Rees, C. L. | bioRxiv Science

bioRxiv2019

Molecular Expression Profiles of Morphologically Defined Hippocampal Neuron Types: Empirical Evidence and Relational Inferences

Gene and protein expressions are key determinants of cellular function. Neurons are the building blocks of brain circuits, yet the relationship between their molecular identity and the spatial distribution of their dendritic inputs and axonal outputs remain incompletely understood. The open-source knowledge base Hippocampome.org amasses such transcriptomic data from the scientific literature for morphologically defined neuron types in the rodent hippocampal formation: dentate gyrus (DG), CA3, CA2, CA1, subiculum (SUB), and entorhinal cortex (EC). Positive, negative, or mixed expression reports were initially obtained from published articles directly connecting molecular evidence to neurons with known axonal and dendritic patterns across hippocampal layers. Here, we supplement this information by collating, formalizing, and leveraging relational expression inferences (REIs) that link a gene or protein expression or lack thereof to that of another molecule or to an anatomical location. With these additional interpretations, we freely release online a comprehensive human- and machine-readable molecular profile for the more than 100 neuron types in Hippocampome.org. Analysis of these data ascertains the ability to distinguish unequivocally most neuron types in each of the major subdivisions of the hippocampus based on currently known biochemical markers. Moreover, grouping neuron types by expression similarity reveals eight super-families characterized by a few defining molecules.\n\nSignificance StatementThe molecular composition of cells underlies their structure, activity, and function. Neurons are arguably the most diverse cell types with their characteristic tree-like shapes mediating synaptic communication throughout the brain. Biochemical marker data are available online for hundreds of morphologically identified neuron types in the mammalian hippocampus, including expression of calcium-binding proteins, receptors, and enzymes. Here, we augment this evidence by systematically applying logical rules empirically derived from the published literature (e.g. \"presence of molecule X implies lack of molecule Y\"). The resulting substantially expanded expression profiles provide nearly unique molecular identities for most known hippocampal neuron types while revealing previously unrecognized genetic similarities across anatomical regions and morphological phenotypes.

neuroscience↗

bioRxiv2017

Firing pattern classification and phenotyping in a knowledge base of hippocampal neuron types

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 (dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex) based on their somatic, axonal, and dendritic locations, putative excitatory/inhibitory outputs, molecular marker expression, and biophysical properties such as time constant and input resistance. Here we augment 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 available published experiments. We designed and implemented objective protocols to classify firing patterns based on both transient and steady-state activity. Specifically, we identified 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). By characterizing the set of all firing responses reported for hippocampal neurons, this automated classification approach revealed 9 unique families of firing pattern phenotypes while distinguishing potential new neuronal subtypes. Several novel statistical associations also emerged between firing responses and other electrophysiological properties, morphological features, and molecular marker expression. The firing pattern parameters, complete experimental conditions (including solution and stimulus details), digitized spike times, exact reference to the original empirical evidence, 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 hippocampal model simulations.\n\nSignificance StatementComprehensive characterization of nerve cells is essential for understanding signal processing in biological neuronal networks. Firing patterns are important identification characteristics of neurons and play crucial roles in information coding in neural systems. Building upon the comprehensive knowledge base Hippocampome.org, we developed and implemented automated protocols to classify all known firing responses exhibited by each neuron type of the rodent hippocampus based on analysis of transient and steady-state activity. This approach identified the most distinguishing elements of every firing phenotype and revealed previously unnoticed statistical associations of firing responses with other electrophysiological, morphological, and molecular properties. The resulting data, freely released online, constitute a powerful resource for designing and interpreting experiments as well as developing and testing hippocampal models.

neuroscience↗