Bidirectional Relationship between Functional Connectivity and Amyloid- Deposition in Mouse Brain

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2012; 32(13):4334-40. DOI: 10.1523/JNEUROSCI.5845-11.2012
Source: PubMed


Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer's disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice before Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.

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Available from: David M Holtzman, Jan 20, 2014
    • "Resting-state spontaneous activity provides samples of brain activity and requisite functional connectivity without requiring the testing subjects to engage in tasks and therefore has utility in physiological and pathological brain states (Zhang and Raichle, 2010;van den Heuvel and Hulshoff Pol, 2010). Cortical restingstate activity assessed by voltage signals (Mohajerani et al., 2013), Ca 2 signals (Vanni and Murphy, 2014) and intrinsic signals (White et al., 2011) have been recently applied to determine regional functional connectivity and also aberrant functional connectivity caused by brain diseases in rodents (Bero et al., 2012;Bauer et al., 2014). To our knowledge, this type of widefield characterization of spontaneous activity by glutamatergic signaling—presumably reflecting synaptic activity— has not been reported previously. "
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    ABSTRACT: Wide-field-of-view mesoscopic cortical imaging with genetically encoded sensors enables decoding of regional activity and connectivity in anesthetized and behaving mice; however, the kinetics of most genetically encoded sensors can be suboptimal for in vivo characterization of frequency bands higher than 1-3 Hz. Furthermore, existing sensors, in particular those that measure calcium (genetically encoded calcium indicators; GECIs), largely monitor suprathreshold activity. Using a genetically encoded sensor of extracellular glutamate and in vivo mesoscopic imaging, we demonstrate rapid kinetics of virally transduced or transgenically expressed glutamate-sensing fluorescent reporter iGluSnFR. In both awake and anesthetized mice, we imaged an 8 × 8 mm field of view through an intact transparent skull preparation. iGluSnFR revealed cortical representation of sensory stimuli with rapid kinetics that were also reflected in correlation maps of spontaneous cortical activities at frequencies up to the alpha band (8-12 Hz). iGluSnFR resolved temporal features of sensory processing such as an intracortical reverberation during the processing of visual stimuli. The kinetics of iGluSnFR for reporting regional cortical signals were more rapid than those for Emx-GCaMP3 and GCaMP6s and comparable to the temporal responses seen with RH1692 voltage sensitive dye (VSD), with similar signal amplitude. Regional cortical connectivity detected by iGluSnFR in spontaneous brain activity identified functional circuits consistent with maps generated from GCaMP3 mice, GCaMP6s mice, or VSD sensors. Viral and transgenic iGluSnFR tools have potential utility in normal physiology, as well as neurologic and psychiatric pathologies in which abnormalities in glutamatergic signaling are implicated.
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    • "On the other hand, the DMN is affected in a wide array of mental disorders , suggesting that it is a vulnerable network. Several studies demonstrated that brain regions with higher baseline neuronal activity are more prone to disease-induced changes (Bero et al. 2012; de Haan et al. 2012). This is consistent with the observation of stronger FC in the DMNlike network in this study and the fact that the DMN is affected in a wide array of neurological disorders. "
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    ABSTRACT: Resting-state functional MRI (rsfMRI) is a widely implemented technique used to investigate large-scale topology in the human brain during health and disease. Studies in mice provide additional advantages, including the possibility to flexibly modulate the brain by pharmacological or genetic manipulations in combination with high-throughput functional connectivity (FC) investigations. Pharmacological modulations that target specific neurotransmitter systems, partly mimicking the effect of pathological events, could allow discriminating the effect of specific systems on functional network disruptions. The current study investigated the effect of cholinergic and serotonergic antagonists on large-scale brain networks in mice. The cholinergic system is involved in cognitive functions and is impaired in, e.g., Alzheimer's disease, while the serotonergic system is involved in emotional and introspective functions and is impaired in, e.g., Alzheimer's disease, depression and autism. Specific interest goes to the default-mode-network (DMN), which is studied extensively in humans and is affected in many neurological disorders. The results show that both cholinergic and serotonergic antagonists impaired the mouse DMN-like network similarly, except that cholinergic modulation additionally affected the retrosplenial cortex. This suggests that both neurotransmitter systems are involved in maintaining integrity of FC within the DMN-like network in mice. Cholinergic and serotonergic modulations also affected other functional networks, however, serotonergic modulation impaired the frontal and thalamus networks more extensively. In conclusion, this study demonstrates the utility of pharmacological rsfMRI in animal models to provide insights into the role of specific neurotransmitter systems on functional networks in neurological disorders.
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    • "In mouse brains, the amount of Aβ in the interstitial fluid and the development of amyloid plaques are associated with synaptic activity (Selkoe 2006; Bero et al. 2011, 2012). These findings suggest that the brain hubs tend to have amyloid plaque deposition that leads to functional disconnections among regions. "
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