Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences

Chameh, Homeira Moradi; Rich, Scott; Wang, Lihua; Chen, Fu-Der; Zhang, Liang; Carlen, Peter L.; Tripathy, Shreejoy J.; Valiante, Taufik A.

doi:10.1101/748988

Cited by 19 publications

(89 citation statements)

References 68 publications

(178 reference statements)

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“…This process yields a full spiking, biophysically detailed, multi-compartment model of a distinctly human L5 cortical pyramidal cell. The resulting model matches the electrophysiological data from hyperpolarizing current clamp experiments in the primary cell remarkably well, while also demonstrating repetitive PIR spiking properties characteristic of human L5 pyramidal cells from Chameh et al (2019). Further, our model makes possible a comparison of these neurons in the human and rodent setting, revealing important differences in both the conductance and kinetics of the h-current across species.…”

Section: Introductionsupporting

confidence: 62%

“…Recently it has been shown that increased expression of h-channels contribute to the observed subthreshold resonance in supragranular layer human pyramidal cells not seen in their rodent counterparts (Kalmbach et al, 2018). Such differential expression of h-channels also appears to be present between superficial and deep layer neurons of human cortex, with layer 5 (L5) pyramidal cells demonstrating a larger sag mediated by h-channels when compared to those in layer 2/3 (L2/3) (Chameh et al, 2019). However, despite the presence of large sag currents in human L5 pyramidal cells, they very rarely exhibit subthreshold resonance (Chameh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Such differential expression of h-channels also appears to be present between superficial and deep layer neurons of human cortex, with layer 5 (L5) pyramidal cells demonstrating a larger sag mediated by h-channels when compared to those in layer 2/3 (L2/3) (Chameh et al, 2019). However, despite the presence of large sag currents in human L5 pyramidal cells, they very rarely exhibit subthreshold resonance (Chameh et al, 2019). This result is surprising considering recent human work in L2/3 (Kalmbach et al, 2018), as well as findings that rodent L5 pyramidal cells commonly exhibit subthreshold resonance (Silva et al, 1991; Ulrich, 2002; Dembrow et al, 2010; Schmidt et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Concerted efforts to understand these relationships are the subject of ongoing theoretical research (Rotstein and Nadim, 2014; Rotstein, 2014). Toward this end, untangling the relationship between the h-current and subthreshold resonance is crucial, especially considering the unexpected results reported by Chameh et al (2019). Unfortunately, while the experimental literature (Kalmbach et al, 2018; Chameh et al, 2019) has revealed that differences in the capacity for subthreshold resonance exist between human and rodent neurons, the reason(s) why these differences arise remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…As these recordings were obtained in the presence of a voltage-gated sodium channel blocker, spiking was not present in this data set. Correspondingly, we analyzed post-inhibitory rebound (PIR) spiking and repetitive firing characteristics from another set of human L5 neurons (Chameh et al, 2019) to impart constraints on the model’s spiking characteristics. A particular emphasis is placed on ensuring our model neuron exhibits reasonable PIR spiking behavior, a dynamic which is shown by Chameh et al (2019) to be reliant upon h-channels in human L5 neurons.…”

Section: Introductionmentioning

confidence: 99%

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Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

Rich

Moradi-Chameh

Sekulić

et al. 2020

Preprint

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15Most existing multi-compartment, mammalian neuron models are built from rodent data. However, 16 our increasing knowledge of differences between human and rodent neurons suggests that, to 17 understand the cellular basis of human brain function, we should build models from human data. 18 Here, we present the first full spiking, multi-compartment model of a human layer 5 cortical 19 pyramidal neuron. Model development balanced prioritizing current clamp data from the neuron 20 providing the model's morphology, while also ensuring the model's generalizability via preservation 21 of spiking properties observed in a secondary population of neurons, by "cycling" between these 22 data sets. The model was successfully validated against electrophysiological data not used in 23 model development, including experimentally observed subthreshold resonance characteristics. 24 Our model highlights kinetic differences in the h-current across species, with the unique 25 relationship between the model and experimental data allowing for a detailed investigation of the 26 relationship between the h-current and subthreshold resonance. 27 28 30 (Womelsdorf et al., 2014) within the six-layered neocortex stems from invasive and in vitro studies 31 in rodents and non-human primates. Whether or not such principles can be extended to human 32 neocortex remains speculative at best. Despite the significant transcriptomic convergence of 33 human and mouse neurons (Hodge et al., 2019), significant differences between human and rodent 34 cell-type properties exist. In vitro studies have identified differences between mouse and human 35 neurons in morphology (Mohan et al., 2015), dendritic integration (Beaulieu-Laroche et al., 2018; 36 Eyal et al., 2016), synaptic properties (Verhoog et al., 2013), and collective dynamics (McGinn and 37 Valiante, 2014; Molnár et al., 2008; Florez et al., 2013). However, less explored are the active 38 1 of 36 Manuscript submitted to eLife membrane properties of human cortical neurons, which together with their passive and synaptic 39 properties underlie oscillations which are of likely physiological relevance (Akam and Kullmann, 40 2014; Womelsdorf et al., 2014; Fries, 2005; Anastassiou et al., 2011; Hanslmayr et al., 2019; Vaz 41 et al., 2019). 42 Recently it has been shown that increased expression of hyperpolarization activated cation chan-43 nels (h-channels) contribute to the observed subthreshold resonance in supragranular layer human 44 pyramidal cells not seen in their rodent counterparts (Kalmbach et al., 2018). Such differential 45 expression of h-channels also appears to be present between superficial and deep layer neurons 46 of human cortex, with layer 5 (L5) pyramidal cells demonstrating a larger sag voltage mediated 47 65 et al., 2013; Beaulieu-Laroche et al., 2018) leads to two important questions for computational 66neuroscientists: in what settings is it appropriate to utilize rodent neuron models to glean insights 67 into the human brain, and when such approximations are u...

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Section: Introductionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

Rich

Moradi-Chameh

Sekulić

et al. 2020

Preprint

Self Cite

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Human neocortical expansion involves glutamatergic neuron diversification

Berg

Sorensen

Ting

et al. 2021

Nature

226

197

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The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease.

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Modeling Reveals Human–Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons

et al. 2020

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While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.

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Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences

Cited by 19 publications

References 68 publications

Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

Human neocortical expansion involves glutamatergic neuron diversification

Modeling Reveals Human–Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons

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