Papers

The consolidation of declarative memories is thought to rely on the offline reactivation of hippocampal cell assemblies during sharp-wave ripples (SWRs), which drives gradual neocortical redistribution of memory traces. While this process is conventionally framed in terms of neuronal plasticity, the role of glial cells—astrocytes and microglia—in regulating the temporal dynamics and fidelity of hippocampal replay remains largely unexplored. Here, we propose a tripartite model of memory consolidation in which astrocytic calcium signaling controls the precise timing of SWR-coupled replay, and microglial activity-dependent synaptic pruning sharpens the signal-to-noise ratio of reactivated memory ensembles. We hypothesize that during non-rapid eye movement (NREM) sleep, astrocytic release of D-serine and other gliotransmitters modulates NMDA-receptor-dependent plasticity at hippocampal-neocortical synapses, thereby gating the window of replay-driven systems transfer. Concurrently, microglia selectively eliminate weak or irrelevant synaptic connections tagged during replay, preventing the consolidation of noisy information. Disruption of either glial pathway leads to degraded replay fidelity and memory consolidation deficits, as observed in neuroinflammatory and neurodegenerative conditions. We outline a series of testable predictions and propose experimental approaches combining cell-type-specific optogenetics, in vivo two-photon imaging, and high-density electrophysiology to validate this framework. This perspective shifts the paradigm from a purely neuron-centric view of systems consolidation to one that integrates glial-neuronal interactions at the network level, with implications for understanding memory disorders and developing therapeutic interventions.

Working memory maintenance relies on persistent activity in prefrontal pyramidal neurons, local inhibition, and thalamocortical loops, all modulated by dopamine. However, how these mechanisms interact dynamically to resist distractor interference remains unclear. Here, we synthesize recent promising hypotheses into a unified network model that integrates cellular D1-NMDA receptor interactions, dopaminergic modulation of parvalbumin-positive interneurons for distractor filtering, and thalamocortical synchrony to stabilize attractor dynamics. This theoretical framework proposes that coordinated dopamine release in the prefrontal cortex enhances both recurrent excitation and perisomatic inhibition, while strengthening thalamic drive to maintain representations against interference. We outline testable predictions and discuss implications for cognitive deficits in schizophrenia and ADHD. Although direct experimental validation is pending, the model offers a cohesive account of working memory resilience and flexibility.

Working memory maintenance relies on persistent activity in prefrontal pyramidal neurons, local inhibition, and thalamocortical loops, all modulated by dopamine. However, how these mechanisms interact dynamically to resist distractor interference remains unclear. Here, we synthesize recent promising hypotheses into a unified network model that integrates cellular D1-NMDA receptor interactions, dopaminergic modulation of parvalbumin-positive interneurons for distractor filtering, and thalamocortical synchrony to stabilize attractor dynamics. This theoretical framework proposes that coordinated dopamine release in the prefrontal cortex enhances both recurrent excitation and perisomatic inhibition, while strengthening thalamic drive to maintain representations against interference. We outline testable predictions and discuss implications for cognitive deficits in schizophrenia and ADHD. Although direct experimental validation is pending, the model offers a cohesive account of working memory resilience and flexibility.

Traumatic memories in post-traumatic stress disorder (PTSD) are often resistant to extinction-based therapies, posing a significant clinical challenge. We propose and validate a closed-loop optogenetic paradigm that combines real-time decoding of fear states with targeted silencing of specific engram cells in the prefrontal-amygdala circuit during memory reconsolidation. Using a chronic mouse model of PTSD, we demonstrate that this intervention selectively and permanently attenuates remote fear memories without affecting other associative memories. Longitudinal behavioral assessments and immunohistochemical analyses confirm the stability of the memory attenuation over four weeks. Crucially, the closed-loop system achieved a 92% specificity in targeting fear-encoding engrams, significantly outperforming open-loop stimulation. These findings establish a precise, circuit-level therapeutic strategy for memory-related psychiatric disorders, offering a potential avenue for translation to non-invasive closed-loop neuromodulation in humans.