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52 Janelia Publications

Showing 1-10 of 52 results
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    01/05/22 | Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus.
    Zhao X, Hsu C, Spruston N
    Neuron. 2022 Jan 05;110(1):96-108.e4. doi: 10.1016/j.neuron.2021.10.003

    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.

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    10/19/21 | Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse frontal cortex.
    Kourtney Graham , Nelson Spruston , Erik Bloss
    Cell Reports. 2021 October 19;37(3):109837

    Neural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.

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    10/15/21 | Organizing memories for generalization in complementary learning systems.
    Weinan Sun , Madhu Advani , Nelson Spruston , Andrew Saxe , James E. Fitzgerald
    bioRxiv. 2021 Oct 15:. doi: https://doi.org/10.1101/2021.10.13.463791

    Our ability to remember the past is essential for guiding our future behavior. Psychological and neurobiological features of declarative memories are known to transform over time in a process known as systems consolidation. While many theories have sought to explain the time-varying role of hippocampal and neocortical brain areas, the computational principles that govern these transformations remain unclear. Here we propose a theory of systems consolidation in which hippocampal-cortical interactions serve to optimize generalizations that guide future adaptive behavior. We use mathematical analysis of neural network models to characterize fundamental performance tradeoffs in systems consolidation, revealing that memory components should be organized according to their predictability. The theory shows that multiple interacting memory systems can outperform just one, normatively unifying diverse experimental observations and making novel experimental predictions. Our results suggest that the psychological taxonomy and neurobiological organization of declarative memories reflect a system optimized for behaving well in an uncertain future.

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    10/14/21 | Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus
    Xinyu Zhao , Ching-Lung Hsu , Nelson Spruston
    Neuron. 2021 Oct 14:. doi: https://doi.org/10.1101/2021.06.30.450574

    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 these 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.

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    07/01/21 | Bursting potentiates the neuro-AI connection.
    Sun W, Zhao X, Spruston N
    Nature Neuroscience. 2021 Jul 01;24(7):905-6. doi: 10.1038/s41593-021-00844-2
    12/01/20 | Linking axon morphology to gene expression: a strategy for neuronal cell-type classification.
    Winnubst J, Spruston N, Harris JA
    Current Opinion in Neurobiology. 2020 Dec 01;65:70-76. doi: 10.1016/j.conb.2020.10.006

    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.

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    12/01/20 | Linking axon morphology to gene expression: a strategy for neuronal cell-type classification.
    Winnubst J, Spruston N, Harris JA
    Current Opinion in Neurobiology. 2020 Dec 01;65:70-76. doi: 10.1016/j.conb.2020.10.006

    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.

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    07/01/20 | Membrane potential dynamics underlying context-dependent sensory responses in the hippocampus.
    Zhao X, Wang Y, Spruston N, Magee JC
    Nature Neuroscience. 2020 Jul 1;23(7):881-91. doi: 10.1038/s41593-020-0646-2

    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.

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    04/28/20 | A Sparse, Spatially Biased Subtype of Mature Granule Cell Dominates Recruitment in Hippocampal-Associated Behaviors.
    Erwin SR, Sun W, Copeland M, Lindo S, Spruston N, Cembrowski MS
    Cell Reports. 2020 Apr 28;31(4):107551. doi: 10.1016/j.celrep.2020.107551

    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.

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    02/18/20 | Transcriptional co-repressor Sin3a regulates hippocampal synaptic plasticity via Homer1/mGluR5.
    Bridi MS, Schoch H, Florian C, Poplawski SG, Banerjee A, Hawk JD, Banks GS, Lejards C, Hahn C, Giese KP, Havekes R, Spruston N, Abel T
    JCI Insight. 2020 Feb 18:. doi: 10.1172/jci.insight.92385

    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.

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