| | Models | Description |
| 1. |
A mathematical model of a neurovascular unit (Dormanns et al 2015, 2016) (Farrs & David 2011)
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Here a lumped parameter numerical model of a neurovascular unit is presented, representing an intercellular communication system based on ion exchange through pumps and channels between neurons, astrocytes, smooth muscle cells, endothelial cells, and the spaces between these cells: the synaptic cleft between the neuron and astrocyte, the perivascular space between the astrocyte and SMC, and the extracellular space surrounding the cells.
The model contains various cellular and chemical pathways such as potassium, astrocytic calcium, and nitric oxide.
The model is able to simulate neurovascular coupling, the process characterised by an increase in neuronal activity followed by a rapid dilation of local blood vessels and hence increased blood supply providing oxygen and glucose to cells in need. |
| 2. |
Ave. neuron model for slow-wave sleep in cortex Tatsuki 2016 Yoshida 2018 Rasmussen 2017 (all et al)
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Averaged neuron(AN) model is a conductance-based (Hodgkin-Huxley type) neuron model which includes a mean-field approximation of a population of neurons. You can simulate previous models (AN model: Tatsuki et al., 2016 and SAN model: Yoshida et al., 2018), and various models with 'X model' based on channel and parameter modules. Also, intracellular and extracellular ion concentration can be taken into consideration using the Nernst equation (See Ramussen et al., 2017). |
| 3. |
Cerebellum granule cell FHF (Dover et al. 2016)
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"Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell's unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Nav)-associated fibroblast growth factor homologous factor (FHF) proteins to delay Nav inactivation, distal axonal Navs show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. ...' |
| 4. |
Computer models of corticospinal neurons replicate in vitro dynamics (Neymotin et al. 2017)
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"Corticospinal neurons (SPI), thick-tufted pyramidal neurons in motor
cortex layer 5B that project caudally via the medullary pyramids,
display distinct class-specific electrophysiological properties in
vitro: strong sag with hyperpolarization, lack of adaptation, and a
nearly linear frequency-current (FI) relationship. We used our
electrophysiological data to produce a pair of large archives of SPI
neuron computer models in two model classes: 1. Detailed models with
full reconstruction; 2. Simplified models with 6 compartments. We
used a PRAXIS and an evolutionary multiobjective optimization (EMO) in
sequence to determine ion channel conductances.
..." |
| 5. |
DCN fusiform cell (Ceballos et al. 2016)
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Dorsal cochlear nucleus principal neurons, fusiform neurons, display heterogeneous spontaneous action potential activity and thus represent an appropriate model to study the role of different conductances in establishing firing heterogeneity. Particularly, fusiform neurons are divided into quiet, with no spontaneous firing, or active neurons, presenting spontaneous, regular firing. These modes are determined by the expression levels of an intrinsic membrane conductance, an inwardly rectifying potassium current (IKir). We used a computational model to test whether other subthreshold conductances vary homeostatically to maintain membrane excitability constant across the two subtypes. We found that Ih expression covaries specifically with IKir in order to maintain membrane resistance constant. The impact of Ih on membrane resistance is dependent on the level of IKir expression, being much smaller in quiet neurons with bigger IKir, but Ih variations are not relevant for creating the quiet and active phenotypes. We conclude that in fusiform neurons the variations of their different subthreshold conductances are limited to specific conductances in order to create firing heterogeneity and maintain membrane homeostasis. |
| 6. |
Dentate gyrus network model pattern separation and granule cell scaling in epilepsy (Yim et al 2015)
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The dentate gyrus (DG) is thought to enable efficient hippocampal memory acquisition via pattern separation. With patterns defined as spatiotemporally distributed action potential sequences, the principal DG output neurons (granule cells, GCs), presumably sparsen and separate similar input patterns from the perforant path (PP). In electrophysiological experiments, we have demonstrated that during temporal lobe epilepsy (TLE), GCs downscale their excitability by transcriptional upregulation of ‘leak’ channels. Here we studied whether this cell type-specific intrinsic plasticity is in a position to homeostatically adjust DG network function. We modified an established conductance-based computer model of the DG network such that it realizes a spatiotemporal pattern separation task, and quantified its performance with and without the experimentally constrained leaky GC phenotype. ... |
| 7. |
Disentangling astroglial physiology with a realistic cell model in silico (Savtchenko et al 2018)
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"Electrically non-excitable astroglia take up neurotransmitters, buffer extracellular K+ and generate Ca2+ signals that release molecular regulators of neural circuitry. The underlying machinery remains enigmatic, mainly because the sponge-like astrocyte morphology has been difficult to access experimentally or explore theoretically. Here, we systematically incorporate multi-scale, tri-dimensional astroglial architecture into a realistic multi-compartmental cell model, which we constrain by empirical tests and integrate into the NEURON computational biophysical environment. This approach is implemented as a flexible astrocyte-model builder ASTRO. As a proof-of-concept, we explore an in silico astrocyte to evaluate basic cell physiology features inaccessible experimentally. ..." |
| 8. |
Effects of Dopamine Modulation and KIR Inactivation in NAc Medium Spiny Neurons (Steephen 2011)
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Due to the involvement of nucleus accumbens (NAc) medium spiny neurons (MSNs) in diverse behaviors, their excitability changes can have broad functional significance. Dopamine modulates the biophysical behavior of MSNs. In ~40% of MSNs, inward rectifying potassium (KIR) currents inactivate significantly, imparting greater excitability. Employing a 189-compartment computational model of the MSN and using spatiotemporally distributed synaptic inputs, the regulation of excitability by KIR inactivation and dopaminergic modulation was investigated and quantitatively characterized. It was shown that by forming different combinations, these regulating agents could fine tune MSN excitability across a wide range. With existing evidence indicating MSNs with and without KIR inactivation to be the likely targets for D2- and D1-receptor mediated modulations, respectively, the present findings suggest that dopaminergic channel modulation may intensify the existing excitability difference between them by suppressing the excitability of MSNs without KIR inactivation while further enhancing the excitability of the more excitable MSNs with KIR inactivation. On the other hand, the combined modulation of channels and synapses by dopamine may reverse the relative excitability of one cell type with respect to the other.
This model contains a complete biophysical model of MSN cell. The application allows the user to vary the cell properties by choosing the type of KIR channels included (inKIR or non-inKIR), the type of Dopamine receptors (D1R or D2R) and the modulation mechanism (Intrinsic modulation , Intrinsic-synaptic modulation, or No modulation). The user can also choose between the single pulse current clamp stimulation or a physiologically realistic synaptic stimulation scheme. More details are available in the Help provided with the application. |
| 9. |
Levodopa-Induced Toxicity in Parkinson's Disease (Muddapu et al, 2022)
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"... We present a systems-level computational model of SNc-striatum, which will help us understand the mechanism behind neurodegeneration postulated above and provide insights into developing disease-modifying therapeutics. It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During L-DOPA therapy, it was observed that higher L-DOPA dosage results in increased loss of terminals in SNc. It was also observed that co-administration of L-DOPA and glutathione (antioxidant) evades L-DOPA-induced toxicity in SNc neurons. Our proposed model of the SNc-striatum system is the first of its kind, where SNc neurons were modeled at a biophysical level, and striatal neurons were modeled at a spiking level. We show that our proposed model was able to capture L-DOPA-induced toxicity in SNc, caused by energy deficiency." |
| 10. |
Modelling platform of the cochlear nucleus and other auditory circuits (Manis & Compagnola 2018)
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"Models of the auditory brainstem have been an invaluable tool for testing hypotheses about auditory information processing and for highlighting the most important gaps in the experimental literature. Due to the complexity of the auditory brainstem, and indeed most brain circuits, the dynamic behavior of the system may be difficult to predict without a detailed, biologically realistic computational model. Despite the sensitivity of models to their exact construction and parameters, most prior models of the cochlear nucleus have incorporated only a small subset of the known biological properties. This confounds the interpretation of modelling results and also limits the potential future uses of these models, which require a large effort to develop. To address these issues, we have developed a general purpose, bio-physically detailed model of the cochlear nucleus for use both in testing hypotheses about cochlear nucleus function and also as an input to models of downstream auditory nuclei. The model implements conductance-based Hodgkin-Huxley representations of cells using a Python-based interface to the NEURON simulator. ..." |
| 11. |
NMDAR & GABAB/KIR Give Bistable Dendrites: Working Memory & Sequence Readout (Sanders et al., 2013)
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" ...Here, we show that the voltage dependence of the inwardly rectifying potassium (KIR) conductance activated by GABA(B) receptors adds substantial robustness to network simulations of bistability and the persistent firing that it underlies. The hyperpolarized state is robust because, at hyperpolarized potentials, the GABA(B)/KIR conductance is high and the NMDA conductance is low; the depolarized state is robust because, at depolarized potentials, the NMDA conductance is high and the GABA(B)/KIR conductance is low. Our results suggest that this complementary voltage dependence of GABA(B)/KIR and NMDA conductances makes them a "perfect couple" for producing voltage bistability." |
| 12. |
Pleiotropic effects of SCZ-associated genes (Mäki-Marttunen et al. 2017)
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Python and MATLAB scripts for studying the dual effects of SCZ-related genes on layer 5 pyramidal cell firing and sinoatrial node cell pacemaking properties. The study is based on two L5PC models (Hay et al. 2011, Almog & Korngreen 2014) and SANC models (Kharche et al. 2011, Severi et al. 2012). |
| 13. |
Single-cell comprehensive biophysical model of SN pars compacta (Muddapu & Chakravarthy 2021)
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Parkinson’s disease (PD) is caused by the loss of dopaminergic cells in substantia nigra pars compacta (SNc), the decisive cause of this inexorable cell loss is not clearly elucidated. We hypothesize that “Energy deficiency at a sub-cellular/cellular/systems-level can be a common underlying cause for SNc cell loss in PD.” Here, we propose a comprehensive computational model of SNc cell which helps us to understand the pathophysiology of neurodegeneration at subcellular-level in PD. We were able to show see how deficits in supply of energy substrates (glucose and oxygen) lead to a deficit in ATP, and furthermore, deficits in ATP are the common factor underlying the pathological molecular-level changes including alpha-synuclein aggregation, ROS formation, calcium elevation, and dopamine dysfunction. The model also suggests that hypoglycemia plays a more crucial role in leading to ATP deficits than hypoxia. We believe that the proposed model provides an integrated modelling framework to understand the neurodegenerative processes underlying PD. |
| 14. |
Specific inhibition of dendritic plateau potential in striatal projection neurons (Du et al 2017)
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We explored dendritic plateau potentials in a biophysically detailed SPN model. We coupled the dendritic plateaus to different types of inhibitions (dendritic fast and slow inhibitions, perisomatic inhibition from FS interneurons , etc.) We found the inhibition provides precise control over the plateau potential, and thus the spiking output of SPNs. |
| 15. |
Spiny Projection Neuron Ca2+ based plasticity is robust to in vivo spike train (Dorman&Blackwell)
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"...we address the sensitivity of plasticity to trial-to-trial variability and delineate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a calcium-based plasticity rule. Using in vivo spike train recordings as inputs, we show that plasticity is strongly robust to trial-to-trial variability of spike timing, and derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity..." |
| 16. |
Striatal D1R medium spiny neuron, including a subcellular DA cascade (Lindroos et al 2018)
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We are investigating how dopaminergic modulation of single channels can be combined to make the D1R possitive MSN more excitable. We also connect multiple channels to substrates of a dopamine induced subcellular cascade to highlight that the classical pathway is too slow to explain DA induced kinetics in the subsecond range (Howe and Dombeck, 2016. doi: 10.1038/nature18942) |
| 17. |
Striatal NN model of MSNs and FSIs investigated effects of dopamine depletion (Damodaran et al 2015)
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This study investigates the mechanisms that are affected in the striatal network after dopamine depletion and identifies potential therapeutic targets to restore normal activity. |
| 18. |
Striatal Spiny Projection Neuron, inhibition enhances spatial specificity (Dorman et al 2018)
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We use a computational model of a striatal spiny projection neuron to investigate dendritic spine calcium dynamics in response to spatiotemporal patterns of synaptic inputs. We show that spine calcium elevation is stimulus-specific, with supralinear calcium elevation in cooperatively stimulated spines. Intermediate calcium elevation occurs in neighboring non-stimulated dendritic spines, predicting heterosynaptic effects. Inhibitory synaptic inputs enhance the difference between peak calcium in stimulated spines, and peak calcium in non-stimulated spines, thereby enhancing stimulus specificity. |
| 19. |
Striatum D1 Striosome and Matrix Upstates (Prager et al., 2020)
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"...We show that dopamine oppositely shapes responses to convergent excitatory inputs in mouse striosome and matrix striatal spiny projection neurons (SPNs). Activation of postsynaptic D1 dopamine receptors promoted the generation of long-lasting synaptically evoked 'up-states' in matrix SPNs but opposed it in striosomes, which were more excitable under basal conditions. Differences in dopaminergic modulation were mediated, in part, by dendritic voltage-gated calcium channels (VGCCs): pharmacological manipulation of L-type VGCCs reversed compartment-specific responses to D1 receptor activation..." |
| 20. |
The electrodiffusive neuron-extracellular-glia (edNEG) model (Sætra et al. 2021)
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"... We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine compartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for action potentials and dendritic calcium spikes in neurons, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. The edNEG model accounts for the concentration-dependent effects on ECS potentials that the standard models neglect. Using the edNEG model, we analyze these effects by splitting the extracellular potential into three components: one due to neural sink/source configurations, one due to glial sink/source configurations, and one due to extracellular diffusive currents ..." |
| 21. |
The microcircuits of striatum in silico (Hjorth et al 2020)
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"Our aim is to reconstruct a full-scale mouse striatal cellular level model to provide a framework to integrate and interpret striatal data. We represent the main striatal neuronal subtypes, the two types of projection neurons (dSPNs and iSPNs) giving rise to the direct and indirect pathways, the fast-spiking interneurons, the low threshold spiking interneurons, and the cholinergic interneurons as detailed compartmental models, with properties close to their biological counterparts. Both intrastriatal and afferent synaptic inputs (cortex, thalamus, dopamine system) are optimized against existing data, including short-term plasticity. This model platform will be used to generate new hypotheses on striatal function or network dynamic phenomena." |
