Ultrafast simulation of large-scale neocortical microcircuitry with biophysically realistic neurons

eLife, Год журнала: 2022, Номер 11

Опубликована: Ноя. 7, 2022

Understanding the activity of mammalian brain requires an integrative knowledge circuits at distinct scales, ranging from ion channel gating to circuit connectomics. Computational models are regularly employed understand how multiple parameters contribute synergistically behavior. However, traditional anatomically and biophysically realistic neurons computationally demanding, especially when scaled model local circuits. To overcome this limitation, we trained several artificial neural network (ANN) architectures multicompartmental cortical neurons. We identified ANN architecture that accurately predicted subthreshold action potential firing. The could correctly generalize previously unobserved synaptic input, including in containing nonlinear dendritic properties. When scaled, processing times were orders magnitude faster compared with approaches, allowing for rapid parameter-space mapping a Rett syndrome. Thus, present novel approach rapid, detailed experiments using inexpensive commonly available computational resources.

Язык: Английский

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SynCAM1 deficiency in the hippocampal parvalbumin interneurons contributes to sevoflurane‐induced cognitive impairment in neonatal rats

CNS Neuroscience & Therapeutics, Год журнала: 2023, Номер 30(1)

Опубликована: Дек. 17, 2023

Sevoflurane is widely used for general anesthesia in children. Previous studies reported that multiple neonatal exposures to sevoflurane can induce long-term cognitive impairment adolescent rats, but the underlying mechanisms were not defined.

Язык: Английский

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Modelling the contributions to hyperexcitability in a mouse model of Alzheimer's disease

The Journal of Physiology, Год журнала: 2023, Номер 601(15), С. 3403 - 3437

Опубликована: Фев. 3, 2023

Neuronal hyperexcitability is a pathological characteristic of Alzheimer's disease (AD). Three main mechanisms have been proposed to explain it: (i) dendritic degeneration leading increased input resistance, (ii) ion channel changes enhanced intrinsic excitability, and (iii) synaptic excitation-inhibition (E/I) imbalance. However, the relative contribution these not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling neuronal excitability in reconstructed CA1 pyramidal neurons from wild-type APP/PS1 mice, well-established animal model AD. We show that, for activation, excitability-promoting effects are cancelled out by decreased excitation due loss. find an interesting balance between regulation basal dendrites cells, potentially apical but Schaffer collateral pathway. Furthermore, our simulations reveal three pathomechanistic scenarios that can account experimentally observed increase firing bursting mice: scenario 1: E/I ratio; 2: alteration channels (IAHP down-regulated; INap , INa ICaT up-regulated) addition 3: excitatory burst input. Our work supports hypothesis network major contributors Overall, results line with concept multi-causality according which multiple different disruptions separately sufficient no single particular disruption necessary hyperexcitability. KEY POINTS: This presents synaptically driven responses cells (PCs) (AD)-related degeneration. Dendritic alone alters PC layer-specific additional required AD as follows. Possible AD-related together inhibitory (E/I imbalance) lead PCs. combined altered properties hyperactivity surrounding PCs during

Язык: Английский

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Native-state proteomics of Parvalbumin interneurons identifies novel molecular signatures and metabolic vulnerabilities to early Alzheimer’s disease pathology

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Май 17, 2023

SUMMARY One of the earliest pathophysiological perturbations in Alzheimer’s Disease (AD) may arise from dysfunction fast-spiking parvalbumin (PV) interneurons (PV-INs). Defining early protein-level (proteomic) alterations PV-INs can provide key biological and translationally relevant insights. Here, we use cell-type-specific vivo biotinylation proteins (CIBOP) coupled with mass spectrometry to obtain native-state proteomes PV interneurons. exhibited proteomic signatures high metabolic, mitochondrial, translational activity, over-representation causally linked AD genetic risk factors. Analyses bulk brain indicated strong correlations between PV-IN cognitive decline humans, progressive neuropathology humans mouse models Aβ pathology. Furthermore, PV-IN-specific revealed unique increased mitochondrial metabolic proteins, but decreased synaptic mTOR signaling response PV-specific changes were not apparent whole-brain proteomes. These findings showcase first native state mammalian brain, revealing a molecular basis for their vulnerabilities AD.

Язык: Английский

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An enhancer-AAV approach selectively targeting dentate granule cells of the mouse hippocampus

Cell Reports Methods, Год журнала: 2024, Номер 4(1), С. 100684 - 100684

Опубликована: Янв. 1, 2024

The mammalian brain contains a diverse array of cell types, including dozens neuronal subtypes with distinct anatomical and functional characteristics. leverages these neuron-type specializations to perform circuit operations thus execute different behaviors properly. Through the use Cre lines, access specific neuron types has improved over past decades. Despite their extraordinary utility, development cross-breeding lines is time consuming expensive, presenting significant barrier entry for investigators. Furthermore, cell-based therapeutics developed in mice are not clinically translatable. Recently, several adeno-associated virus (AAV) vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer-AAVs) were that overcome limitations. Using publicly available RNA sequencing (RNA-seq) dataset, we evaluated potential candidate enhancers targeting hippocampus. Here, demonstrate previously identified enhancer-AAV selectively targets dentate granule cells other excitatory hippocampus wild-type adult mice.

Язык: Английский

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Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 122(1)

Опубликована: Дек. 31, 2024

Use-dependent spike broadening (UDSB) results from inactivation of the voltage-gated K + (Kv) channels that regulate repolarization action potential. However, specific signaling and molecular processes modulate UDSB have remained elusive. Here, we applied an adeno-associated viral vector approach dynamic clamping to conclusively demonstrate how multisite phosphorylation N-terminal domain (NTID) Kv3.4 channel modulates in rat dorsal root ganglion (DRG) neurons. The phosphonull variant promotes slow recovery inactivation, cumulative UDSB. In contrast, phosphomimic fast robust resistance Furthermore, knocking down maximizes AP width eliminates modulation. Together with evidence previous work, concretely suggest modulation governed by NTID DRG neurons may play a significant role mechanosensory transduction pain

Язык: Английский

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Altered firing output of VIP interneurons and early dysfunctions in CA1 hippocampal circuits in the 3xTg mouse model of Alzheimer’s disease

Опубликована: Апрель 8, 2024

Alzheimer’s disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed human animal studies. GABAergic interneurons (INs) within hippocampus coordinate network activity, which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide calretinin play a crucial role. These provide primarily disinhibition principal excitatory (PCs) CA1 region, regulating incoming inputs formation. However, it remains unclear whether AD pathology induces changes activity of I-S3 cells, impacting motifs. Here, using young adult 3xTg-AD mice, we found that while density morphology IS-3 remain unaffected, there were significant their firing output. Specifically, displayed elongated action potentials decreased rates, was associated with reduced inhibition INs higher recruitment during spatial decision-making object exploration tasks. Furthermore, activation PCs also impacted, signifying early disruptions functionality. findings suggest altered patterns might initiate early-stage dysfunction circuits, potentially influencing progression pathology.

Язык: Английский

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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 6, 2023

Abstract Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in remain unknown. In human patients with Disease, one the earliest observed pathophysiological correlates to cognitive decline hyperexcitability. mouse models, hyperexcitability has been shown entorhinal cortex, first cortical region impacted by Disease. The origin early-stage disease why it preferentially emerges specific regions unclear. Using cortical-region cell-type-specific proteomics coupled ex vivo electrophysiology, we uncovered differential susceptibility human-specific amyloid precursor protein (hAPP) a model sporadic Alzheimer’s. Unexpectedly, our findings reveal that may result from intrinsic parvalbumin (PV) interneurons, rather than suspected layer II excitatory neurons. This PV interneurons hAPP, as could not be recapitulated increased murine APP expression. However, partial replication seen after introduction chimera containing humanized amyloid-beta sequence. Surprisingly, neurons Somatosensory Cortex showed no such adult-onset hAPP hAPP-induced cortex ameliorated enhancing interneuron excitability vivo. Co-expression Tau decreased circuit hyperexcitability, but at expense pathological tau species. study suggests interventions targeting non-excitatory cell types protect symptoms downstream decline.

Язык: Английский

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Altered firing output of VIP interneurons and early dysfunctions in CA1 hippocampal circuits in the 3xTg mouse model of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 13, 2024

Abstract Alzheimer’s disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed human animal studies. GABAergic interneurons (INs) within hippocampus coordinate network activity, which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide calretinin play a crucial role. These provide primarily disinhibition principal excitatory (PCs) CA1 region, regulating incoming inputs formation. However, it remains unclear whether AD pathology induces changes activity of I-S3 cells, impacting motifs. Here, using young adult 3xTg-AD mice, we found that while density morphology remain unaffected, there were significant their firing output. Specifically, displayed elongated action potentials decreased rates, was associated with reduced inhibition INs higher recruitment during spatial decision-making object exploration tasks. Furthermore, activation PCs also impacted, signifying early disruptions functionality. findings suggest altered patterns might initiate early-stage dysfunction circuits, potentially influencing progression pathology. Significance This study examines VIP affected by While these maintain structural integrity, they exhibit mice. correlate enhanced impact cells. shed light on circuits as potential mechanism offer insights into prospective therapeutic targets.

Язык: Английский

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Altered firing output of VIP interneurons and early dysfunctions in CA1 hippocampal circuits in the 3xTg mouse model of Alzheimer’s disease

Опубликована: Авг. 23, 2024

Alzheimer’s disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed human animal studies. GABAergic interneurons (INs) within hippocampus coordinate network activity, which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide calretinin play a crucial role. These provide primarily disinhibition principal excitatory (PCs) CA1 region, regulating incoming inputs formation. However, it remains unclear whether AD pathology induces changes activity of I-S3 cells, impacting motifs. Here, using young adult 3xTg-AD mice, we found that while density morphology remain unaffected, there were significant their firing output. Specifically, displayed elongated action potentials decreased rates, was associated with reduced inhibition INs higher recruitment during spatial decision-making object exploration tasks. Furthermore, activation PCs also impacted, signifying early disruptions functionality. findings suggest altered patterns might initiate early-stage dysfunction circuits, potentially influencing progression pathology.

Язык: Английский

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