Van Hook, M. | bioRxiv Science

bioRxiv2026

Plaque-associated Microglial Polarization in Visual Brain Regions of the 5xFAD Mouse Model

Alzheimers disease (AD), a neurodegenerative disorder associated with amyloid beta (A{beta}) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are some of the first reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis using immunohistochemistry and 2-photon imaging techniques in the 5xFAD mouse model of amyloidosis to examine specifically how A{beta}, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brains environment, respond to this AD-like pathology. We found that in the pathway for image-forming vision, including the dorsolateral geniculate nucleus (dLGN) and the primary visual cortex (V1), there was significant A{beta} pathology and shifts in microglial morphology to an amoeboid state and increased phagocytic activity. However, in non-image-forming visual brain regions such as the superior colliculus (SC) and suprachiasmatic nucleus (SCN), there was minimal A{beta} pathology, ramified microglial morphology, and minimal phagocytic activity. Overall, visual brain regions associated with A{beta} plaque deposition experience significant microglial polarization when examining both morphology and function.

neuroscience↗

bioRxiv2020

Bilateral enucleation induces homeostatic plasticity in the dorsolateral geniculate nucleus of mice.

Within the nervous system, plasticity mechanisms attempt to stabilize network activity following disruption by injury, disease, or degeneration. Optic nerve injury and age-related diseases can induce homeostatic-like responses in adulthood. We tested this possibility in the thalamocortical (TC) neurons in the dorsolateral geniculate nucleus (dLGN) using patch-clamp electrophysiology, optogenetics, immunostaining, and single-cell dendritic analysis following loss of visual input via bilateral enucleation. We observed progressive loss of vGlut2-positive retinal terminals in the dLGN indicating degeneration post-enucleation that was coincident with changes in microglial morphology indicative of microglial activation. Consistent with the decline of vGlut2 puncta, we also observed loss of retinogeniculate (RG) synaptic function assessed using optogenetic activation of RG axons while performing whole-cell voltage clamp recordings from TC neurons in brain slices. Surprisingly, we did not detect any significant changes in the frequency of miniature post-synaptic currents (mEPSCs) or corticothalamic feedback synapses. Analysis of TC neuron dendritic structure from single-cell dye fills revealed a gradual loss of dendrites proximal to the soma, where TC neurons receive the bulk of RG inputs. Finally, analysis of action potential firing demonstrated that TC neurons have increased excitability following enucleation, firing more action potentials in response to depolarizing current injections. Our findings show that degeneration of the retinal axons/optic nerve and loss of RG synaptic inputs induces structural and functional changes in TC neurons, consistent with neuronal attempts at compensatory plasticity in the dLGN.

neuroscience↗