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We present a functionally relevant, quantitative characterization of the neural circuitry of Drosophila melanogaster at the mesoscopic level of neuron types as classified exclusively based on potential network connectivity. Starting from a large neuron-to-neuron brain-wide connectome of the fruit fly, we use stochastic block modeling and spectral graph clustering to group neurons together into a common “cell class” if they connect to neurons of other classes according to the same probability distributions. We then characterize the connectivity-based cell classes with standard neuronal biomarkers, including neurotransmitters, developmental birthtimes, morphological features, spatial embedding, and functional anatomy. Mutual information indicates that connectivity-based classification reveals aspects of neurons that are not adequately captured by traditional classification schemes. Next, using graph theoretic and random walk analyses to identify neuron classes as hubs, sources, or destinations, we detect pathways and patterns of directional connectivity that potentially underpin specific functional interactions in the Drosophila brain. We uncover a core of highly interconnected dopaminergic cell classes functioning as the backbone communication pathway for multisensory integration. Additional predicted pathways pertain to the facilitation of circadian rhythmic activity, spatial orientation, fight-or-flight response, and olfactory learning. Our analysis provides experimentally testable hypotheses critically deconstructing complex brain function from organized connectomic architecture.

 

Deep neural networks (DNNs) are known for extracting useful information from large amounts of data. However, the representations learned in DNNs are typically hard to interpret, especially in dense layers. One crucial issue of the classical DNN model such as multilayer perceptron (MLP) is that neurons in the same layer of DNNs are conditionally independent of each other, which makes co-training and emergence of higher modularity difficult. In contrast to DNNs, biological neurons in mammalian brains display substantial dependency patterns. Specifically, biological neural networks encode representations by so-called neuronal assemblies: groups of neurons interconnected by strong synaptic interactions and sharing joint semantic content. The resulting population coding is essential for human cognitive and mnemonic processes. Here, we propose a novel Biologically Enhanced Artificial Neuronal assembly (BEAN) regularization 1 to model neuronal correlations and dependencies, inspired by cell assembly theory from neuroscience. Experimental results show that BEAN enables the formation of interpretable neuronal functional clusters and consequently promotes a sparse, memory/computation-efficient network without loss of model performance. Moreover, our few-shot learning experiments demonstrate that BEAN could also enhance the generalizability of the model when training samples are extremely limited. 

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal–hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org . We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function. 

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.

 

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 remains incompletely understood. The open‐source knowledge baseHippocampome.orgamasses such transcriptomic data from the scientific literature for morphologically defined neuron types in the rodent hippocampal formation: dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex. 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 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 more than 100 neuron types inHippocampome.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 superfamilies characterized by a few defining molecules.

 

Hippocampome.org is a comprehensive knowledge base of neuron types in the rodent hippocampal formation (dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex). Although the hippocampal literature is remarkably information-rich, neuron properties are often reported with incompletely defined and notoriously inconsistent terminology, creating a formidable challenge for data integration. Our extensive literature mining and data reconciliation identified 122 neuron types based on neurotransmitter, axonal and dendritic patterns, synaptic specificity, electrophysiology, and molecular biomarkers. All ∼3700 annotated properties are individually supported by specific evidence (∼14,000 pieces) in peer-reviewed publications. Systematic analysis of this unprecedented amount of machine-readable information reveals novel correlations among neuron types and properties, the potential connectivity of the full hippocampal circuitry, and outstanding knowledge gaps. User-friendly browsing and online querying of Hippocampome.org may aid design and interpretation of both experiments and simulations. This powerful, simple, and extensible neuron classification endeavor is unique in its detail, utility, and completeness.