Entorhinal Cortex

The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains, provide a mechanistic understanding of the hippocampal role in generalization, and offer unifying principles underlying many entorhinal and hippocampal cell types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells display diverse properties resembling apparently bespoke spatial responses, such as grid, band, border, and object-vector cells. TEM hippocampal cells include place and landmark cells that remap between environments. Crucially, TEM also aligns with empirically recorded representations in complex non-spatial tasks. TEM also generates predictions that hippocampal remapping is not random as previously believed; rather, structural knowledge is preserved across environments. We confirm this structural transfer over remapping in simultaneously recorded place and grid cells.

BackgroundRecent studies suggest that microglia contribute to tau pathology progression in Alzheimer's disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells in the brain, into neurodegenerative microglia (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p-tau). It remains unclear how microglia promote disease progression while actively phagocytosing pathological proteins, therefore ameliorating pathology.MethodsAdeno-associated virus expressing P301L tau mutant (AAV-P301L-tau) was stereotaxically injected into the medial entorhinal cortex (MEC) in C57BL/6 (WT) and humanized APP mutant knock-in homozygote (AppNL-G-F) mice at 5 months of age. Mice were fed either chow containing a colony stimulating factor-1 receptor inhibitor (PLX5622) or control chow from 4 to 6 months of age to test the effect of microglia depletion. Animals were tested at 6 months of age for immunofluorescence, biochemistry, and FACS of microglia. In order to monitor microglial extracellular vesicle secretion in vivo, a novel lentiviral EV reporter system was engineered to express mEmerald-CD9 (mE-CD9) specifically in microglia, which was injected into the same region of MEC.ResultsExpressing P301L tau mutant in the MEC induced tau propagation to the granule cell layer of the hippocampal dentate gyrus, which was significantly exacerbated in AppNL-G-F mice compared to WT control mice. Administration of PLX5622 depleted nearly all microglia in mouse brains and dramatically reduced propagation of p-tau in WT and to a greater extent in AppNL-G-F mice, although it increased plaque burden and plaque-associated p-tau+ dystrophic neurites. Plaque-associated MGnD microglia strongly expressed an EV marker, tumor susceptibility gene 101, indicative of heightened synthesis of EVs. Intracortical injection of mE-CD9 lentivirus successfully induced microglia-specific expression of mE-CD9+ EV particles, which were significantly enhanced in Mac2+ MGnD microglia compared to Mac2- homeostatic microglia. Finally, consecutive intracortical injection of mE-CD9 lentivirus and AAV-P301L-tau into AppNL-G-F mice revealed encapsulation of p-tau in microglia-specific mE-CD9+ EVs as determined by super-resolution microscopy and immuno-electron microscopy.DiscussionOur findings suggest that MGnD microglia hyper-secrete p-tau+ EVs while compacting Aβ plaques and clearing NP tau, which we propose as a novel mechanistic link between amyloid plaque deposition and exacerbation of tau propagation in AppNL-G-F mice.

Learning-related changes in brain activity are thought to underlie adaptive behaviours1,2. For instance, the learning of a reward site by rodents requires the development of an over-representation of that location in the hippocampus3-6. How this learning-related change occurs remains unknown. Here we recorded hippocampal CA1 population activity as mice learned a reward location on a linear treadmill. Physiological and pharmacological evidence suggests that the adaptive over-representation required behavioural timescale synaptic plasticity (BTSP)7. BTSP is known to be driven by dendritic voltage signals that we proposed were initiated by input from entorhinal cortex layer 3 (EC3). Accordingly, the CA1 over-representation was largely removed by optogenetic inhibition of EC3 activity. Recordings from EC3 neurons revealed an activity pattern that could provide an instructive signal directing BTSP to generate the over-representation. Consistent with this function, our observations show that exposure to a second environment possessing a prominent reward-predictive cue resulted in both EC3 activity and CA1 place field density that were more elevated at the cue than at the reward. These data indicate that learning-related changes in the hippocampus are produced by synaptic plasticity directed by an instructive signal from the EC3 that seems to be specifically adapted to the behaviourally relevant features of the environment.

The entorhinal cortex is the first region to develop tau pathology in Alzheimer's disease and primary age-related tauopathy, yet the reasons for this selective vulnerability remain unclear. We developed a computational model in which neuronal activity and amyloid-β (Aβ) modulate tau transport, hypothesizing that this mechanism explains entorhinal vulnerability to early tau pathology. The model combines structural connectivity with either neuronal activity (measured by FDG PET) or Aβ burden (measured by Aβ PET). We analysed Alzheimer's Disease Neuroimaging Initiative (ADNI) data comprising 527 FDG PET scans (mean age 71.8 years; 174 cognitively normal, 293 mild cognitive impairment, 60 Alzheimer's disease) and 1244 Aβ PET scans (mean age 72.4 years; 501 cognitively normal, 588 mild cognitive impairment, 155 Alzheimer's disease). From these, 253 FDG-tau and 453 Aβ-tau PET pairs were used in regression analyses. Key results were replicated in the Harvard Aging Brain Study (HABS; 300 FDG, 348 Aβ, 116 FDG-tau and 255 Aβ-tau pairs). Both FDG- and Aβ-based models consistently identified the entorhinal cortex as a primary tau seeding region in ADNI (FDG: z ≈ 4.6-4.9, P < 0.0066; Aβ: z ≈ 4.0-8.7, P ≤ 0.011) and in HABS (FDG: z = 5.7, P = 0.030; Aβ: z = 6.0, P = 0.0018). Simple linear regression showed modest associations between model-derived seeding and empirical entorhinal tau in ADNI (FDG: β = 6.7, P = 0.0039; Aβ: β = 11.3, P < 0.001), which remained significant after adjustment for age, sex, and APOE4 status (FDG: β = 7.1, P < 0.001; Aβ: β = 9.7, P < 0.001). Aβ-based associations replicated in HABS (β = 3.3, P < 0.001), while FDG-based correlations were not detectable in this predominantly cognitively normal cohort (β = -0.43, P = 0.80; power = 49%). These findings support a mechanistic role for neuronal activity and Aβ in initiating tau pathology, with the entorhinal cortex consistently emerging as highly vulnerable. Our computational model reliably identifies this region as the epicentre of pathology, supporting the idea that brain-wide patterns of neuronal activity and amyloid burden determine where tau pathology begins.