Cortical glutamatergic and GABAergic inputs support learning-driven hippocampal stability.
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| Title: | Cortical glutamatergic and GABAergic inputs support learning-driven hippocampal stability. |
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| Authors: | Robert, Vincent (AUTHOR), O'Neil, Keelin (AUTHOR), Moore, Jason J. (AUTHOR), Rashid, Shannon K. (AUTHOR), Johnson, Cara D. (AUTHOR), De La Torre, Rodrigo G. (AUTHOR), Zemelman, Boris V. (AUTHOR), Clopath, Claudia (AUTHOR), Basu, Jayeeta (AUTHOR) |
| Source: | Science. 12/11/2025, Vol. 390 Issue 6778, p1-16. 16p. |
| Subjects: | Hippocampus (Brain), Glutamate receptors, Neural pathways, Brain mapping, GABAergic neurons, Neural circuitry, Spatial memory |
| Abstract: | Flexibility and stability of neuronal ensembles are crucial features of brain function. Little is known about how these properties of local circuits are influenced by long-range inputs. We show, in mice, that lateral entorhinal cortex glutamatergic (LECGLU) and γ-aminobutyric acid (GABA)–ergic (LECGABA) projections to CA3 recruit specific microcircuits that conjunctively provide stability to neuronal ensembles, thereby supporting learning. LECGLU drives excitation in CA3 but also substantial feedforward inhibition that prevents somatic and dendritic spikes. Conversely, LECGABA suppresses this local inhibition to disinhibit CA3 activity with compartment and pathway specificity by selectively boosting somatic output to integrated LECGLU and CA3 recurrent inputs. This synergy allows the stabilization of spatial representations relevant to learning, as both LECGLU and LECGABA control the formation and maintenance of CA3 place cells across contexts and over time. Editor's summary: Discrimination and generalization are critical functions for recognizing and classifying objects and features and memory processing that relies on pattern separation and completion. We still don't fully understand the specific circuit mechanisms that provide neuronal ensembles a dynamic range to perform both pattern separation and completion according to external inputs and contextual demands. Robert et al. examined the specific roles of long-range circuit interactions between the entorhinal cortex and hippocampal area CA3 to find out how a single brain area can dynamically perform these fundamental information-processing operations. Lateral entorhinal cortex glutamatergic and GABAergic inputs independently and conjunctively shaped pattern separation and completion in CA3 by recruiting pathway- and compartment-specific feedforward inhibition and disinhibition, endowing CA3 with both novelty discrimination and context generalization functions. —Peter Stern INTRODUCTION: The brain encodes memories through the activation of specific ensembles of neurons. Memory formation and recall require both flexibility and stability of neuronal ensembles. How do long-range connections interact with local circuits to form flexible yet stable ensembles? Projections across brain regions are chemically diverse, notably comprising both glutamatergic and γ-aminobutyric acid–ergic (GABAergic) neurons in memory circuits, such as those between the entorhinal cortex (EC) and hippocampus. Hippocampal pyramidal neurons (PNs) integrate sensory information from EC to form internal representations of the environment. These place-cell ensembles display both flexibility and stability of their spatial tuning depending on environmental variability, allowing for adaptive learned behaviors and memory recall from partial cues. Recurrent connections within the CA3 hippocampal subregion are well suited to form and reactivate neuronal ensembles during learning and recall. However, the influence of long-range EC inputs on the function of the CA3 local circuit remains underexplored. Therefore, we examined the role of lateral EC (LEC) glutamatergic (LECGLU) and GABAergic (LECGABA) inputs on driving CA3 activity and learning-associated ensemble coding. RATIONALE: CA3 neuronal ensembles display context-dependent place-map dynamics, but their mnemonic contributions and underlying circuit mechanisms are not sufficiently understood. We hypothesized that LEC, which conveys contextual information to the hippocampus, may shape CA3 ensemble activity to support learning. Recent research described the role of LEC inputs to hippocampal area CA1 in modulating dendritic excitability, synaptic plasticity, and contextual memory. However, the conjunctive roles of LECGLU and LECGABA inputs to the hippocampus remain to be explored, and their interactions with CA3 recurrent connections and ensemble dynamics are unknown. Here, we leveraged multiplexed optogenetic and chemogenetic approaches to manipulate LECGLU and LECGABA inputs to CA3 simultaneously and decipher their impact on single-neuron and ensemble activity with compartment-specific ex vivo electrophysiology and in vivo two-photon imaging during a spatial-contextual learning behavior in mice. RESULTS: Using dual-color optogenetics combined with intracellular somatic and dendritic recordings, we mapped the functional connectivity from LECGLU and LECGABA inputs to CA3. LECGLU drove excitation in CA3 PNs but also substantial feedforward inhibition that prevented somatic and dendritic spikes. LECGABA exclusively inhibited a subset of soma-targeting local CA3 inhibitory neurons recruited by LECGLU, thereby reducing feedforward inhibition onto CA3 PNs. This LECGABA-mediated disinhibition selectively increased CA3 PN somatic, but not dendritic, spiking in response to integrated LECGLU and CA3 feedback but not DG feedforward inputs. Using dual-chemogenetic silencing of CA3-projecting LECGLU or LECGABA and two-photon calcium imaging of CA3 PN somas and dendrites, we tested how this circuit supports memory-related ensemble activity and behavior. Head-fixed mice were trained in a goal-oriented learning task that required spatial-contextual associations in different environments with graded degrees of similarity. Behavioral task performance was impaired with either LECGLU or LECGABA silencing during learning but not during recall. In control conditions, CA3 somatic and dendritic ensembles differentially remapped between distinct environments and became more correlated within each environment with learning. Silencing of either LECGLU or LECGABA destabilized CA3 place maps, thereby reducing the contrast in spatial representations of different environments and preventing their stabilization associated with learning. Computational modeling of CA3 assembly formation showed that both LECGLU and LECGABA silencing could impair reactivation despite their differences in circuit organization. CONCLUSION: LECGLU and LECGABA long-range inputs synergistically drive CA3 local excitatory, inhibitory, and disinhibitory circuit dynamics in a pathway- and compartment-specific manner. The resultant boost in CA3 recurrent activity helps stabilize CA3 place maps, supporting discrimination between environments and learning of spatial-contextual associations. Cortical inputs support hippocampal stability.: On the left, LECGLU input excites hippocampal CA3 dendrites and inhibitory neurons (INs) that prevent somatic activity. LECGABA input relieves CA3 somas from inhibition, allowing recurrent circuit (RC) activity. On the right, chemogenetic silencing (Δ) reveals that both LEC inputs contribute to stabilizing CA3 neuronal ensembles as mice learn to navigate in different environments (A versus B) based on spatial-contextual associations. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Flexibility and stability of neuronal ensembles are crucial features of brain function. Little is known about how these properties of local circuits are influenced by long-range inputs. We show, in mice, that lateral entorhinal cortex glutamatergic (LECGLU) and γ-aminobutyric acid (GABA)–ergic (LECGABA) projections to CA3 recruit specific microcircuits that conjunctively provide stability to neuronal ensembles, thereby supporting learning. LECGLU drives excitation in CA3 but also substantial feedforward inhibition that prevents somatic and dendritic spikes. Conversely, LECGABA suppresses this local inhibition to disinhibit CA3 activity with compartment and pathway specificity by selectively boosting somatic output to integrated LECGLU and CA3 recurrent inputs. This synergy allows the stabilization of spatial representations relevant to learning, as both LECGLU and LECGABA control the formation and maintenance of CA3 place cells across contexts and over time. Editor's summary: Discrimination and generalization are critical functions for recognizing and classifying objects and features and memory processing that relies on pattern separation and completion. We still don't fully understand the specific circuit mechanisms that provide neuronal ensembles a dynamic range to perform both pattern separation and completion according to external inputs and contextual demands. Robert et al. examined the specific roles of long-range circuit interactions between the entorhinal cortex and hippocampal area CA3 to find out how a single brain area can dynamically perform these fundamental information-processing operations. Lateral entorhinal cortex glutamatergic and GABAergic inputs independently and conjunctively shaped pattern separation and completion in CA3 by recruiting pathway- and compartment-specific feedforward inhibition and disinhibition, endowing CA3 with both novelty discrimination and context generalization functions. —Peter Stern INTRODUCTION: The brain encodes memories through the activation of specific ensembles of neurons. Memory formation and recall require both flexibility and stability of neuronal ensembles. How do long-range connections interact with local circuits to form flexible yet stable ensembles? Projections across brain regions are chemically diverse, notably comprising both glutamatergic and γ-aminobutyric acid–ergic (GABAergic) neurons in memory circuits, such as those between the entorhinal cortex (EC) and hippocampus. Hippocampal pyramidal neurons (PNs) integrate sensory information from EC to form internal representations of the environment. These place-cell ensembles display both flexibility and stability of their spatial tuning depending on environmental variability, allowing for adaptive learned behaviors and memory recall from partial cues. Recurrent connections within the CA3 hippocampal subregion are well suited to form and reactivate neuronal ensembles during learning and recall. However, the influence of long-range EC inputs on the function of the CA3 local circuit remains underexplored. Therefore, we examined the role of lateral EC (LEC) glutamatergic (LECGLU) and GABAergic (LECGABA) inputs on driving CA3 activity and learning-associated ensemble coding. RATIONALE: CA3 neuronal ensembles display context-dependent place-map dynamics, but their mnemonic contributions and underlying circuit mechanisms are not sufficiently understood. We hypothesized that LEC, which conveys contextual information to the hippocampus, may shape CA3 ensemble activity to support learning. Recent research described the role of LEC inputs to hippocampal area CA1 in modulating dendritic excitability, synaptic plasticity, and contextual memory. However, the conjunctive roles of LECGLU and LECGABA inputs to the hippocampus remain to be explored, and their interactions with CA3 recurrent connections and ensemble dynamics are unknown. Here, we leveraged multiplexed optogenetic and chemogenetic approaches to manipulate LECGLU and LECGABA inputs to CA3 simultaneously and decipher their impact on single-neuron and ensemble activity with compartment-specific ex vivo electrophysiology and in vivo two-photon imaging during a spatial-contextual learning behavior in mice. RESULTS: Using dual-color optogenetics combined with intracellular somatic and dendritic recordings, we mapped the functional connectivity from LECGLU and LECGABA inputs to CA3. LECGLU drove excitation in CA3 PNs but also substantial feedforward inhibition that prevented somatic and dendritic spikes. LECGABA exclusively inhibited a subset of soma-targeting local CA3 inhibitory neurons recruited by LECGLU, thereby reducing feedforward inhibition onto CA3 PNs. This LECGABA-mediated disinhibition selectively increased CA3 PN somatic, but not dendritic, spiking in response to integrated LECGLU and CA3 feedback but not DG feedforward inputs. Using dual-chemogenetic silencing of CA3-projecting LECGLU or LECGABA and two-photon calcium imaging of CA3 PN somas and dendrites, we tested how this circuit supports memory-related ensemble activity and behavior. Head-fixed mice were trained in a goal-oriented learning task that required spatial-contextual associations in different environments with graded degrees of similarity. Behavioral task performance was impaired with either LECGLU or LECGABA silencing during learning but not during recall. In control conditions, CA3 somatic and dendritic ensembles differentially remapped between distinct environments and became more correlated within each environment with learning. Silencing of either LECGLU or LECGABA destabilized CA3 place maps, thereby reducing the contrast in spatial representations of different environments and preventing their stabilization associated with learning. Computational modeling of CA3 assembly formation showed that both LECGLU and LECGABA silencing could impair reactivation despite their differences in circuit organization. CONCLUSION: LECGLU and LECGABA long-range inputs synergistically drive CA3 local excitatory, inhibitory, and disinhibitory circuit dynamics in a pathway- and compartment-specific manner. The resultant boost in CA3 recurrent activity helps stabilize CA3 place maps, supporting discrimination between environments and learning of spatial-contextual associations. Cortical inputs support hippocampal stability.: On the left, LECGLU input excites hippocampal CA3 dendrites and inhibitory neurons (INs) that prevent somatic activity. LECGABA input relieves CA3 somas from inhibition, allowing recurrent circuit (RC) activity. On the right, chemogenetic silencing (Δ) reveals that both LEC inputs contribute to stabilizing CA3 neuronal ensembles as mice learn to navigate in different environments (A versus B) based on spatial-contextual associations. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adn0623 |
