-altering strategy, automatic satisfaction of equilibrium constraints (microscopic reversibility), and multiple-protocol fitting using sequential goal programming rather than explicit weighting. Application of this genetic algorithm to design a sodium-channel model exhibiting both fast and prolonged inactivation yields a six-state model that produces realistic activity-dependent attenuation of action-potential backpropagation in current-clamp simulations of a CA1 pyramidal neuron.

}, keywords = {Algorithms, Cell Membrane, Ion Channels, Models, Mutation, Neurons, Sodium Channels, Theoretical}, issn = {1091-6490}, doi = {10.1073/pnas.0903766106}, author = {Menon, Vilas and Spruston, Nelson and Kath, William L} } @article {6784, title = {Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons.}, journal = {Neuron}, volume = {63}, year = {2009}, month = {2009 Jul 30}, pages = {171-7}, abstract = {

Competing models have been proposed to explain how neurons integrate the thousands of inputs distributed throughout their dendritic trees. In a simple global integration model, inputs from all locations sum in the axon. In a two-stage integration model, inputs contribute directly to dendritic spikes, and outputs from multiple branches sum in the axon. These two models yield opposite predictions of how synapses at different dendritic locations should be scaled if they are to contribute equally to neuronal output. We used serial-section electron microscopy to reconstruct individual apical oblique dendritic branches of CA1 pyramidal neurons and observe a synapse distribution consistent with the two-stage integration model. Computational modeling suggests that the observed synapse distribution enhances the contribution of each dendritic branch to neuronal output.

}, keywords = {Animals, Dendrites, Electron, Hippocampus, Humans, Microscopy, Models, Neural Networks (Computer), Neural Pathways, Neurological, Neurons, Synapses}, issn = {1097-4199}, doi = {10.1016/j.neuron.2009.06.023}, author = {Katz, Yael and Menon, Vilas and Nicholson, Daniel A and Geinisman, Yuri and Kath, William L and Spruston, Nelson} } @article {6785, title = {Synaptic depolarization is more effective than back-propagating action potentials during induction of associative long-term potentiation in hippocampal pyramidal neurons.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {29}, year = {2009}, month = {2009 Mar 11}, pages = {3233-41}, abstract = {

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75\% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (\< or =25\% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

}, keywords = {Action Potentials, Animals, Ganglia, Hippocampus, Long-Term Potentiation, Neuronal Plasticity, Neurons, Pyramidal Cells, Rats, Spinal, Synapses, Synaptic Transmission, Wistar}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.6000-08.2009}, author = {Hardie, Jason and Spruston, Nelson} } @article {45930, title = {Compartmental neural simulations with spatial adaptivity.}, journal = {Journal of Computational Neuroscience}, volume = {25}, year = {2008}, month = {2008 Dec}, pages = {465-80}, abstract = {

Since their inception, computational models have become increasingly complex and useful counterparts to laboratory experiments within the field of neuroscience. Today several software programs exist to solve the underlying mathematical system of equations, but such programs typically solve these equations in all parts of a cell (or network of cells) simultaneously, regardless of whether or not all of the cell is active. This approach can be inefficient if only part of the cell is active and many simulations must be performed. We have previously developed a numerical method that provides a framework for spatial adaptivity by making the computations local to individual branches rather than entire cells (Rempe and Chopp, SIAM Journal on Scientific Computing, 28: 2139-2161, 2006). Once the computation is reduced to the level of branches instead of cells, spatial adaptivity is straightforward: the active regions of the cell are detected and computational effort is focused there, while saving computations in other regions of the cell that are at or near rest. Here we apply the adaptive method to four realistic neuronal simulation scenarios and demonstrate its improved efficiency over non-adaptive methods. We find that the computational cost of the method scales with the amount of activity present in the simulation, rather than the physical size of the system being simulated. For certain problems spatial adaptivity reduces the computation time by up to 80\%.

}, keywords = {Action Potentials, Adaptation, Biological, Algorithms, Animals, Computer Simulation, Dendrites, Gap Junctions, Hippocampus, Ion Channel Gating, Ion Channels, Models, Neurological, Nerve Net, Neural Networks (Computer), Pyramidal Cells, Signal Processing, Computer-Assisted}, issn = {1573-6873}, doi = {10.1007/s10827-008-0089-3}, author = {Rempe, Michael J and Spruston, Nelson and Kath, William L and Chopp, David L} } @article {45932, title = {Distribution of bursting neurons in the CA1 region and the subiculum of the rat hippocampus.}, journal = {Journal of Comparative Neurology}, volume = {506}, year = {2008}, month = {2008 Feb 1}, pages = {535-47}, abstract = {

We performed patch-clamp recordings from morphologically identified and anatomically mapped pyramidal neurons of the ventral hippocampus to test the hypothesis that bursting neurons are distributed on a gradient from the CA2/CA1 border (proximal) through the subiculum (distal), with more bursting observed at distal locations. We find that the well-defined morphological boundaries between the hippocampal subregions CA1 and subiculum do not correspond to abrupt changes in electrophysiological properties. Rather, we observed that the percentage of bursting neurons is linearly correlated with position in the proximal-distal axis across the CA1 and the subiculum, the percentages of bursting neurons being 10\% near the CA1-CA2 border, 24\% at the CA1-subiculum border, and higher than 50\% in the distal subiculum. The distribution of bursting neurons was paralleled by a gradient in afterdepolarization (ADP) amplitude. We also tested the hypothesis that there was an association between bursting and two previously described morphologically distinct groups of pyramidal neurons (twin and single apical dendrites) in the CA1 region. We found no difference in output mode between single and twin apical dendrite morphologies, which was consistent with the observation that the two morphologies were equally distributed across the transverse axis of the CA1 region. Taken together with the known organization of connections from CA3 to CA1 and CA1 to subiculum, our results indicate that bursting neurons are most likely to be connected to regular spiking neurons and vice versa.

}, keywords = {Action Potentials, Animals, Axons, Cell Shape, Dendrites, Hippocampus, Lysine, Neural Pathways, Organ Culture Techniques, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Staining and Labeling}, issn = {0021-9967}, doi = {10.1002/cne.21564}, author = {Jarsky, Tim and Mady, Rina and Kennedy, Benjamin and Spruston, Nelson} } @article {45920, title = {Pyramidal neurons: dendritic structure and synaptic integration.}, journal = {Nature Reviews Neuroscience}, volume = {9}, year = {2008}, month = {2008 Mar}, pages = {206-21}, abstract = {

Pyramidal neurons are characterized by their distinct apical and basal dendritic trees and the pyramidal shape of their soma. They are found in several regions of the CNS and, although the reasons for their abundance remain unclear, functional studies--especially of CA1 hippocampal and layer V neocortical pyramidal neurons--have offered insights into the functions of their unique cellular architecture. Pyramidal neurons are not all identical, but some shared functional principles can be identified. In particular, the existence of dendritic domains with distinct synaptic inputs, excitability, modulation and plasticity appears to be a common feature that allows synapses throughout the dendritic tree to contribute to action-potential generation. These properties support a variety of coincidence-detection mechanisms, which are likely to be crucial for synaptic integration and plasticity.

}, keywords = {Animals, Dendrites, Hippocampus, Models, Neurological, Neocortex, Pyramidal Cells, Synapses}, issn = {1471-0048}, doi = {10.1038/nrn2286}, author = {Spruston, Nelson} } @article {45889, title = {Coincidence detection of place and temporal context in a network model of spiking hippocampal neurons.}, journal = {PLoS Computational Biology}, volume = {3}, year = {2007}, month = {2007 Dec}, pages = {e234}, abstract = {

Recent advances in single-neuron biophysics have enhanced our understanding of information processing on the cellular level, but how the detailed properties of individual neurons give rise to large-scale behavior remains unclear. Here, we present a model of the hippocampal network based on observed biophysical properties of hippocampal and entorhinal cortical neurons. We assembled our model to simulate spatial alternation, a task that requires memory of the previous path through the environment for correct selection of the current path to a reward site. The convergence of inputs from entorhinal cortex and hippocampal region CA3 onto CA1 pyramidal cells make them potentially important for integrating information about place and temporal context on the network level. Our model shows how place and temporal context information might be combined in CA1 pyramidal neurons to give rise to splitter cells, which fire selectively based on a combination of place and temporal context. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical basis of information processing in the hippocampus.

}, keywords = {Action Potentials, Algorithms, Animals, Computer Simulation, Hippocampus, Models, Neurological, Nerve Net, Neurons, Rats, Synaptic Transmission}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.0030234}, author = {Katz, Yael and Kath, William L and Spruston, Nelson and Hasselmo, Michael E} } @article {45900, title = {Dendritic D-type potassium currents inhibit the spike afterdepolarization in rat hippocampal CA1 pyramidal neurons.}, journal = {The Journal of Physiology}, volume = {581}, year = {2007}, month = {2007 May 15}, pages = {175-87}, abstract = {

In CA1 pyramidal neurons, burst firing is correlated with hippocampally dependent behaviours and modulation of synaptic strength. One of the mechanisms underlying burst firing in these cells is the afterdepolarization (ADP) that follows each action potential. Previous work has shown that the ADP results from the interaction of several depolarizing and hyperpolarizing conductances located in the soma and the dendrites. By using patch-clamp recordings from acute rat hippocampal slices we show that D-type potassium current modulates the size of the ADP and the bursting of CA1 pyramidal neurons. Sensitivity to alpha-dendrotoxin suggests that Kv1-containing potassium channels mediate this current. Dual somato-dendritic recording, outside-out dendritic recordings, and focal application of dendrotoxin together indicate that the channels mediating this current are located in the apical dendrites. Thus, our data present evidence for a dendritic segregation of Kv1-like channels in CA1 pyramidal neurons and identify a novel action for these channels, showing that they inhibit action potential bursting by restricting the size of the ADP.

}, keywords = {Action Potentials, Animals, Dendritic Cells, Elapid Venoms, Evoked Potentials, Hippocampus, Male, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Shaker Superfamily of Potassium Channels}, issn = {0022-3751}, doi = {10.1113/jphysiol.2006.127068}, author = {Metz, Alexia E and Spruston, Nelson and Martina, Marco} } @article {45917, title = {Dendritic spikes induce single-burst long-term potentiation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {104}, year = {2007}, month = {2007 Oct 23}, pages = {17192-7}, abstract = {

The hippocampus is essential for episodic memory, which requires single-trial learning. Although long-term potentiation (LTP) of synaptic strength is a candidate mechanism for learning, it is typically induced by using repeated synaptic activation to produce precisely timed, high-frequency, or rhythmic firing. Here we show that hippocampal synapses potentiate robustly in response to strong activation by a single burst. The induction mechanism of this single-burst LTP requires activation of NMDA receptors, L-type voltage-gated calcium channels, and dendritic spikes. Thus, dendritic spikes are a critical trigger for a form of LTP that is consistent with the function of the hippocampus in episodic memory.

}, keywords = {Action Potentials, Animals, Dendrites, Excitatory Postsynaptic Potentials, Inhibitory Postsynaptic Potentials, Long-Term Potentiation, Pyramidal Cells, Rats, Rats, Wistar, Synapses}, issn = {0027-8424}, doi = {10.1073/pnas.0707919104}, author = {Remy, Stefan and Spruston, Nelson} } @article {45895, title = {Stability and plasticity of intrinsic membrane properties in hippocampal CA1 pyramidal neurons: effects of internal anions.}, journal = {The Journal of Physiology}, volume = {578}, year = {2007}, month = {2007 Feb 1}, pages = {799-818}, abstract = {

CA1 pyramidal neurons from animals that have acquired hippocampal tasks show increased neuronal excitability, as evidenced by a reduction in the postburst afterhyperpolarization (AHP). Studies of AHP plasticity require stable long-term recordings, which are affected by the intracellular solutions potassium methylsulphate (KMeth) or potassium gluconate (KGluc). Here we show immediate and gradual effects of these intracellular solutions on measurement of the AHP and basic membrane properties, and on the induction of AHP plasticity in CA1 pyramidal neurons from rat hippocampal slices. The AHP measured immediately after establishing whole-cell recordings was larger with KMeth than with KGluc. In general, the AHP in KMeth was comparable to the AHP measured in the perforated-patch configuration. However, KMeth induced time-dependent changes in the intrinsic membrane properties of CA1 pyramidal neurons. Specifically, input resistance progressively increased by 70\% after 50 min; correspondingly, the current required to trigger an action potential and the fast afterdepolarization following action potentials gradually decreased by about 50\%. Conversely, these measures were stable in KGluc. We also demonstrate that activity-dependent plasticity of the AHP occurs with physiologically relevant stimuli in KGluc. AHPs triggered with theta-burst firing every 30 s were progressively reduced, whereas AHPs elicited every 150 s were stable. Blockade of the apamin-sensitive AHP current (I(AHP)) was insufficient to block AHP plasticity, suggesting that plasticity is manifested through changes in the apamin-insensitive slow AHP current (sI(AHP)). These changes were observed in the presence of synaptic blockers, and therefore reflect changes in the intrinsic properties of the neurons. However, no AHP plasticity was observed using KMeth. In summary, these data show that KMeth produces time-dependent changes in basic membrane properties and prevents or obscures activity-dependent reduction of the AHP. In whole-cell recordings using KGluc, repetitive theta-burst firing induced AHP plasticity that mimics learning-related reduction in the AHP.

}, keywords = {Animals, Anions, Apamin, Gluconates, Male, Membrane Potentials, Neuronal Plasticity, Norepinephrine, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Sulfuric Acid Esters, Time Factors}, issn = {0022-3751}, doi = {10.1113/jphysiol.2006.124586}, author = {Kaczorowski, Catherine Cook and Disterhoft, John and Spruston, Nelson} } @article {45891, title = {Dendritic patch-clamp recording.}, journal = {Nature Protocols}, volume = {1}, year = {2006}, month = {2006}, pages = {1235-47}, abstract = {

The patch-clamp technique allows investigation of the electrical excitability of neurons and the functional properties and densities of ion channels. Most patch-clamp recordings from neurons have been made from the soma, the largest structure of individual neurons, while their dendrites, which form the majority of the surface area and receive most of the synaptic input, have been relatively neglected. This protocol describes techniques for recording from the dendrites of neurons in brain slices under direct visual control. Although the basic technique is similar to that used for somatic patching, we describe refinements and optimizations of slice quality, microscope optics, setup stability and electrode approach that are required for maximizing the success rate for dendritic recordings. Using this approach, all configurations of the patch-clamp technique (cell-attached, inside-out, whole-cell, outside-out and perforated patch) can be achieved, even for relatively distal dendrites, and simultaneous multiple-electrode dendritic recordings are also possible. The protocol--from the beginning of slice preparation to the end of the first successful recording--can be completed in 3 h.

}, keywords = {Dendrites, Patch-Clamp Techniques}, issn = {1750-2799}, doi = {10.1038/nprot.2006.164}, author = {Davie, Jenny T and Kole, Maarten H P and Letzkus, Johannes J and Rancz, Ede A and Spruston, Nelson and Stuart, Greg J and H{\"a}usser, Michael} } @article {45909, title = {Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons.}, journal = {Neuron}, volume = {50}, year = {2006}, month = {2006 May 4}, pages = {431-42}, abstract = {

The ability of synapses throughout the dendritic tree to influence neuronal output is crucial for information processing in the brain. Synaptic potentials attenuate dramatically, however, as they propagate along dendrites toward the soma. To examine whether excitatory axospinous synapses on CA1 pyramidal neurons compensate for their distance from the soma to counteract such dendritic filtering, we evaluated axospinous synapse number and receptor expression in three progressively distal regions: proximal and distal stratum radiatum (SR), and stratum lacunosum-moleculare (SLM). We found that the proportion of perforated synapses increases as a function of distance from the soma and that their AMPAR, but not NMDAR, expression is highest in distal SR and lowest in SLM. Computational models of pyramidal neurons derived from these results suggest that they arise from the compartment-specific use of conductance scaling in SR and dendritic spikes in SLM to minimize the influence of distance on synaptic efficacy.

}, keywords = {Animals, Cell Polarity, Cell Shape, Crosses, Genetic, Dendritic Spines, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Image Cytometry, Immunohistochemistry, Male, Microscopy, Electron, Transmission, Perforant Pathway, Presynaptic Terminals, Pyramidal Cells, Rats, Rats, Inbred BN, Rats, Inbred F344, Receptors, AMPA, Synapses, Synaptic Transmission}, issn = {0896-6273}, doi = {10.1016/j.neuron.2006.03.022}, author = {Nicholson, Daniel A and Trana, Rachel and Katz, Yael and Kath, William L and Spruston, Nelson and Geinisman, Yuri} } @article {45918, title = {Conditional dendritic spike propagation following distal synaptic activation of hippocampal CA1 pyramidal neurons.}, journal = {Nat Neurosci}, volume = {8}, year = {2005}, month = {2005 Dec}, pages = {1667-76}, abstract = {

The perforant-path projection to the hippocampus forms synapses in the apical tuft of CA1 pyramidal neurons. We used computer modeling to examine the function of these distal synaptic inputs, which led to three predictions that we confirmed in experiments using rat hippocampal slices. First, activation of CA1 neurons by the perforant path is limited, a result of the long distance between these inputs and the soma. Second, activation of CA1 neurons by the perforant path depends on the generation of dendritic spikes. Third, the forward propagation of these spikes is unreliable, but can be facilitated by modest activation of Schaffer-collateral synapses in the upper apical dendrites. This {\textquoteright}gating{\textquoteright} of dendritic spike propagation may be an important activation mode of CA1 pyramidal neurons, and its modulation by neurotransmitters or long-term, activity-dependent plasticity may be an important feature of dendritic integration during mnemonic processing in the hippocampus.

}, keywords = {Action Potentials, Animals, Dendrites, Hippocampus, Long-Term Potentiation, Long-Term Synaptic Depression, Male, Memory, Neural Inhibition, Neural Networks (Computer), Neural Pathways, Neurotransmitter Agents, Organ Culture Techniques, Patch-Clamp Techniques, Perforant Pathway, Pyramidal Cells, Rats, Rats, Wistar, Synaptic Transmission}, issn = {1097-6256}, doi = {10.1038/nn1599}, author = {Jarsky, Tim and Roxin, Alex and Kath, William L and Spruston, Nelson} } @article {45924, title = {Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites.}, journal = {J Physiol}, volume = {568}, year = {2005}, month = {2005 Oct 1}, pages = {69-82}, abstract = {

We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 microm from the soma in control and 409 microm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both.

}, keywords = {Animals, Dendrites, Excitatory Postsynaptic Potentials, Hippocampus, In Vitro Techniques, Male, Models, Neurological, Neural Conduction, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Synaptic Transmission}, issn = {0022-3751}, doi = {10.1113/jphysiol.2005.086793}, author = {Golding, Nace L and Mickus, Timothy J and Katz, Yael and Kath, William L and Spruston, Nelson} } @article {45901, title = {Output-mode transitions are controlled by prolonged inactivation of sodium channels in pyramidal neurons of subiculum.}, journal = {PLoS Biol}, volume = {3}, year = {2005}, month = {2005 Jun}, pages = {e175}, abstract = {

Transitions between different behavioral states, such as sleep or wakefulness, quiescence or attentiveness, occur in part through transitions from action potential bursting to single spiking. Cortical activity, for example, is determined in large part by the spike output mode from the thalamus, which is controlled by the gating of low-voltage-activated calcium channels. In the subiculum--the major output of the hippocampus--transitions occur from bursting in the delta-frequency band to single spiking in the theta-frequency band. We show here that these transitions are influenced strongly by the inactivation kinetics of voltage-gated sodium channels. Prolonged inactivation of sodium channels is responsible for an activity-dependent switch from bursting to single spiking, constituting a novel mechanism through which network dynamics are controlled by ion channel gating.

}, keywords = {Adenosine Diphosphate, Animals, Cognition, Evoked Potentials, Hippocampus, In Vitro Techniques, Membrane Potentials, Pyramidal Cells, Rats, Sodium Channels}, issn = {1545-7885}, doi = {10.1371/journal.pbio.0030175}, author = {Cooper, Donald C and Chung, Sungkwon and Spruston, Nelson} } @article {45921, title = {Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity.}, journal = {Nat Neurosci}, volume = {8}, year = {2005}, month = {2005 Jul}, pages = {839-41}, abstract = {

Long-term potentiation and long-term depression require postsynaptic depolarization, which many current models attribute to backpropagating action potentials. New experimental work suggests, however, that other mechanisms can lead to dendritic depolarization, and that backpropagating action potentials may be neither necessary nor sufficient for synaptic plasticity in vivo.

}, keywords = {Action Potentials, Animals, Dendrites, Electrophysiology, Excitatory Postsynaptic Potentials, Humans, Long-Term Potentiation, Long-Term Synaptic Depression, Neuronal Plasticity, Reaction Time, Synapses}, issn = {1097-6256}, author = {Lisman, John and Spruston, Nelson} } @article {45926, title = {R-type calcium channels contribute to afterdepolarization and bursting in hippocampal CA1 pyramidal neurons.}, journal = {J Neurosci}, volume = {25}, year = {2005}, month = {2005 Jun 15}, pages = {5763-73}, abstract = {

Action potentials in pyramidal neurons are typically followed by an afterdepolarization (ADP), which in many cells contributes to intrinsic burst firing. Despite the ubiquity of this common excitable property, the responsible ion channels have not been identified. Using current-clamp recordings in hippocampal slices, we find that the ADP in CA1 pyramidal neurons is mediated by an Ni2+-sensitive calcium tail current. Voltage-clamp experiments indicate that the Ni2+-sensitive current has a pharmacological and biophysical profile consistent with R-type calcium channels. These channels are available at the resting potential, are activated by the action potential, and remain open long enough to drive the ADP. Because the ADP correlates directly with burst firing in CA1 neurons, R-type calcium channels are crucial to this important cellular behavior, which is known to encode hippocampal place fields and enhance synaptic plasticity.

}, keywords = {Action Potentials, Adenosine Diphosphate, Animals, Calcium Channels, R-Type, Hippocampus, In Vitro Techniques, Male, Membrane Potentials, Neuronal Plasticity, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Synapses}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0624-05.2005}, author = {Metz, Alexia E and Jarsky, Tim and Martina, Marco and Spruston, Nelson} } @article {45894, title = {Intracellular correlate of EPSP-spike potentiation in CA1 pyramidal neurons is controlled by GABAergic modulation.}, journal = {Hippocampus}, volume = {13}, year = {2003}, month = {2003}, pages = {801-5}, abstract = {

The hippocampus has been used extensively as a model to study plastic changes in the brain{\textquoteright}s neural circuitry. Immediately after high-frequency stimulation to hippocampal Schaffer collateral axons, a dramatic change occurs in the relationship between the presynaptic CA3 and the postsynaptic CA1 pyramidal neurons. For a fixed excitatory postsynaptic potential (EPSP), there arises an increased likelihood of action potential generation in the CA1 pyramidal neuron. This phenomenon is called EPSP-spike (E-S) potentiation. We explored E-S potentiation, using patch-clamp techniques in the hippocampal slice preparation. A specific protocol was developed to measure the action potential probability for a given synaptic strength, which allowed us to quantify the amount of E-S potentiation for a single neuron. E-S potentiation was greatest when gamma-aminobutyric acid (GABA)ergic inhibition was intact, suggesting that modulation of inhibition is a major aspect of E-S potentiation. Expression of E-S potentiation also correlated with a reduced action-potential threshold, which was greatest when GABAergic inhibition was intact. Conditioning stimuli produced a smaller threshold reduction when inhibition was blocked, but some reduction also occurred in the absence of a conditioning stimulus. Together, these results suggest that E-S potentiation is caused primarily through a reduction of GABAergic inhibition, leading to larger EPSPs and reduced action potential threshold. Our findings do not rule out, however, the possibility that modulation of voltage-gated conductances also contributes to E-S potentiation.

}, keywords = {Action Potentials, Animals, Dendrites, Excitatory Postsynaptic Potentials, GABA Antagonists, GABA-A Receptor Antagonists, GABA-B Receptor Antagonists, gamma-Aminobutyric Acid, Hippocampus, In Vitro Techniques, Intracellular Fluid, Neural Inhibition, Neuronal Plasticity, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Wistar, Receptors, GABA-A, Receptors, GABA-B, Synaptic Transmission}, issn = {1050-9631}, doi = {10.1002/hipo.10129}, author = {Staff, Nathan P and Spruston, Nelson} } @article {45915, title = {Dendritic spikes as a mechanism for cooperative long-term potentiation.}, journal = {Nature}, volume = {418}, year = {2002}, month = {2002 Jul 18}, pages = {326-31}, abstract = {

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.

}, keywords = {Action Potentials, Animals, Axons, Calcium, Calcium Signaling, Dendrites, Excitatory Postsynaptic Potentials, Long-Term Potentiation, Pyramidal Cells, Rats, Rats, Wistar, Synapses, Theta Rhythm}, issn = {0028-0836}, doi = {10.1038/nature00854}, author = {Golding, Nace L and Staff, Nathan P and Spruston, Nelson} }