Low-frequency hippocampal–cortical activity drives brain-wide resting-state functional MRI connectivity

Chan, Russell W.; Leong, Alex T. L.; Ho, Leon C.; Gao, Patrick P.; Wong, Ella Lai‐Ming; Dong, Celia M.; Wang, Xunda; He, Jufang; Chan, Yuen-Yan; Lim, Lee Wei; Wu, Ed X.

doi:10.1073/pnas.1703309114

Cited by 95 publications

(94 citation statements)

References 87 publications

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“…Photostimulation at frequencies ranging from 5 to 20 Hz indicated spatially overlapping results ( Supplementary Fig. 10e), in contrast to previous research 39 . In fact, the nonspecific, visually-associated response amplitude was stronger at lower frequencies ( Supplementary Fig.…”

Section: Functional Connectome Of the Entl Revealed By Optogeneticscontrasting

confidence: 99%

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Mandino

Yeow

et al. 2020

Preprint

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Functional activity alterations are one of the earliest hallmarks of Alzheimer's disease (AD), already detected prior to beta-amyloid plaque and tau-tangle accumulation. To reveal the physiological basis underpinning these changes at the onset of the pathology, we leveraged fMRI in the 3xTgAD mouse model for AD. Resting-state fMRI revealed functional connectivity loss within areas homologous to the human temporal lobe, particularly the entorhinal cortex. Optogenetic activation of the entorhinal cortex results, instead, in enhanced fMRI signal, thus denoting an increase in metabolic demand under load. This is corroborated by synaptic hyperexcitability in the highlighted projection targets, reported with electrophysiological recordings. Thus, 3xTgAD mice reveal a dichotomic behavior between resting and evoked states, resulting in a functional brain-wide reorganization with local underpinnings, which reconciles evidence from the human literature. The 3xTgAD tauopathy profile resembles that in AD patients closely, suggesting that similar pathophysiological mechanisms might underlie network dysfunction in clinical cases. Results Phosphorylated tau in ventral-amygdaloid-striatal networks precedes amyloid depositionTo determine the pathological state, brain slices from 3xTgAD and control animals aged 3, 6, and 10 months were examined for immunoreactivity to 6e10 (targeting the N-terminus of beta-amyloid, Aβ) and AT8 (targeting phospho-tau (Ser202, Thr205)). Consistent with previous description 9,16 , no immunoreactivity was observed to 6e10 at 3 and 6 months of age ( Supplementary Fig. 1), while AT8 binding was revealed in the amygdala at 3 months, spreading to the hippocampus at 6 and 10 months ( Fig. 1d, Supplementary Fig. 2). Only at 10 months of age did 3xTgAD exhibit the immunoreactivity patterns attributable to neurofibrillary tangles ( Supplementary Fig. 2c).We confirmed these results with ELISA performed on brain tissue homogenate. Soluble Aβ1-40 levels in 3xTgAD were of comparable magnitude (~12000/~16000 pg/mg) to that of age-matched control animals at 3 months of age; a difference of 1.7-fold in soluble Aβ1-40 was seen between controls (~9000 pg/ml) and 3xTgAD (~16000 pg/ml) at 6 months of age. No difference was reported for insoluble Aβ1-40 at both age points. Furthermore, 3xTgAD mice showed an increase in total tau of several orders of magnitude compared to age-matched controls at both age points, e.g., 20-fold increment at 6 months of age. We conclude that 3xTgAD mice aged 3 and 6 months represent a preplaque and pre-tangle stage of AD-like pathology. The 3-and 6-months age points were, therefore, examined in the remainder of this study. The ventral-amygdaloid-striatal network is affected during tauopathy in mice and humansTo examine spontaneous fluctuations in brain activity, we recorded rsfMRI in male 3xTgAD and wildtype control mice on the same background strain (129sv/c57bl6) at 3 (N3xTgAD = 19, Ncontrols = 10) and 6 months of age (N3xTgAD = 13, Ncontrols = 10), longitudinally. The rsfMRI protocol empl...

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Section: Functional Connectome Of the Entl Revealed By Optogeneticscontrasting

confidence: 99%

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Mandino

Yeow

et al. 2020

Preprint

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“…These data suggest that Olfr de-repression in PGNs coincides with the cascade of transcriptional responses to recent strong activation, which naturally occurs in CA1 PGNs during spatial tasks and is critical for long-term memory formation [33][34][35] .…”

Section: A Sub-population Of Activated Pgns Express a Single Olfr Genmentioning

confidence: 73%

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Winick-Ng

Kukalev

Harabula

et al. 2020

Preprint

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Neurons and oligodendrocytes are terminally differentiated cells that perform highly specialized functions, which depend on cascades of gene activation and repression to retain homeostatic control over a lifespan. Gene expression is regulated by threedimensional (3D) genome organisation, from local levels of chromatin compaction to the organisation of topological domains and chromosome compartments. Whereas our understanding of 3D genome architecture has vastly increased in the past decade, it remains difficult to study specialized cells in their native environment without disturbing their activity. To develop the application of Genome Architecture Mapping (GAM) in small numbers of specialized cells in complex tissues, we combined GAM with immunoselection. We applied immunoGAM to map the genome architecture of specific cell populations in the juvenile/adult mouse brain: dopaminergic neurons (DNs) from the midbrain, pyramidal glutamatergic neurons (PGNs) from the hippocampus, and oligodendrocyte lineage cells (OLGs) from the cortex. We integrate 3D genome organisation with single-cell transcriptomics data, and find specific chromatin structures that relate with cell-type specific patterns of gene expression. We discover abundant changes in compartment organisation, especially a strengthening of heterochromatin compartments which establish strong contacts spanning tens of megabases, especially in brain cells. These compartments contain olfactory and taste receptor genes, which are de-repressed in a subpopulation of PGNs with molecular signatures of long-term potentiation (LTP). We also show extensive reorganisation of topological domains where activation of neuronal or oligodendrocyte genes coincides with formation of new TAD borders.Finally, we discover loss of TAD organisation, or 'TAD melting', at long (>1Mb) neuronal genes when they are most highly expressed. Our work shows that the 3D 3 organisation of the genome is highly cell-type specific in terminally differentiated cells of the brain, and essential to better understand brain-specific mechanisms of gene regulation.

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“…Previous work has explored how optogenetic stimulation at different frequencies may also result in different magnitudes of regional activation and static functional connectivity [43][44][45] . Furthermore, a recent study has also demonstrated how driving neuronal activity with optogenetics results in static patterns of effective connectivity as determined through dynamical causal modeling 46 .…”

Section: Discussionmentioning

confidence: 99%

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

Salvan

Lazari

Vidaurre

et al. 2020

Preprint

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An important question in neuroscience is how local activity can be flexibly and selectively routed across the brain network. A proposed mechanism to flexibly route information is frequency division multiplexing: selective readout can be achieved by segregating the signal into non-overlapping frequency bands. Here, in wild-type mice and in a transgenic model (3xTgAD) of Alzheimer's Disease (AD), we use optogenetic activation of the entorhinal cortex, concurrent whole-brain fMRI, and hidden Markov modeling. We demonstrate how inducing neuronal spiking with different theta frequencies causes spatially distinct states of brain network dynamics to emerge and to preferentially respond to one frequency, showing how selective information streams can arise from a single neuronal source of activity. This theta modulation mechanism, however, is impaired in the AD model. This work demonstrates that neuronal multiplexing is a sufficient mechanism to enable flexible brain network communication, and provides insight into the aberrant mechanisms underlying cognitive decline. ResultsOscillations result from the dynamic interaction between cellular and circuit properties. At microscopic scales, oscillatory synchronizations are constrained by axon conduction and synaptic delays; at macroscopic scales, oscillatory synchronizations are thought to be influenced by the architectural properties of the brain network (for review: 8 ). This complex interplay between oscillatory patterns and brain network topology may, therefore, allow neuronal signalling to selectively propagate along distinct subdivisions of anatomical projections or circuits 6 , giving rise to multiple temporal and spatial scales 8 or information streams 4 . From a modeling perspective, it is possible to utilize the sequential nature of BOLD fMRI data in order to characterize transient network states in brain hemodynamic activity. HMMs are well-suited because they provide a time-point-by-time-point description of network activity at the single-trial level, facilitating the characterisation of how such responses may evolve across time 7 or in response to perturbations such as stimulation.While HMMs provide a novel way of interrogating information within fMRI data, their use has not been previously applied to species other than humans. Here, using HMMs, we show that spontaneous hemodynamic fluctuations in the mouse brain at rest are temporally organized in a series of states that mirror well-established resting-state networks 9-11 ( Fig. S1-3 , see Supplementary results). Furthermore, we show that these states are organized in a hierarchical fashion, similar to what has been previously observed in humans 7 . Together, these results show that spontaneous brain network activity in mice is characterized by similar principles of temporal organization as in humans, thus providing further evidence of how the mouse brain is a relevant model to causally study neuronal mechanisms of mammalian brain network dynamics.Single-area evoked neuronal spiking is sufficient to cause spatiall...

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Low-frequency hippocampal–cortical activity drives brain-wide resting-state functional MRI connectivity

Cited by 95 publications

References 87 publications

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

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