Systematically organizing the anatomical, molecular, and physiological properties of cortical neurons is important for understanding their computational functions. Hippocampome.org defines 122 neuron types in the rodent hippocampal formation based on their somatic, axonal, and dendritic locations, putative excitatory/inhibitory outputs, molecular marker expression, and biophysical properties. We augmented the electrophysiological data of this knowledge base by collecting, quantifying, and analyzing the firing responses to depolarizing current injections for every hippocampal neuron type from published experiments. We designed and implemented objective protocols to classify firing patterns based on 5 transients (delay, adapting spiking, rapidly adapting spiking, transient stuttering, and transient slow-wave bursting) and 4 steady states (non-adapting spiking, persistent stuttering, persistent slow-wave bursting, and silence). This automated approach revealed 9 unique (plus one spurious) families of firing pattern phenotypes while distinguishing potential new neuronal subtypes. Novel statistical associations emerged between firing responses and other electrophysiological properties, morphological features, and molecular marker expression. The firing pattern parameters, experimental conditions, spike times, references to the original empirical evidences, and analysis scripts are released open-source through Hippocampome.org for all neuron types, greatly enhancing the existing search and browse capabilities. This information, collated online in human- and machine-accessible form, will help design and interpret both experiments and model simulations.
Systematic generation of biophysically detailed models with generalization capability for non-spiking neurons
Unlike spiking neurons which compress continuous inputs into digital signals for transmitting information via action potentials, non-spiking neurons modulate analog signals through graded potential responses. Such neurons have been found in a large variety of nervous tissues in both vertebrate and invertebrate species, and have been proven to play a central role in neuronal information processing. If general and vast efforts have been made for many years to model spiking neurons using conductance-based models (CBMs), very few methods have been developed for non-spiking neurons. When a CBM is built to characterize the neuron behavior, it should be endowed with generalization capabilities ( i.e . the ability to predict acceptable neuronal responses to different novel stimuli not used during the model’s building). Yet, since CBMs contain a large number of parameters, they may typically suffer from a lack of such a capability. In this paper, we propose a new systematic approach based on multi-objective optimization which builds general non-spiking models with generalization capabilities. The proposed approach only requires macroscopic experimental data from which all the model parameters are simultaneously determined without compromise. Such an approach is applied on three non-spiking neurons of the nematode Caenorhabditis elegans ( C. elegans ), a well-known model organism in neuroscience that predominantly transmits information through non-spiking signals. These three neurons, arbitrarily labeled by convention as RIM, AIY and AFD, represent, to date, the three possible forms of non-spiking neuronal responses of C. elegans .
more »
« less
- Award ID(s):
- 2113120
- NSF-PAR ID:
- 10337991
- Editor(s):
- Guo, Daqing
- Date Published:
- Journal Name:
- PLOS ONE
- Volume:
- 17
- Issue:
- 5
- ISSN:
- 1932-6203
- Page Range / eLocation ID:
- e0268380
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
Morrison, Abigail (Ed.)Assessing directional influences between neurons is instrumental to understand how brain circuits process information. To this end, Granger causality, a technique originally developed for time-continuous signals, has been extended to discrete spike trains. A fundamental assumption of this technique is that the temporal evolution of neuronal responses must be due only to endogenous interactions between recorded units, including self-interactions. This assumption is however rarely met in neurophysiological studies, where the response of each neuron is modulated by other exogenous causes such as, for example, other unobserved units or slow adaptation processes. Here, we propose a novel point-process Granger causality technique that is robust with respect to the two most common exogenous modulations observed in real neuronal responses: within-trial temporal variations in spiking rate and between-trial variability in their magnitudes. This novel method works by explicitly including both types of modulations into the generalized linear model of the neuronal conditional intensity function (CIF). We then assess the causal influence of neuron i onto neuron j by measuring the relative reduction of neuron j ’s point process likelihood obtained considering or removing neuron i . CIF’s hyper-parameters are set on a per-neuron basis by minimizing Akaike’s information criterion. In synthetic data sets, generated by means of random processes or networks of integrate-and-fire units, the proposed method recovered with high accuracy, sensitivity and robustness the underlying ground-truth connectivity pattern. Application of presently available point-process Granger causality techniques produced instead a significant number of false positive connections. In real spiking responses recorded from neurons in the monkey pre-motor cortex (area F5), our method revealed many causal relationships between neurons as well as the temporal structure of their interactions. Given its robustness our method can be effectively applied to real neuronal data. Furthermore, its explicit estimate of the effects of unobserved causes on the recorded neuronal firing patterns can help decomposing their temporal variations into endogenous and exogenous components.more » « less
-
INTRODUCTION Neurons are by far the most diverse of all cell types in animals, to the extent that “cell types” in mammalian brains are still mostly heterogeneous groups, and there is no consensus definition of the term. The Drosophila optic lobes, with approximately 200 well-defined cell types, provides a tractable system with which to address the genetic basis of neuronal type diversity. We previously characterized the distinct developmental gene expression program of each of these types using single-cell RNA sequencing (scRNA-seq), with one-to-one correspondence to the known morphological types. RATIONALE The identity of fly neurons is determined by temporal and spatial patterning mechanisms in stem cell progenitors, but it remained unclear how these cell fate decisions are implemented and maintained in postmitotic neurons. It was proposed in Caenorhabditis elegans that unique combinations of terminal selector transcription factors (TFs) that are continuously expressed in each neuron control nearly all of its type-specific gene expression. This model implies that it should be possible to engineer predictable and complete switches of identity between different neurons just by modifying these sustained TFs. We aimed to test this prediction in the Drosophila visual system. RESULTS Here, we used our developmental scRNA-seq atlases to identify the potential terminal selector genes in all optic lobe neurons. We found unique combinations of, on average, 10 differentially expressed and stably maintained (across all stages of development) TFs in each neuron. Through genetic gain- and loss-of-function experiments in postmitotic neurons, we showed that modifications of these selector codes are sufficient to induce predictable switches of identity between various cell types. Combinations of terminal selectors jointly control both developmental (e.g., morphology) and functional (e.g., neurotransmitters and their receptors) features of neurons. The closely related Transmedullary 1 (Tm1), Tm2, Tm4, and Tm6 neurons (see the figure) share a similar code of terminal selectors, but can be distinguished from each other by three TFs that are continuously and specifically expressed in one of these cell types: Drgx in Tm1, Pdm3 in Tm2, and SoxN in Tm6. We showed that the removal of each of these selectors in these cell types reprograms them to the default Tm4 fate. We validated these conversions using both morphological features and molecular markers. In addition, we performed scRNA-seq to show that ectopic expression of pdm3 in Tm4 and Tm6 neurons converts them to neurons with transcriptomes that are nearly indistinguishable from that of wild-type Tm2 neurons. We also show that Drgx expression in Tm1 neurons is regulated by Klumpfuss, a TF expressed in stem cells that instructs this fate in progenitors, establishing a link between the regulatory programs that specify neuronal fates and those that implement them. We identified an intronic enhancer in the Drgx locus whose chromatin is specifically accessible in Tm1 neurons and in which Klu motifs are enriched. Genomic deletion of this region knocked down Drgx expression specifically in Tm1 neurons, leaving it intact in the other cell types that normally express it. We further validated this concept by demonstrating that ectopic expression of Vsx (visual system homeobox) genes in Mi15 neurons not only converts them morphologically to Dm2 neurons, but also leads to the loss of their aminergic identity. Our results suggest that selector combinations can be further sculpted by receptor tyrosine kinase signaling after neurogenesis, providing a potential mechanism for postmitotic plasticity of neuronal fates. Finally, we combined our transcriptomic datasets with previously generated chromatin accessibility datasets to understand the mechanisms that control brain wiring downstream of terminal selectors. We built predictive computational models of gene regulatory networks using the Inferelator framework. Experimental validations of these networks revealed how selectors interact with ecdysone-responsive TFs to activate a large and specific repertoire of cell surface proteins and other effectors in each neuron at the onset of synapse formation. We showed that these network models can be used to identify downstream effectors that mediate specific cellular decisions during circuit formation. For instance, reduced levels of cut expression in Tm2 neurons, because of its negative regulation by pdm3 , controls the synaptic layer targeting of their axons. Knockdown of cut in Tm1 neurons is sufficient to redirect their axons to the Tm2 layer in the lobula neuropil without affecting other morphological features. CONCLUSION Our results support a model in which neuronal type identity is primarily determined by a relatively simple code of continuously expressed terminal selector TFs in each cell type throughout development. Our results provide a unified framework of how specific fates are initiated and maintained in postmitotic neurons and open new avenues to understanding synaptic specificity through gene regulatory networks. The conservation of this regulatory logic in both C. elegans and Drosophila makes it likely that the terminal selector concept will also be useful in understanding and manipulating the neuronal diversity of mammalian brains. Terminal selectors enable predictive cell fate reprogramming. Tm1, Tm2, Tm4, and Tm6 neurons of the Drosophila visual system share a core set of TFs continuously expressed by each cell type (simplified). The default Tm4 fate is overridden by the expression of a single additional terminal selector to generate Tm1 ( Drgx ), Tm2 ( pdm3 ), or Tm6 ( SoxN ) fates.more » « less
-
Biological neural computation is inherently asynchronous due to large variations in neuronal spike timing and transmission delays. So-far, most theoretical work on neural networks assumes the synchronous setting where neurons fire simultaneously in discrete rounds. In this work we aim at understanding the barriers of asynchronous neural computation from an algorithmic perspective. We consider an extension of the widely studied model of synchronized spiking neurons [Maass, Neural= Networks 97] to the asynchronous setting by taking into account edge and node delays. Edge Delays: We define an asynchronous model for spiking neurons in which the latency values (i.e., transmission delays) of non self-loop edges vary adversarially over time. This extends the recent work of [Hitron and Parter, ESA’19] in which the latency values are restricted to be fixed over time. Our first contribution is an impossibility result that implies that the assumption that self-loop edges have no delays (as assumed in Hitron and Parter) is indeed necessary. Interestingly, in real biological networks self-loop edges (a.k.a. autapse) are indeed free of delays, and the latter has been noted by neuroscientists to be crucial for network synchronization. To capture the computational challenges in this setting, we first consider the implementation of a single NOT gate. This simple function already captures the fundamental difficulties in the asynchronous setting. Our key technical results are space and time upper and lower bounds for the NOT function, our time bounds are tight. In the spirit of the distributed synchronizers [Awerbuch and Peleg, FOCS’90] and following [Hitron and Parter, ESA’19], we then provide a general synchronizer machinery. Our construction is very modular and it is based on efficient circuit implementation of threshold gates. The complexity of our scheme is measured by the overhead in the number of neurons and the computation time, both are shown to be polynomial in the largest latency value, and the largest incoming degree ∆ of the original network. Node Delays: We introduce the study of asynchronous communication due to variations in the response rates of the neurons in the network. In real brain networks, the round duration varies between different neurons in the network. Our key result is a simulation methodology that allows one to transform the above mentioned synchronized solution under edge delays into a synchronized under node delays while incurring a small overhead w.r.t space and time.more » « less
-
Biological neural computation is inherently asynchronous due to large variations in neuronal spike timing and transmission delays. So-far, most theoretical work on neural networks assumes the synchronous setting where neurons fire simultaneously in discrete rounds. In this work we aim at understanding the barriers of asynchronous neural computation from an algorithmic perspective. We consider an extension of the widely studied model of synchronized spiking neurons [Maass, Neural Networks 97] to the asynchronous setting by taking into account edge and node delays. - Edge Delays: We define an asynchronous model for spiking neurons in which the latency values (i.e., transmission delays) of non self-loop edges vary adversarially over time. This extends the recent work of [Hitron and Parter, ESA'19] in which the latency values are restricted to be fixed over time. Our first contribution is an impossibility result that implies that the assumption that self-loop edges have no delays (as assumed in Hitron and Parter) is indeed necessary. Interestingly, in real biological networks self-loop edges (a.k.a. autapse) are indeed free of delays, and the latter has been noted by neuroscientists to be crucial for network synchronization. To capture the computational challenges in this setting, we first consider the implementation of a single NOT gate. This simple function already captures the fundamental difficulties in the asynchronous setting. Our key technical results are space and time upper and lower bounds for the NOT function, our time bounds are tight. In the spirit of the distributed synchronizers [Awerbuch and Peleg, FOCS'90] and following [Hitron and Parter, ESA'19], we then provide a general synchronizer machinery. Our construction is very modular and it is based on efficient circuit implementation of threshold gates. The complexity of our scheme is measured by the overhead in the number of neurons and the computation time, both are shown to be polynomial in the largest latency value, and the largest incoming degree Δ of the original network. - Node Delays: We introduce the study of asynchronous communication due to variations in the response rates of the neurons in the network. In real brain networks, the round duration varies between different neurons in the network. Our key result is a simulation methodology that allows one to transform the above mentioned synchronized solution under edge delays into a synchronized under node delays while incurring a small overhead w.r.t space and time.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1371/journal.pone.0268380
