During the reporting period, the DormantAD project advanced its core scientific objectives through a combination of electrophysiological, molecular, and computational studies. The work focused on understanding how brain circuits maintain stability and memory during the early, silent phase of Alzheimer’s disease (AD), when cellular and network disturbances first appear. The project’s experiments were conducted in both healthy and Alzheimer’s mouse models, integrating high-density in vivo electrophysiological recordings, calcium imaging, chemogenetic manipulations, molecular assays, and advanced data analytics to map homeostatic processes in the hippocampus and connected regions.
1. Sleep-dependent recovery of hippocampal function
The first research aim explored how hippocampal network resilience is regulated following perturbations. Using chemogenetic activation to artificially increase inhibition in the hippocampal CA1 area, the team tracked neuronal firing and population dynamics across multiple days. The perturbation suppressed the activity of regular-spiking neurons and altered the collective structure of network dynamics. Remarkably, during continued inhibition, the system gradually recovered—largely during sleep—re-establishing firing rates and correlations to stable, state-specific set points. This recovery was accompanied by an increase in the intrinsic excitability of pyramidal neurons. Behaviorally, memory retrieval that had been impaired during perturbation normalized as the network regained stability. These findings reveal how homeostatic processes operating across vigilance states preserve stored information and stabilize circuit function under changing conditions.
2. NMDA receptors and the firing rate set point
The second major line of research investigated how NMDA receptors (NMDARs) contribute to the regulation of hippocampal activity levels. Traditionally associated with synaptic plasticity and learning, NMDARs were found to play a broader role in maintaining network homeostasis. Chronic inhibition of NMDARs reduced overall network activity without changing single-neuron dynamics, suggesting a shift in the network’s firing rate set point rather than an acute suppression. Mechanistic analyses identified the NMDAR–eEF2K signaling pathway as a key regulator of this process. The effect was mediated through changes in excitatory synapses and in the intrinsic excitability of parvalbumin-positive interneurons. These discoveries redefine the functional scope of NMDARs, linking them to global stability mechanisms rather than only local synaptic plasticity. This insight also provides a conceptual framework for understanding how NMDAR-targeting drugs—such as ketamine or magnesium—may modulate pathological activity in neurological disorders.
3. Deep brain stimulation restores resilience in Alzheimer’s model
A major breakthrough was achieved in understanding circuit-level mechanisms of resilience to AD. In a mouse model of familial Alzheimer’s disease (APP/PS1), the team identified aberrant interictal epileptiform spikes (IESs) in the hippocampus and medial prefrontal cortex during anesthesia, driven by hyperactive input from the thalamic nucleus reuniens (nRE). Applying tonic deep brain stimulation (tDBS) to the nRE effectively suppressed these pathological spikes, restored firing rate homeostasis, and prevented further degradation of hippocampal-prefrontal synaptic communication. Long-term stimulation in young mice during the prodromal stage mitigated age-related memory decline. These results establish the nRE as a key regulator of cortical–hippocampal excitability and demonstrate the feasibility of neuromodulatory interventions to preserve cognition in early AD stages. The findings position tDBS-nRE as a promising therapeutic approach for restoring circuit and cognitive resilience.
4. Methodological innovations and interdisciplinary integration
The team implemented novel pipelines for quantifying population-level stability, dynamical dimensionality, and firing rate distributions. These techniques are being shared within and beyond the neuroscience community and have potential applications in fields such as cellular metabolism and systems biology. The interdisciplinary collaboration between molecular biologists, physiologists, and computational neuroscientists has enabled the project to connect molecular signaling pathways with circuit-level behavior and cognition.
