Computational Modeling of Genetic Contributions to Excitability and Neural Coding in Layer V Pyramidal Cells: Applications to Schizophrenia Pathology

Mäki‐Marttunen, Tuomo; Devor, Anna; Phillips, William A.; Dale, Anders M.; Andreassen, Ole A.; Einevoll, Gaute T.

doi:10.3389/fncom.2019.00066

Cited by 10 publications

(11 citation statements)

References 125 publications

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“…Uhlhaas and Silverstein, 2005Silverstein, 2010Silverstein and Keane, 2011). Computational modeling of L5p cells has now related that to apical function and risk genes for schizophrenia by showing that many of them could affect context-sensitivity via their direct effects on apical function (Mäki-Marttunen, et al, 2019). A Bayesian interpretation of the positive symptoms of schizophrenia (Fletcher and Frith, 2009;Sterzer et al, 2018;Corlett et al, 2019) is highly compatible with the hypotheses presented here because it suggests that when internal information is used to drive cells in perceptual regions then that 'perceiving' is believing.…”

Section: Apical Drive and Hallucinationssupporting

confidence: 64%

Apical drive—A cellular mechanism of dreaming?

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Phillips

et al. 2020

Neuroscience & Biobehavioral Reviews

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Dreams are internally generated experiences that occur independently of current sensory input. Here we argue, based on cortical anatomy and function, that dream experiences are tightly related to the workings of a specific part of cortical pyramidal neurons, the apical integration zone (AIZ). The AIZ receives and processes contextual information from diverse sources and could constitute a major switch point for transitioning from externally to internally generated experiences such as dreams. We propose that during dreams the output of certain pyramidal neurons is mainly driven by input into the AIZ. We call this mode of functioning "apical drive". Our hypothesis is based on the evidence that the cholinergic and adrenergic arousal systems, which show different dynamics between waking, slow wave sleep, and rapid eye movement sleep, have specific effects on the AIZ. We suggest that apical drive may also contribute to waking experiences, such as mental imagery. Future studies, investigating the different modes of apical function and their regulation during sleep and wakefulness are likely to be richly rewarded.

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Section: Apical Drive and Hallucinationssupporting

confidence: 64%

Apical drive—A cellular mechanism of dreaming?

Aru

Siclari

Phillips

et al. 2020

Neuroscience & Biobehavioral Reviews

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“…For in-depth discussion of impaired context-sensitivity in schizophrenia see [86]. For detailed compartmental modelling of ion channels by which risk genes for schizophrenia could impair apical function see [87].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Bayesian modeling of BAC firing as a mechanism for apical amplification in neocortical pyramidal neurons

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Phillips

Aru

et al. 2019

Preprint

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Pyramidal cells in layer 5 of the neocortex have two distinct integration sites. These cells integrate inputs to basal dendrites in the soma while integrating inputs to the tuft in a site at the top of the apical trunk. The two sites communicate by action potentials that backpropagate to the apical site and by backpropagation-activated calcium spikes (BAC firing) that travel from the apical to the somatic site. Six key messages arise from the probabilistic information-theoretic analyses of BAC firing presented here. First, we suggest that pyramidal neurons with BAC firing could convert the odds in favour of the presence of a feature given the basal data into the odds in favour of the presence of a feature given the basal data and the apical input, by a simple Bayesian calculation. Second, the strength of the cell's response to basal input can be amplified when relevant to the current context, as specified by the apical input, without corrupting the message that it sends. Third, these analyses show rigorously how this apical amplification depends upon communication between the sites. Fourth, we use data on action potentials from a very detailed multi-compartmental biophysical model to study our general model in a more realistic setting, and demonstrate that it describes the data well. Fifth, this form of BAC firing meets criteria for distinguishing modulatory from driving interactions that have been specified using recent definitions of multivariate mutual information. Sixth, our general decomposition can be extended to cases where, instead of being purely driving or purely amplifying, apical and basal inputs can be partly driving and partly amplifying to various extents. These conclusions imply that an advance beyond the assumption of a single site of integration within pyramidal cells is needed, and suggest that the evolutionary success of neocortex may depend upon the cellular mechanisms of context-sensitive selective amplification hypothesized here. Author summaryThe cerebral cortex has a key role in conscious perception, thought, and action, and is predominantly composed of a particular kind of neuron: the pyramidal cells. The distinct shape of the pyramidal neuron with a long dendritic shaft separating two regions of profuse dendrites allows them to integrate inputs to the two regions separately and combine the results non-linearly to produce output. Here we show how inputs to this more distant site strengthen the cell's output 1 when it is relevant to the current task and environment. By showing that such neurons have capabilities that transcend those of neurons with the single site of integration assumed by many neuroscientists, this 'splitting of the neuronal atom' offers a radically new viewpoint from which to understand the evolution of the cortex and some of its many pathologies. This also suggests that approaches to artificial intelligence using neural networks might come closer to something analogous to real intelligence, if, instead of basing them on processing elements with a single site of integra...

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“…S2). The relatively small effects of blockade of HVA Ca 2+ channels and SK channels was surprising in light of our previous computational studies highlighting the role of these channels in shaping L5PC activity [Mäki-Marttunen et al, 2017, Mäki-Marttunen et al, 2019.…”

Section: Activation Of I H Increases L5pc Activity When Stimulated At...mentioning

confidence: 95%

Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells

Mäki‐Marttunen

Mäki-Marttunen

2022

Preprint

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Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation by dopamine (gain of Ih function) and acetylcholine (loss of Ih function). We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal apical dendrite and Ih-inhibiting modulation at the distal apical dendrite can increase the layer V pyramidal excitability more than any of the two neuromodulators alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.

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Computational Modeling of Genetic Contributions to Excitability and Neural Coding in Layer V Pyramidal Cells: Applications to Schizophrenia Pathology

Cited by 10 publications

References 125 publications

Apical drive—A cellular mechanism of dreaming?

Apical drive—A cellular mechanism of dreaming?

Bayesian modeling of BAC firing as a mechanism for apical amplification in neocortical pyramidal neurons

Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells

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