mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Oct. 19, 2021

Abstract Postmortem studies have revealed increased density of excitatory synapses in the brains individuals with autism spectrum disorder (ASD), a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured resting-state fMRI (rsfMRI). These observations raise question whether excess causes ASD. Using rsfMRI, electrophysiology and silico modelling Tsc2 haploinsufficient mice, we show that spine associated -like stereotypies cortico-striatal hyperconnectivity. deficits are completely rescued pharmacological inhibition mTOR. Notably, further demonstrate children idiopathic exhibit analogous cortical-striatal hyperconnectivity, document this fingerprint enriched for ASD-dysregulated genes interacting mTOR or Tsc2. Finally, identified transcriptomic signature predominantly expressed subset autism, thereby defining segregable subtype. Our findings causally mTOR-related pathology large-scale network aberrations, revealing unifying multi-scale framework mechanistically reconciles developmental synaptopathy hyperconnectivity autism.

Language: Английский

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Unique spatiotemporal fMRI dynamics in the awake mouse brain

Current Biology, Journal Year: 2022, Volume and Issue: 32(3), P. 631 - 644.e6

Published: Jan. 7, 2022

Human imaging studies have shown that spontaneous brain activity exhibits stereotypic spatiotemporal reorganization in awake, conscious conditions with respect to minimally states. However, whether and how this phenomenon can be generalized lower mammalian species remains unclear. Leveraging a robust protocol for resting-state fMRI (rsfMRI) mapping non-anesthetized, head-fixed mice, we investigated functional network topography dynamic structure of wakeful animals. We found rsfMRI networks the awake state, while anatomically comparable those observed under anesthesia, are topologically configured maximize interregional communication, departing from underlying community mouse axonal connectome. further report animals unique dynamics characterized by state-dependent, dominant occurrence coactivation patterns encompassing prominent participation arousal-related forebrain nuclei anti-coordination between visual-auditory polymodal cortical areas. finally show mice stereotypical temporal structure, which state-dominant as attractors. These findings suggest is critically shaped state-specific involvement basal arousal systems document its recapitulates distinctive, evolutionarily relevant principles predictive states higher species.

Language: Английский

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Increased fMRI connectivity upon chemogenetic inhibition of the mouse prefrontal cortex

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 25, 2022

Abstract While shaped and constrained by axonal connections, fMRI-based functional connectivity reorganizes in response to varying interareal input or pathological perturbations. However, the causal contribution of regional brain activity whole-brain fMRI network organization remains unclear. Here we combine neural manipulations, resting-state vivo electrophysiology probe how inactivation a cortical node causally affects brain-wide coupling mouse. We find that chronic inhibition medial prefrontal cortex (PFC) via overexpression potassium channel increases between inhibited area its direct thalamo-cortical targets. Acute chemogenetic PFC produces analogous patterns overconnectivity. Using electrophysiology, enhances low frequency (0.1–4 Hz) oscillatory power suppression firing not phase-locked slow rhythms, resulting increased δ band coherence areas exhibit These results provide evidence can counterintuitively increase enhanced, less-localized processes.

Language: Английский

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Gradients of neurotransmitter receptor expression in the macaque cortex

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(7), P. 1281 - 1294

Published: June 19, 2023

Abstract Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map receptor organization across cortical regions is needed. In this study, we used in vitro autoradiography to measure the density 14 neurotransmitter types 109 areas macaque cortex. We integrated data with anatomical, genetic functional connectivity into common space. uncovered principal gradient expression per neuron. This aligns hierarchy from sensory cortex higher cognitive areas. A second gradient, driven serotonin 5-HT 1A receptors, peaks anterior cingulate, default mode salience networks. found similar pattern human brain. Thus, may be promising translational model serotonergic processing disorders. The gradients enable rapid, reliable information slow, flexible integration

Language: Английский

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Intrinsic macroscale oscillatory modes driving long range functional connectivity in female rat brains detected by ultrafast fMRI

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 6, 2023

Abstract Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals correlate across distant brain areas, shaping functionally relevant intrinsic networks. However, the generative mechanism of fMRI signal correlations, and particular link with locally-detected ultra-slow oscillations, are not fully understood. To investigate this link, we record ultrafast ultrahigh field (9.4 Tesla, temporal resolution = 38 milliseconds) from female rats three anesthesia conditions. Power at frequencies extending up to 0.3 Hz is detected consistently rat brains modulated by level. Principal component analysis reveals a repertoire modes, which transient oscillations organize fixed phase relationships distinct cortical subcortical structures. Oscillatory modes found vary between conditions, resonating faster under medetomidine sedation reducing both number, frequency, duration addition isoflurane. Peaking power within clear anatomical boundaries, these oscillatory point an emergent systemic property. This work provides additional insight into origin organizing principles underpinning spontaneous long-range connectivity.

Language: Английский

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Multimodal measures of spontaneous brain activity reveal both common and divergent patterns of cortical functional organization

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 3, 2024

Abstract Large-scale functional networks have been characterized in both rodent and human brains, typically by analyzing fMRI-BOLD signals. However, the relationship between underlying neural activity is complex incompletely understood, which poses challenges to interpreting network organization obtained using this technique. Additionally, most work has assumed a disjoint (i.e., brain regions belong one only network). Here, we employ wide-field Ca 2+ imaging simultaneously with mice expressing GCaMP6f excitatory neurons. We determine cortical discovered each modality mixed-membership algorithm test hypothesis that exhibit overlapping organization. find there considerable overlap (both modalities) addition Our results show multiple BOLD are detected via signals, determined low-frequency signals modestly more similar networks. In addition, principal gradient of connectivity nearly identical for Despite similarities, important differences also across modalities, such as measures strength diversity. conclusion, uncovers mouse reflects several, but not all, properties observed

Language: Английский

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Regional, Layer, and Cell-Type-Specific Connectivity of the Mouse Default Mode Network

Neuron, Journal Year: 2020, Volume and Issue: 109(3), P. 545 - 559.e8

Published: Dec. 7, 2020

The evolutionarily conserved default mode network (DMN) is a distributed set of brain regions coactivated during resting states that vulnerable to disorders. How disease affects the DMN unknown, but detailed anatomical descriptions could provide clues. Mice offer an opportunity investigate structural connectivity across spatial scales with cell-type resolution. We co-registered maps from functional magnetic resonance imaging and axonal tracing experiments into 3D Allen mouse reference atlas. find consists preferentially interconnected cortical regions. As population, layer 2/3 (L2/3) neurons project almost exclusively other regions, whereas L5 in out DMN. In retrosplenial cortex, core region, we identify two projection types differentiated by in- or out-DMN targets, laminar position, gene expression. These results multi-scale description correlates

Language: Английский

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Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(12), P. 7610 - 7620

Published: Aug. 11, 2021

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation fMRI-based connectivity mouse, which specific ASD-relevant mutations can be isolated modeled minimizing environmental contributions. By performing brain-wide mapping across 16 mouse mutants, show that different ASD-associated etiologies cause broad spectrum connectional diverse, often diverging, signatures are recognizable. Despite identified alterations could classified into four subtypes discrete network dysfunction. Our findings variability key determinant heterogeneity ASD, hence reconciling conflicting clinical populations. The identification etiologically-relevant improve diagnostic label accuracy non-syndromic population paves way for personalized treatment approaches.

Language: Английский

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Chemogenetic stimulation of tonic locus coeruleus activity strengthens the default mode network

Science Advances, Journal Year: 2022, Volume and Issue: 8(17)

Published: April 29, 2022

The default mode network (DMN) of the brain is functionally associated with a wide range behaviors. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber photometry to investigate selective neuromodulatory effect norepinephrine (NE)–releasing noradrenergic neurons in locus coeruleus (LC) on mouse DMN. Chemogenetic-induced tonic LC activity decreased cerebral blood volume (CBV) glucose uptake increased synchronous low-frequency fMRI within frontal cortices Fiber results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, reduced CBV anterior cingulate cortex. These data suggest alters conventional coupling between We also demonstrated chemogenetic strengthened connectivity DMN, was causally mediated by modulatory inputs from retrosplenial hippocampal regions association

Language: Английский

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Functional Connectivity of the Brain Across Rodents and Humans

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: March 8, 2022

Resting-state functional magnetic resonance imaging (rs-fMRI), which measures the spontaneous fluctuations in blood oxygen level-dependent (BOLD) signal, is increasingly utilized for investigation of brain's physiological and pathological activity. Rodents, as a typical animal model neuroscience, play an important role studies that examine neuronal processes underpin BOLD signal connectivity results. Translating this knowledge from rodents to humans requires basic similarities differences across species terms both resulting connectivity. This review begins by examining anatomical features, acquisition parameters, preprocessing techniques, factors contribute Homologous networks are compared species, aspects such topography global relationship between structural examined. Time-varying features connectivity, obtained sliding windowed approaches, quasi-periodic patterns, coactivation species. Applications demonstrating use rs-fMRI translational tool cross-species analysis discussed, with emphasis on neurological psychiatric disorders. Finally, open questions presented encapsulate future direction field.

Language: Английский

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