Functional connectivity measurements in APP/PS‐1 mice revealed hypo‐connectivity with transient hyper‐connectivity

Abstract

AbstractBackgroundChanges in brain functional connectivity (FC) have gained traction as an early event in Alzheimer’s disease (AD), especially reports of hyper‐connectivity preceding hypo‐connectivity.1 In the present study, we characterized changes in neuronal and hemodynamic connectivity in AD mice from 3‐12 months of age.MethodAmyloid precursor protein/presenlin‐1 (APP/PS‐1) mice (n=8) were injected with AAV‐Syn‐GCaMP6f into cortical regions. Mice were head‐fixed and imaged monthly from 3‐12 months of age. Simultaneous neuronal and hemodynamic signals were measured using wide‐field optical imaging (Fig 1a). Plaque characterization was performed via methoxy‐04 labelled images (Fig 1b). Resting‐state connectivity was calculated via Pearson correlation derived from the average timeseries of functionally clustered brain regions using a K‐means algorithm (Fig 2). Repeated measures Wilcoxon Rank Sum was used to assess statistical differences. Findings were considered significant for p<0.05.ResultAmyloid plaques were predominately seen after 6 months old (mo) and increased linearly till 12‐mo (Fig 3). The average neuronal connectivity (Fig 4a) steadily declined between 3‐ to 12‐mo, with the steepest decrease occurring around 6‐mo (r=0.65 ± 0.01 @ 3‐mo to r=0.57 ± 0.01 @ 6‐mo; p=0.01). The exception being around 9‐mo, connectivity spiked (r=0.63 ± 0.01; p=0.94, compared to 3‐mo) before returning to r=0.55 ± 0.03 (p = 0.005, 10‐mo compared to 9‐months). Hemodynamic connectivity decreased between 3‐ to 12‐mo to r= 0.43 ± 0.01 (p=0.32; compared to 3‐mo; Fig 4b) with a trough around 9‐mo r=0.41 ± 0.02 (p=0.28; compared to 3‐mo). Average correlation between neuronal and hemodynamic activity remained stable but spiked around 9‐mo, though the transient hyper‐connectivity was not significant (Fig 5).ConclusionThe observed neuronal transient hyper‐connectivity coincides with an acceleration in insoluble amyloid plaque deposition. Though insoluble amyloid continues to accumulate in the form of plaque and around blood vessels as the mouse ages, the steepest change in regional hypo‐connectivity seemed to occur around 6‐mo. We are currently exploring the decline in hemodynamic FC overtime and the detection of hemodynamic changes around the transient neuronal hyper‐connectivity at 9‐mo.Reference: Schultz et al., J Neurosci. 2017 Apr 19; 37(16): 4323–4331.