Neuron Geometry Underlies Universal Network Features in Cortical Microcircuits

ABSTRACTWhy do cortical microcircuits in a variety of brain regions express similar, highly nonrandom, network motifs? To what extent this structure is innate and how much of it is molded by plasticity and learning processes? To address these questions, we developed a general network science framework to quantify the contribution of neurons’ geometry and their embedding in cortical volume to the emergence of three-neuron network motifs. Applying this framework to a dense in silico reconstructed cortical microcircuits showed that the innate asymmetric neuron’s geometry underlies the universally recurring motif architecture. It also predicted the spatial alignment of cells composing the different triplets-motifs. These predictions were directly validated via in vitro 12-patch whole-cell recordings (7,309 triplets) from rat somatosensory cortex. We conclude that the local geometry of neurons imposes an innate, already structured, global network architecture, which serves as a skeleton upon which fine-grained structural and functional plasticity processes take place.

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Delineating Neural Responses and Functional Connectivity Changes During Vestibular and Nociceptive Stimulation Reveal the Uniqueness of Cortical Vestibular Processing

10.21203/rs.3.rs-573690/v1 ◽

2021 ◽

Author(s):

Judita Huber ◽

Ria Maxine Rühl ◽

Virginia Flanagin ◽

Peter zu Eulenburg

Keyword(s):

Network Architecture ◽

Vestibular Stimulation ◽

Brain Regions ◽

Global Network ◽

Proprioceptive Information ◽

Nociceptive Stimulation ◽

Vestibular Information ◽

Nociceptive Responses ◽

Vestibular Perception ◽

Heterogeneous Region

Abstract Vestibular information is ubiquitous and often processed jointly with visual, somatosensory and proprioceptive information. Among the cortical brain regions associated with human vestibular processing, area OP2 in the parietal operculum has been proposed as vestibular core region. However, delineating responses uniquely to vestibular stimulation in this region using neuroimaging is challenging for several reasons: Firstly, the parietal operculum is a cytoarchitectonically heterogeneous region responding to multisensory stimulation. Secondly, artificial vestibular stimulation evokes confounding somatosensory and nociceptive responses blurring responses contributing to vestibular perception. Furthermore, immediate effects of vestibular stimulation on the organization of functional networks have not been investigated in detail yet.Here, we compared two equally salient stimuli - galvanic vestibular stimulation (GVS) and galvanic nociceptive stimulation (GNS)- to disentangle the processing of both modalities in the parietal operculum and characterize their effects on functional network architecture. GNS and GVS gave joint responses in area OP1,3,4, and the anterior and middle insula, but not in area OP2. Contrasting both stimulation modalities resulted in stronger responses in parts of the parietal operculum adjacent to OP3 and OP4 during GVS, whereas GNS evoked stronger responses in area OP1,3 and 4. Our results underline the importance of considering this common multisensory trunk when interpreting vestibular neuroimaging experiments and further underpin the role of area OP2 in central vestibular processing. Global network changes were found during GNS, but not during GVS. This lack of network reconfiguration despite the saliency of GVS may reflect the continuous processing of vestibular information in the awake human.

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Delineating neural responses and functional connectivity changes during vestibular and nociceptive stimulation reveal the uniqueness of cortical vestibular processing

Brain Structure and Function ◽

10.1007/s00429-021-02394-6 ◽

2021 ◽

Author(s):

Judita Huber ◽

Maxine Ruehl ◽

Virginia Flanagin ◽

Peter zu Eulenburg

Keyword(s):

Functional Connectivity ◽

Network Architecture ◽

Vestibular Stimulation ◽

Brain Regions ◽

Global Network ◽

Proprioceptive Information ◽

Nociceptive Stimulation ◽

Vestibular Information ◽

Nociceptive Responses ◽

Vestibular Perception

AbstractVestibular information is ubiquitous and often processed jointly with visual, somatosensory and proprioceptive information. Among the cortical brain regions associated with human vestibular processing, area OP2 in the parietal operculum has been proposed as vestibular core region. However, delineating responses uniquely to vestibular stimulation in this region using neuroimaging is challenging for several reasons: First, the parietal operculum is a cytoarchitectonically heterogeneous region responding to multisensory stimulation. Second, artificial vestibular stimulation evokes confounding somatosensory and nociceptive responses blurring responses contributing to vestibular perception. Furthermore, immediate effects of vestibular stimulation on the organization of functional networks have not been investigated in detail yet. Using high resolution neuroimaging in a task-based and functional connectivity approach, we compared two equally salient stimuli—unilateral galvanic vestibular (GVS) and galvanic nociceptive stimulation (GNS)—to disentangle the processing of both modalities in the parietal operculum and characterize their effects on functional network architecture. GNS and GVS gave joint responses in area OP1, 3, 4, and the anterior and middle insula, but not in area OP2. GVS gave stronger responses in the parietal operculum just adjacent to OP3 and OP4, whereas GNS evoked stronger responses in area OP1, 3 and 4. Our results underline the importance of considering this common pathway when interpreting vestibular neuroimaging experiments and underpin the role of area OP2 in central vestibular processing. Global network changes were found during GNS, but not during GVS. This lack of network reconfiguration despite the saliency of GVS may reflect the continuous processing of vestibular information in the awake human.

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Event-related network changes unfold the dynamics of cortical integration during face processing

10.1101/2020.06.29.177436 ◽

2020 ◽

Author(s):

Antonio Maffei ◽

Paola Sessa

Keyword(s):

Face Perception ◽

Network Topology ◽

Face Processing ◽

Visual Processing ◽

Network Architecture ◽

Time Window ◽

Brain Regions ◽

Data Availability ◽

Global Network ◽

State And Local

AbstractFace perception arises from a collective activation of brain regions in the occipital, parietal and temporal cortices. Despite wide acknowledgement that these regions act in an intertwined network, the network behavior itself is poorly understood. Here we present a study in which time-varying connectivity estimated from EEG activity elicited by facial expressions presentation was characterized using graph-theoretical measures of node centrality and global network topology. Results revealed that face perception results from a dynamic reshaping of the network architecture, characterized by the emergence of hubs located in the occipital and temporal regions of the scalp. The importance of these nodes can be observed from early stages of visual processing and reaches a climax in the same time-window in which the face-sensitive N170 is observed. Furthermore, using Granger causality, we found that the time-evolving centrality of these nodes is associated with ERP amplitude, providing a direct link between the network state and local neural response. Additionally, investigating global network topology by means of small-worldness and modularity, we found that face processing requires a functional network with a strong small-world organization that maximizes integration, at the cost of segregated subdivisions. Interestingly, we found that this architecture is not static, but instead it is implemented by the network from stimulus onset to ~200 msec. Altogether, this study reveals the event-related changes underlying face processing at the network level, suggesting that a distributed processing mechanism operates through dynamically weighting the contribution of the cortical regions involved.Data AvailabilityData and code related to this manuscript can be accessed through the OSF at this link https://osf.io/hc3sk/?view_only=af52bc4295c044ffbbd3be019cc083f4

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Incerto-thalamic modulation of fear via GABA and dopamine

Neuropsychopharmacology ◽

10.1038/s41386-021-01006-5 ◽

2021 ◽

Author(s):

Archana Venkataraman ◽

Sarah C. Hunter ◽

Maria Dhinojwala ◽

Diana Ghebrezadik ◽

JiDong Guo ◽

...

Keyword(s):

Brain Regions ◽

Zona Incerta ◽

Dependent Manner ◽

Post Traumatic Stress ◽

Functional Roles ◽

Functional Connections ◽

Optogenetic Stimulation ◽

Fear Generalization ◽

Stimulation Of

AbstractFear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

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miR-142 downregulation alleviates rat PTSD-like behaviors, reduces the level of inflammatory cytokine expression and apoptosis in hippocampus, and upregulates the expression of fragile X mental retardation protein

Journal of Neuroinflammation ◽

10.1186/s12974-020-02064-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Peng-Yin Nie ◽

Lei Tong ◽

Ming-Da Li ◽

Chang-Hai Fu ◽

Jun-Bo Peng ◽

...

Keyword(s):

Fragile X ◽

Brain Regions ◽

Synaptic Proteins ◽

Sprague Dawley ◽

Post Traumatic Stress ◽

Proinflammatory Mediators ◽

Upstream Regulator ◽

Trace Fear ◽

Factor Α

Abstract Background FMRP is a selective mRNA-binding protein that regulates protein synthesis at synapses, and its loss may lead to the impairment of trace fear memory. Previously, we found that FMRP levels in the hippocampus of rats with post-traumatic stress disorder (PTSD) were decreased. However, the mechanism underlying these changes remains unclear. Methods Forty-eight male Sprague-Dawley rats were randomly divided into four groups. The experimental groups were treated with the single-prolonged stress (SPS) procedure and injected with a lentivirus-mediated inhibitor of miR-142-5p. Behavior test as well as morphology and molecular biology experiments were performed to detect the effect of miR-142 downregulation on PTSD, which was further verified by in vitro experiments. Results We found that silence of miRNA-142 (miR-142), an upstream regulator of FMRP, could alleviate PTSD-like behaviors of rats exposed to the SPS paradigm. MiR-142 silence not only decreased the levels of proinflammatory mediators, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, but also increased the expressive levels of synaptic proteins including PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We further detected that miR-142 silence also downregulated the transportation of nuclear factor kappa-B (NF-κB) into the nuclei of neurons and might further affect the morphology of neurons. Conclusions The results revealed miR-142 downregulation could alleviate PTSD-like behaviors through attenuating neuroinflammation in the hippocampus of SPS rats by binding to FMRP.

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Reconfiguration of human evolving large-scale epileptic brain networks prior to seizures: an evaluation with node centralities

Scientific Reports ◽

10.1038/s41598-020-78899-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rieke Fruengel ◽

Timo Bröhl ◽

Thorsten Rings ◽

Klaus Lehnertz

Keyword(s):

Large Scale ◽

Brain Networks ◽

Brain Regions ◽

Brain Network ◽

Theoretical Concept ◽

Global Network ◽

Time Resolved ◽

Functional Connections ◽

Node Centrality ◽

Network Mechanism

AbstractPrevious research has indicated that temporal changes of centrality of specific nodes in human evolving large-scale epileptic brain networks carry information predictive of impending seizures. Centrality is a fundamental network-theoretical concept that allows one to assess the role a node plays in a network. This concept allows for various interpretations, which is reflected in a number of centrality indices. Here we aim to achieve a more general understanding of local and global network reconfigurations during the pre-seizure period as indicated by changes of different node centrality indices. To this end, we investigate—in a time-resolved manner—evolving large-scale epileptic brain networks that we derived from multi-day, multi-electrode intracranial electroencephalograpic recordings from a large but inhomogeneous group of subjects with pharmacoresistant epilepsies with different anatomical origins. We estimate multiple centrality indices to assess the various roles the nodes play while the networks transit from the seizure-free to the pre-seizure period. Our findings allow us to formulate several major scenarios for the reconfiguration of an evolving epileptic brain network prior to seizures, which indicate that there is likely not a single network mechanism underlying seizure generation. Rather, local and global aspects of the pre-seizure network reconfiguration affect virtually all network constituents, from the various brain regions to the functional connections between them.

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005 Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist in animal models of sleep disorders

SLEEP ◽

10.1093/sleep/zsab072.004 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A2-A2

Author(s):

Saivishal Daripelli ◽

Parusharamulu Molgara ◽

Nageswararao Muddana ◽

Pradeep Jayarajan ◽

Venkat Reddy Mekala ◽

...

Keyword(s):

Knockout Mice ◽

Radioligand Binding ◽

Research Work ◽

Brain Regions ◽

Inverse Agonist ◽

Abuse Liability ◽

Histamine H3 Receptor ◽

H3 Receptor ◽

Histamine H3

Abstract Introduction Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been diverted on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). Samelisant (SUVN-G3031) is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). In the current research work, Samelisant was evaluated for neurotransmitter changes in rats and sleep EEG in orexin knockout mice, a reliable proof-of-concept study for treatment of excessive daytime sleepiness and cataplexy in narcolepsy. Methods Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTP□S assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters like histamine, dopamine and norepinephrine. Male orexin knockout mice were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Effects of Samelisant (3 and 10 mg/kg, p.o.) were evaluated during active period of animals. Results Samelisant is an inverse agonist at histamine H3 receptors with hKi of 8.7 nM and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in cortex. Samelisant produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant also significantly decreased number of cataplectic episodes in orexin knockout mice. Conclusion Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of Samelisant in the treatment of narcolepsy with and without cataplexy. Support (if any):

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Physiology, Pharmacology, and Topography of Cholinergic Neocortical Oscillations In Vitro

Journal of Neurophysiology ◽

10.1152/jn.1997.77.5.2427 ◽

1997 ◽

Vol 77 (5) ◽

pp. 2427-2445 ◽

Cited By ~ 61

Author(s):

Heath S. Lukatch ◽

M. Bruce Maciver

Keyword(s):

Current Source ◽

Brain Slices ◽

Receptor Activation ◽

Brain Regions ◽

Oscillatory Activity ◽

Cortical Layers ◽

Eeg Activity ◽

Layer 2

Lukatch, Heath S. and M. Bruce MacIver. Physiology, pharmacology, and topography of cholinergic neocortical oscillations in vitro. J. Neurophysiol. 77: 2427–2445, 1997. Rat neocortical brain slices generated rhythmic extracellular field [microelectroencephalogram (micro-EEG)] oscillations at theta frequencies (3–12 Hz) when exposed to pharmacological conditions that mimicked endogenous ascending cholinergic and GABAergic inputs. Use of the specific receptor agonist and antagonist carbachol and bicuculline revealed that simultaneous muscarinic receptor activation and γ-aminobutyric acid-A (GABAA)-mediated disinhibition werenecessary to elicit neocortical oscillations. Rhythmic activity was independent of GABAB receptor activation, but required intact glutamatergic transmission, evidenced by blockade or disruption of oscillations by 6-cyano-7-nitroquinoxaline-2,3-dione and (±)-2-amino-5-phosphonovaleric acid, respectively. Multisite mapping studies showed that oscillations were localized to areas 29d and 18b (Oc2MM) and parts of areas 18a and 17. Peak oscillation amplitudes occurred in layer 2/3, and phase reversals were observed in layers 1 and 5. Current source density analysis revealed large-amplitude current sinks and sources in layers 2/3 and 5, respectively. An initial shift in peak inward current density from layer 1 to layer 2/3 indicated that two processes underlie an initial depolarization followed by oscillatory activity. Laminar transections localized oscillation-generating circuitry to superficial cortical layers and sharp-spike-generating circuitry to deep cortical layers. Whole cell recordings identified three distinct cell types based on response properties during rhythmic micro-EEG activity: oscillation-on (theta-on) and -off (theta-off) neurons, and transiently depolarizing glial cells. Theta-on neurons displayed membrane potential oscillations that increased in amplitude with hyperpolarization (from −30 to −90 mV). This, taken together with a glutamate antagonist-induced depression of rhythmic micro-EEG activity, indicated that cholinergically driven neocortical oscillations require excitatory synaptic transmission. We conclude that under the appropriate pharmacological conditions, neocortical brain slices were capable of producing localized theta frequency oscillations. Experiments examining oscillation physiology, pharmacology, and topography demonstrated that neocortical brain slice oscillations share many similarities with the in vivo and in vitro theta EEG activity recorded in other brain regions.

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Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2764831 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Senthilkumar Sivanesan ◽

Ravi Mundugaru ◽

Jayakumar Rajadas

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ketone Bodies ◽

Brain Regions ◽

Pentose Phosphate ◽

Lactate Shuttle ◽

Carboxy Terminal ◽

Brain Energy

Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer’s disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

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