Biology subjects

Guet-McCreight, A.

Publications and source records attributed to Guet-McCreight, A..

13 recordsLinked to original sources

bioRxiv2026

Preserving spiking and EEG in detailed models of human cortical microcircuits with morphological reductions

Biophysically detailed models of human cortical microcircuit provide key insights into brain function and disease biomarkers, yet their computational cost lengthens simulation runtime and limits scalability. To address this, we systematically evaluated recent simplification methods for morphological reduction and synapse merging in terms of preserving spiking and electroencephalographic (EEG) properties of human cortical microcircuit models. At the single- cell level, reduced compartmental models accurately reproduced spiking behaviors. However, at the microcircuit level, while achieving a 5-fold speed-up, morphological reduction failed to preserve spectral dynamics of spiking and EEG despite maintaining average baseline and response firing rates. Conversely, applying synapse merging alone on the full morphology successfully reproduced both spiking activity and EEG dynamics, when constrained to [≤] 50 m spatial intervals, and yielded a 2-fold speed-up. These results were consistent across both cortical layer 2/3 and layer 5 models, and in depression models with reduced somatostatin interneuron inhibition. Our study identifies model simplification methods that speed up cortical microcircuit simulations while preserving the accuracy of the simulated brain signals.

neuroscience↗

bioRxiv2026

Median raphe input to dorsal CA1 shapes VIP interneuron recruitment and novelty-guided spatial memory

Vasoactive intestinal peptide-expressing interneurons (VIP-INs) gate hippocampal inhibition during novel experience, but the long-range signals that engage these cells remain poorly understood. Here we identify median raphe (MnR) projections as a brainstem pathway that tunes dorsal CA1 VIP-IN recruitment through coordinated glutamatergic and serotonergic mechanisms. Anatomical mapping and optogenetic recordings showed that MnR axons innervate multiple VIP-IN subtypes, while transcriptomic and pharmacological analyses revealed fast glutamatergic excitation together with serotonin receptor-dependent modulation of synaptic and intrinsic responsiveness. In vivo calcium imaging showed that novelty preferentially recruited a speed-coupled VIP-IN ensemble, and inhibition of MnR input selectively reduced the magnitude of this response. A hippocampal circuit model linked this pathway to dendritic disinhibition and place-cell recruitment. Behaviorally, inhibition of MnR input preserved exploratory engagement but disrupted the organization of spatial sampling and impaired object-location memory. Thus, MnR input organizes hippocampal disinhibition to support novelty-guided exploration and memory encoding.

neuroscience↗

bioRxiv2025

Linking age changes in human cortical microcircuits to impaired brain function and EEG biomarkers

Human brain aging involves a variety of cellular and synaptic changes, but how these changes affect brain function and signals remains poorly understood due to experimental limitations in humans, meriting the use of detailed computational models. We identified key human cellular and synaptic changes occurring with age from previous studies, including a loss of inhibitory cells, NMDA receptors, and spines. We integrated these changes into our detailed human cortical microcircuit models and simulated activity in middle-age ([~]50 yrs) and older ([~]70 yrs) microcircuits, and linked the altered mechanisms to reduced spike rates and impaired signal detection. We then simulated EEG potentials arising from the microcircuit activity and found that the emergent power spectral changes due to these aging cellular mechanisms reproduced most of the resting-state EEG biomarkers seen in human aging, including reduced aperiodic offset, exponent, and periodic peak center frequency. Using machine learning, we demonstrated that the changes to the cellular and synaptic aging mechanisms can be estimated accurately from the simulated EEG aging biomarkers. Our results link cellular and synaptic mechanisms of aging with impaired cortical function and physiological biomarkers in clinically-relevant brain signals.

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bioRxiv2024

Deriving connectivity from spiking activity in biophysical cortical microcircuits

Inferring detailed cortical microcircuit connectivity is essential for uncovering how information is processed in the brain. A common method in vivo uses short-lag spike cross-correlations to derive putative monosynaptic connections, but inactive neurons and correlated firing can hinder the derivation accuracy. Previous computational studies that developed methods to derive connectivity from cross-correlations employed simplified or small network models and thus did not address the above key confounds of physiological large-scale networks. We tested connectivity derivation using simulated ground-truth spiking from detailed models of human cortical microcircuits in different layers and between key neuron types. While derivation accuracy was high for cortical layer 5 microcircuits, we showed that low-firing and inactive neurons in layer 2/3 microcircuits resulted in poor performance. We then showed that general activation paradigms for layer 2/3 microcircuits led to only a moderate improvement in derivation performance, due to a trade-off between reducing the proportion of inactive neurons and increasing correlated overactive neurons. We further improved the connection derivation performance using a more refined activation paradigm leading to jittered moderate spiking, which decreased inactive neurons without incurring unwanted correlations. Our results address key physiological challenges and provide methods to improve performance in deriving connections from spiking activity in large-scale neuronal microcircuits.

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bioRxiv2024

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of 5-GABAA receptors (5-PAM) offers a promising effective treatment. However, testing the effect of 5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and 5-PAM effects, to simulate EEG of virtual subjects across depression severity and 5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for 5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of 5-PAM treatment to clinical use.

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bioRxiv2024

EEG biomarkers of GABA α5 positive allosteric modulators in rodents

Reduced cortical inhibition mediated by gamma-aminobutyric acid (GABA) is reported in depression, anxiety disorders, and aging. Novel positive allosteric modulator that specifically target 5-GABAA receptor subunit (5-PAM), ligand GL-II-73, shows anxiolytic, antidepressant, and pro-cognitive effects without the common side effects associated with non-specific modulation by benzodiazepines such as diazepam (DZP), thus suggesting novel therapeutic potential. However, it is unknown if 5-PAM has detectable signatures in clinically-relevant brain electroencephalography (EEG). We analyzed EEG in freely moving rats at baseline and following injections of 5-PAM and DZP. We showed that 5-PAM specifically decreased theta peak power whereas DZP shifted peak power from high to low theta, while increasing beta and gamma power. EEG decomposition showed that these effects were periodic and corresponded to changes in theta oscillation event duration. Our study thus shows that 5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable non-invasive monitoring of 5-PAM treatment efficacy.

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bioRxiv2023

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of 5 subunit-containing GABAA receptor (5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of 5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of 5-PAM on tonic inhibition as measured in human neurons, and tested in silico 5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that 5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an 5-PAM dose response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate 5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.

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bioRxiv2021

Age-dependent increased sag current in human pyramidal neurons dampens baseline cortical activity

Aging involves various neurobiological changes, although their effect on brain function in humans remains poorly understood. The growing availability of human neuronal and circuit data provides opportunities for uncovering age-dependent changes of brain networks and for constraining models to predict consequences on brain activity. Here we found increased sag voltage amplitude in human middle temporal gyrus layer 5 pyramidal neurons from older subjects, and captured this effect in biophysical models of younger and older pyramidal neurons. We used these models to simulate detailed layer 5 microcircuits and found lower baseline firing in older pyramidal neuron microcircuits, with minimal effect on response. We then validated the predicted reduced baseline firing using extracellular multi-electrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties and provide fundamental insights on the neuronal mechanisms of altered cortical excitability and resting state activity in human aging.

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bioRxiv2021

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

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bioRxiv2020

Deciphering how specialized interneuron-specific cell types contribute to circuit function

The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells - an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons - during simulated theta rhythms. We use previously developed multi-compartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs during in vitro and in vivo scenarios contribute to theta. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via post-inhibitory rebound mechanisms, and contribute to theta frequency spike resonance during simulated in vivo scenarios. To elicit recruitment similar to in vitro experiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Using in vivo virtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at theta frequencies. Further, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways. New & NoteworthyHow information is processed across different brain structures is an important question that relates to the different functions that the brain performs. Using modelling and theoretical analyses, we show that an inhibitory cell type that only inhibits other inhibitory cells can broaden the window for disinhibition of excitatory cells, manage input pathway switching, and modulate inhibitory cell spiking. This work contributes to knowledge of how coordination between sensory and memory consolidation information can be attained.

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bioRxiv2019

Somatodendritic HCN channels in hippocampal OLM cells revealed by a convergence of computational models and experiments

Determining details of spatially extended neurons is a challenge that needs to be overcome. The oriens-lacunosum/moleculare (OLM) interneuron has been implicated as a critical controller of hippocampal memory making it essential to understand how its biophysical properties contribute to function. We previously used computational models to show that OLM cells exhibit theta spiking resonance frequencies that depend on their dendrites having hyperpolarization-activated cation channels (h-channels). However, whether OLM cells have dendritic h-channels is unknown. We performed a set of whole-cell recordings of OLM cells from mouse hippocampus and constructed multi-compartment models using morphological and electrophysiological parameters extracted from the same cell. The models matched experiments only when dendritic h-channels were present. Immunohistochemical localization of the HCN2 subunit confirmed dendritic expression. These models can be used to obtain insight into hippocampal function. Our work shows that a tight integration of model and experiment tackles the challenge of characterizing spatially extended neurons.

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bioRxiv2018

Synaptic properties and network state-dependent recruitment of VIP-expressing interneuron-specific interneurons in the CA1 hippocampus

In the hippocampus, a highly specialized population of vasoactive intestinal peptide (VIP)-expressing interneuron-specific (IS) inhibitory cells provides local circuit disinhibition via preferential innervation of different types of GABAergic interneurons. While disinhibition can be critical in modulating network activity and different forms of hippocampal learning, the synaptic and integrative properties of IS cells and their recruitment during network oscillations remain unknown. Using a combination of patch-clamp recordings, photostimulation, computational modelling as well as recordings of network oscillations simultaneously with two-photon Ca2+-imaging in awake mice in vivo, we identified synaptic mechanisms that can control the firing of IS cells, and explored their impact on the cell recruitment during theta oscillations and sharp-wave-associated ripples. We found that IS cells fire spikes in response to both the Schaffer collateral and the temporoammonic pathway activation. Moreover, integrating their intrinsic and synaptic properties into computational models predicted recruitment of these cells during the rising to peak phases of theta oscillations and during ripples depending on inhibitory contributions. In vivo Ca2+-imaging in awake mice confirmed in part the theoretical predictions, revealing a significant speed modulation of IS cells and their preferential albeit delayed recruitment during theta-run epochs, with firing at the rising phase to peak of the theta cycle. However, it also uncovered that IS cells are not activated during ripples. Thus, given the preferential theta-modulated firing of IS cells in awake hippocampus, we postulate that these cells may be important for information gating during spatial navigation and memory encoding.

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bioRxiv2018

Weak and equally balanced synaptic inputs to interneurons in the CA1 hippocampus characterize in vivo rhythmic states

Brain coding strategies are enabled by the balance of synaptic inputs that individual neurons receive as determined by the networks in which they reside. Inhibitory cell types contribute to brain function in distinct ways but recording from specific, inhibitory cell types during behaviour to determine their contributions is difficult. In particular, the in vivo activities of vasoactive intestinal peptide-expressing interneuron specific 3 (IS3) cells in the hippocampus that only target other inhibitory cells are unknown at present. We perform a massive, computational exploration of possible synaptic inputs to IS3 cells using multi-compartment models and optimized synaptic parameters. We find that asynchronous in vivo-like states that are sensitive to additional theta-timed inputs exist when excitatory and inhibitory synaptic conductances are equally balanced and there are low amounts of correlated inputs. Thus, using a generally applicable computational approach we predict the existence of balanced states in hippocampal circuits during rhythmic activities.

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