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

Bero, Adam W.; Bauer, Adam Q.; Stewart, Floy R.; White, Brian R.; Cirrito, John R.; Raichle, Marcus E.; Culver, Joseph P.; Holtzman, David M.

doi:10.1523/jneurosci.5845-11.2012

Cited by 166 publications

(182 citation statements)

References 27 publications

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“…Converging evidence from human and animal studies suggests that metabolic demands render the prefrontal cortex preferentially vulnerable to Alzheimer's disease (AD)-related neuropathology (40,(46)(47)(48)(49). For instance, the mPFC is among the first brain regions to develop amyloid-β (Aβ) plaque deposition, an early pathological hallmark of AD (50).…”

Section: Discussionmentioning

confidence: 99%

Early remodeling of the neocortex upon episodic memory encoding

Bero

Meng

Cho

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal-hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states.learning | transcriptome | neuroplasticity | optogenetics | hippocampus

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Section: Discussionmentioning

confidence: 99%

Early remodeling of the neocortex upon episodic memory encoding

Bero

Meng

Cho

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…OIS imaging of resting-state functional connectivity in mice was performed as previously described (28,29). Briefly, mice were anesthetized with an i.p.…”

Section: Methodsmentioning

confidence: 99%

“…This approach visualizes alterations in regional cortical blood flow in anesthetized mice and generates maps of resting-state functional connectivity between contralateral brain regions. fcOIS is highly sensitive to neuritic pathology in the absence of overt neuronal loss in mouse models of brain aging and Alzheimer disease (AD) (29). As shown in Figure 2, E and F, 5-to 6-month-old Bmal1 KO mice exhibited diminished functional connectivity throughout the cortex, most significantly in the retrosplenial cortex, a region that is severely affected in mouse models of brain aging and AD (29) and that showed severe astrogliosis in Bmal1 KO mice (see Figure 1E).…”

Section: Oscillation Of Circadian Clock Genes Is Controlled By Bmal1 mentioning

confidence: 99%

“…fcOIS is highly sensitive to neuritic pathology in the absence of overt neuronal loss in mouse models of brain aging and Alzheimer disease (AD) (29). As shown in Figure 2, E and F, 5-to 6-month-old Bmal1 KO mice exhibited diminished functional connectivity throughout the cortex, most significantly in the retrosplenial cortex, a region that is severely affected in mouse models of brain aging and AD (29) and that showed severe astrogliosis in Bmal1 KO mice (see Figure 1E). Thus, the neuropathology seen in Bmal1 KO mice coincides in space and time with impaired neuronal network functional connectivity.…”

Section: Oscillation Of Circadian Clock Genes Is Controlled By Bmal1 mentioning

confidence: 99%

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Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Musiek¹,

Lim²,

Yang³

et al. 2013

J. Clin. Invest.

403

448

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Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

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“…However, achieving a sufficient SNR is challenging owing to the need both for high magnetic fields and small voxel size for imaging the mouse brain and for the Researchers have recently introduced functional connectivity mapping with optical intrinsic signal imaging (fcOIS) as an alternative approach in mice. 5 However, due to the diffusion of light in tissue, the spatial resolution of fcOIS is limited, and experiments thus far performed used an exposed skull preparation, which increases the complexity of longitudinal imaging.…”

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confidence: 99%