The primary visual cortex as a model of Alzheimer's disease: acute effects of Amyloid-β 1-42 Oligomer on neuronal spiking activity and orientation selectivity

Abstract

Alzheimer’s Disease (AD) is the most prevalent form of dementia, accounting for approximately 70% of the 55 million global cases (WHO). This disease is characterized by a progressive decline in memory and cognitive functions, as well as behavioral changes and visual dysfunctions, such as deficits in perception and visual processing. Neuroimaging studies reveal atrophy in the hippocampus and neocortical regions. According to the amyloid cascade hypothesis, the beta-amyloid 1-42 oligomer (Aβ42) plays a central role in the pathology, promoting the formation of amyloid plaques and neurofibrillary tangles. These pathological changes may begin up to 20 years before the onset of the first clinical symptoms. Transgenic models suggest that an imbalance in the excitation/inhibition ratio causes episodes of neuronal silencing followed by hyperactivity, contributing to sensory disintegration and behavioral deficits. Unlike rodents, which do not naturally develop AD, domestic cats (Felis catus) possess selective circuits and columnar cortical maps homologous to those of primates. When aged, they can develop Cognitive Dysfunction Syndrome, a condition similar to human AD, characterized by amyloid plaques, neurofibrillary tangles, and neurodegeneration in various cortical areas, including the visual cortex. In this study, our primary goal is to introduce the primary visual cortex of domestic cats as a promising translational model for the study of AD. Next, we investigate the impact of acute exposure to Aβ42 oligomers on neuronal activity and functional connectivity in the primary visual cortex of cats. The experimental protocol involves the implantation of 4x4 microelectrode arrays (250 µm spacing) in bilateral homologs of areas 17 or 18 in anesthetized cats (n=5), with visual stimulation using moving gratings (2500 ms) in 16 directions at 2 Hz and 0.5 cycles/degree (area 17) or 0.15 cycles/degree (area 18). We analyze changes in fundamental neuronal computations, such as firing rate and orientation selectivity index. Additionally, we examine how the peptide modifies network dynamics through a short-term plasticity adaptation protocol. This study allows precise spatial and temporal control over the action of the Aβ42 oligomer, avoiding compensatory mechanisms typical of transgenic models, in a cortex homologous to that of humans. The results aim to contribute to the understanding of the early pathophysiological mechanisms of AD.