Adenosine‐Dependent Arousal Induced by Astrocytes in a Brainstem Circuit

Advanced Science · 2024-11-04 · 11 citations

Abstract Astrocytes play a crucial role in regulating sleep‐wake behavior. However, how astrocytes govern a specific sleep‐arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep‐wake cycles with state‐differential Ca 2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non‐rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A 1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZ GABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal‐promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level.

Untamed: Unconstrained Tensor Decomposition and Graph Node Embedding for Cortical Parcellation

bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-06

ABSTRACT Cortical parcellation is fundamental to neuroscience, enabling the division of cerebral cortex into distinct, non-overlapping regions to support interpretation and comparison of complex neuroimaging data. Although extensive literature has investigated cortical parcellation and its connection to functional brain networks, the optimal spatial features for deriving parcellations from resting-state fMRI (rsfMRI) remain unclear. Traditional methods such as Independent Component Analysis (ICA) have been widely used to identify large-scale functional networks, while other approaches define disjoint cortical parcellations. However, bridging these perspectives through effective feature extraction remains an open challenge. To address this, we introduce Untamed , a novel framework that integrates unconstrained tensor decomposition using NASCAR to identify functional networks, with state-of-the-art graph node embedding to generate cortical parcellations. Our method produces near-homogeneous, spatially coherent regions aligned with large-scale functional networks, while avoiding strong assumptions like statistical independence required in ICA. Across multiple datasets, Untamed consistently demonstrates improved or comparable performance in functional connectivity homogeneity and task contrast alignment compared to existing atlases. The pipeline is fully automated, allowing for rapid adaptation to new datasets and the generation of custom parcellations. The atlases derived from the Genomics Superstruct Project (GSP) dataset, along with the code for generating customizable parcel numbers, are publicly available at https://untamed-atlas.github.io .

HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors

bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-08

Abstract Aggression behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding are unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extend amygdala region critical for aggressive behaviors in both sexes of mice, with males exhibiting higher neuronal activity during the attack. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male GABAergic pSI neurons exhibited remarkable hyperexcitability due to increased Ih currents. Strikingly, modulating HCN1 expression not only adjusted this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the GABAergic pSI neurons reduced male aggression, while its overexpression markedly heightened aggression in females. Furthermore, testosterone was shown to intensify aggression by upregulating HCN1 and remodeling pSI circuits. These findings provide detailed sex-specific molecular mechanisms underlying social behaviors.

Identification of overlapping and interacting networks reveals intrinsic spatiotemporal organization of the human brain

NeuroImage · 2023 · 17 citations

• Computer Science
• Artificial Intelligence
• Computer Science

The human brain is a complex network that exhibits dynamic fluctuations in activity across space and time. Depending on the analysis method, canonical brain networks identified from resting-state fMRI (rs-fMRI) are typically constrained to be either orthogonal or statistically independent in their spatial and/or temporal domains. We avoid imposing these potentially unnatural constraints through the combination of a temporal synchronization process ("BrainSync") and a three-way tensor decomposition method ("NASCAR") to jointly analyze rs-fMRI data from multiple subjects. The resulting set of interacting networks comprises minimally constrained spatiotemporal distributions, each representing one component of functionally coherent activity across the brain. We show that these networks can be clustered into six distinct functional categories and naturally form a representative functional network atlas for a healthy population. This functional network atlas could help explore group and individual differences in neurocognitive function, as we demonstrate in the context of ADHD and IQ prediction.

Untamed: Unconstrained Tensor Decomposition and Graph Node Embedding for Cortical Parcellation

Figshare · 2023-12-06

Atlases generated from resting-state fMRI of the 1400 subjects in Brain Genomics Superstruct Project (GSP) dataset. Available in fsaverage6 and fsLR 32K surface space. If you use Untamed, please cite the following paper<pre>@techreport{liu2026untamed,<br> title={Untamed: Unconstrained Tensor Decomposition and Graph Node Embedding for Cortical Parcellation},<br> author={Liu, Yijun and Li, Jian and Wisnowski, Jessica L and Leahy, Richard M},<br> year={2026},<br> institution={Wiley Online Library}<br>}</pre>

A hybrid high-resolution anatomical MRI atlas with sub-parcellation of cortical gyri using resting fMRI

Journal of Neuroscience Methods · 2022 · 46 citations

• Neuroscience
• Psychology

The intrinsic spatiotemporal organization of the human brain - A multi-dimensional functional network atlas

bioRxiv (Cold Spring Harbor Laboratory) · 2021-12-10

Abstract The human brain is a complex, integrative and segregative network that exhibits dynamic fluctuations in activity across space and time. A canonical set of large-scale networks has been historically identified from resting-state fMRI (rs-fMRI), including the default mode, visual, somatomotor, salience, attention, and executive control. However, the methods used in identification of these networks have relied on assumptions that may inadvertently constrain their properties and consequently our understanding of the human connectome. Here we define a brain “network” as a functional component that jointly describes its spatial distribution and temporal dynamics, where neither domain suffers from unrealistic constraints. Using our recently developed BrainSync algorithm and the Nadam-Accelerated SCAlable and Robust (NASCAR) tensor decomposition, we identified twenty-three brain networks using rs-fMRI data from a large group of healthy subjects acquired by the Human Connectome Project. These networks are spatially overlapped, temporally correlated, and highly reproducible across two independent groups and sessions. We show that these networks can be clustered into six distinct functional categories and naturally form a representative functional network atlas for a healthy population. Using this atlas, we demonstrate that individuals with attention-deficit/hyperactivity disorder display disproportionate brain activity increases, relative to neurotypical subjects, in visual, auditory, and somatomotor networks concurrent with decreases in the default mode and higher-order cognitive networks. Thus, this work not only yields a highly reproducible set of spatiotemporally overlapped functional brain networks, but also provides convergent evidence that individual differences in these networks can be used to explain individual differences in neurocognitive functioning.

Author response: Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors

2020-08-21

Memory is the record of what we learn over time and is essential to our survival. But not all memories are helpful. Repeatedly recalling a traumatic event – such as an assault – can be harmful. About 1 in 3 people who experience severe trauma go on to develop post-traumatic stress disorder (PTSD), in which they re-live the traumatic event in the form of flashbacks and nightmares. Others develop panic disorder, phobias or depression. Preventing this chain of events is challenging because fear memories form rapidly and last a long time. Current treatments involve re-exposing individuals to the traumatic event. This could be real-life exposure in the case of a phobia. Or it could involve visualizing the event, in the case of PTSD. Controlled re-exposure can help individuals learn new coping strategies. But it does not erase the initial fear memory. A better approach might be to take advantage of the fact that new memories are unstable. To form a long-lasting memory trace, newly acquired information must go through a process called consolidation to stabilize it. This process takes place in an area of the brain called the hippocampus. If consolidation does not occur, new memory traces can fade away. Li, Li et al. now show that preventing consolidation in the rat brain stops the animals from forming lasting memories of a stressful event, namely a foot shock. In the study, the rats first learned to associate a foot shock with a tone. This training took place inside a specific chamber. After learning the association, the rats began to freeze – a sign of fear – whenever they entered the chamber. This happened even if the tone was not played. But Li, Li et al. showed that they could reduce this fear response by activating cells in the hippocampus known as astrocytes, shortly after the learning episode. Activating the astrocytes made them release a substance called adenosine. Molecules of adenosine then bound to and activated proteins called adenosine A1 receptors. Administering a drug that activated these receptors directly had the same effect as activating the astrocytes themselves. This suggests that drugs of this type could one day help patients with fear-related disorders such as PTSD and phobias. For this to become a reality, new studies must test different drugs and find the best ways of administering them. After testing in animal models, the next step will be preliminary clinical trials in people.

A hybrid high-resolution anatomical MRI atlas with sub-parcellation of cortical gyri using resting fMRI

bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 9 citations

• Computer Science
• Artificial Intelligence
• Computer Science

Abstract We present a new high-quality, single-subject atlas with sub-millimeter voxel resolution, high SNR, and excellent grey-white tissue contrast to resolve fine anatomical details. The atlas is labeled into two parcellation schemes: 1) the anatomical BCI-DNI atlas, which is manually labeled based on known morphological and anatomical features, and 2) the hybrid USCBrain atlas, which incorporates functional information to guide the sub-parcellation of cerebral cortex. In both cases, we provide consistent volumetric and cortical surface-based parcellation and labeling. The intended use of the atlas is as a reference template for structural coregistration and labeling of individual brains. A single-subject T1-weighted image was acquired at a resolution of 0.547mm × 0.547mm × 0.800mm five times and averaged. Images were processed by an expert neuroanatomist using semi-automated methods in BrainSuite to extract the brain, classify tissue-types, and render anatomical surfaces. Sixty-six cortical and 29 noncortical regions were manually labeled to generate the BCI-DNI atlas. The cortical regions were further sub-parcellated into 130 cortical regions based on multi-subject connectivity analysis using resting fMRI (rfMRI) data from the Human Connectome Project (HCP) database to produce the USCBrain atlas. In addition, we provide a delineation between sulcal valleys and gyral crowns, which offer an additional set of 26 sulcal subregions per hemisphere. Lastly, a probabilistic map is provided to give users a quantitative measure of reliability for each gyral subdivision. Utility of the atlas was assessed by computing adjusted Rand indices between individual sub-parcellations obtained through structural-only coregistration to the USCBrain atlas and sub-parcellations obtained directly from each subject’s resting fMRI data. Both atlas parcellations can be used with the BrainSuite, FreeSurfer, and FSL software packages.

Roles of microRNA in the pathophysiology of Alzheimer's disease

Guoji mazuixue yu fusu zazhi · 2017-12-15

Background Alzheimer's disease(AD) is the most common neurodegenerative disorder in the elderly with dementia as featured symptom. The microRNA(miRNA) are a class of non-coding single-stranded RNA composed of 22 nucleotides. They target coding miRNA and cause degradation of the miRNA, inhibiting their translation. Through these procedures, miRNA regulate various physiological functions, including the development and progress of AD. Objective To review the effects of miRNA on the levels of β-amyloid peptide(Aβ) and tau, neuroinflammation, and synaptic plasticity in AD. Content Amyloid plaques and neurofibrillary tangles are major pathophysiological hallmarks of AD. Amyloid plaques are formed by the accumulation of Aβ, while neurofibrillary tangles are generated by the excess phosphorylation of tau protein. Some miRNA were discovered to promote or reduce the accumulation of Aβ or production/phosphorylation of tau protein in certain stages of AD. Some miRNA modulate inflammation through TNF-α/NF-κB pathway or IL-1/IL-6 pathway, regulating the development and progress of AD. The levels of miRNA are also demonstrated to involve in the impairment of synaptic plasticity in AD. Trend Pathological evidence has demonstrated that miRNA may play important role in the progress of AD, suggesting that some miRNA can be potential biomarkers for stage classifications of AD. Further mechanistic investigations are required to clarify whether miRNA can be therapeutic targets to reverse or curb the deterioration of AD. Key words: MicroRNA; Alzheimer's disease