Drosophila Connectome
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A ''Drosophila'' connectome is a list of
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s in the ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
'' (fruit fly) nervous system, and the chemical
synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
s between them. The fly's central nervous system consists of the brain plus the
ventral nerve cord The ventral nerve cord is a major structure of the invertebrate central nervous system. It is the functional equivalent of the vertebrate spinal cord. The ventral nerve cord coordinates neural signaling from the brain to the body and vice ve ...
, and both are known to differ considerably between male and female. Dense connectomes have been completed for the female adult brain, the male and female nerve cords, and the female larval stage. The available connectomes show only chemical synapses - other forms of inter-neuron communication such as
gap junction Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites. Gap junctions were first described as ''close appositions'' alongside tight ...
s or
neuromodulator Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a secon ...
s are not represented. ''Drosophila'' is the most complex creature with a connectome, which had only been previously obtained for three other simpler organisms, first '' C. elegans''. The connectomes have been obtained by the methods of neural circuit reconstruction, which over the course of many years worked up through various subsets of the fly brain to current efforts aimed at a unified central brain and VNC connectome, for both male and female flies.


Why ''Drosophila''

Connectome A connectome () is a comprehensive map of neural connections in the brain, and may be thought of as its " wiring diagram". These maps are available in varying levels of detail. A functional connectome shows connections between various brain ...
research (
connectomics Connectomics is the production and study of connectomes, which are comprehensive maps of connections within an organism's nervous system. Study of neuronal wiring diagrams looks at how they contribute to the health and behavior of an organism. ...
) has a number of competing objectives. On the one hand, investigators prefer an organism small enough that the connectome can be obtained in a reasonable amount of time. This argues for a small creature. On the other hand, one of the main uses of a connectome is to relate structure and behavior, so an animal with a large behavioral repertoire is desirable. It's also very helpful to use an animal with a large existing community of experimentalists, and many available genetic tools. ''Drosophila'' meets all of these requirements: * The brain contains about 135,000 neurons, small enough to be currently reconstructed. * The fruit fly exhibits many complex behaviors. Hundreds of different behaviors (feeding, grooming, flying, mating, learning, and so on) have been qualitatively and quantitatively studied over the years. * The genetics of the fruit fly are well understood, and many (tens of thousands) of genetic variants are available. * There are many
electrophysiological Electrophysiology (from ee the Electron#Etymology, etymology of "electron" ; and ) is the branch of physiology that studies the electrical properties of biological cell (biology), cells and tissues. It involves measurements of voltage change ...
,
calcium imaging Calcium imaging is a microscopy technique to optically measure the calcium (Ca2+) status of an isolated cell, tissue or medium. Calcium imaging takes advantage of calcium indicators, fluorescent molecules that respond to the binding of Ca2+ ions b ...
, and other studies ongoing with ''Drosophila''.


Structure of the fly connectome

Synapses in the ''Drosophila'' are ''polyadic'', meaning they have multiple post-synaptic elements (commonly call PSDs, for post-synaptic densities) opposed to one pre-synaptic element (commonly called a T-bar, due to its most common appearance). Synapse counts can be reported either way - as number of structures, or number of partners. Cell and synapse counts are known to vary between individuals. For the larva, there is one full female connectome available. For adults, a full connectomes of the female brain (~120,000 neurons, ~30,000,000 synapses) and both the male and female ventral nerve cord (VNC, the fly's equivalent of the spinal cord, ~14,600 neurons) are also available. At least two teams are working on complete adult CNS connectomes that includes both the brain and the VNC, in both male and female flies.


Adult brain

''Drosophila'' connectomics started in 1991 with a description of the circuits of the
lamina Lamina may refer to: People * Saa Emerson Lamina, Sierra Leonean politician * Tamba Lamina, Sierra Leonean politician and diplomat Science and technology * Planar lamina, a two-dimensional planar closed surface with mass and density, in mathem ...
. However the methods used were largely manual and further progress awaited more automated techniques. In 2011, a high-level connectome, at the level of brain compartments and interconnecting tracts of neurons, for the full fly brain was published, and is available online. New techniques such as digital image processing began to be applied to detailed neural reconstruction. Reconstructions of larger regions soon followed, including a column of the medulla, also in the visual system of the fruit fly, and the alpha lobe of the mushroom body. In 2020, a dense connectome of half the central brain of ''Drosophila'' was released, along with a web site that allows queries and exploration of this data. The methods used in reconstruction and initial analysis of the 'hemibrain' connectome followed. This effort was a collaboration between the Janelia FlyEM team and
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. This dataset is an incomplete but large section of the fly central brain. It was collected using
focused ion beam Focused ion beam, also known as FIB, is a technique used particularly in the semiconductor industry, materials science and increasingly in the biological field for site-specific analysis, deposition, and ablation of materials. A FIB setup is a sc ...
scanning electron microscopy A scanning electron microscope (SEM) is a type of electron microscope that produces images of a sample by scanning the surface with a focused beam of electrons. The electrons interact with atoms in the sample, producing various signals that ...
(FIB-SEM) which generated an 8 nm isotropic dataset, then automatically segmented using a flood-filling network before being manually proofread by a team of experts. Finally, estimated
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
IDs were added. In 2017, a full adult fly brain (FAFB) volume was imaged by a team at
Janelia Research Campus Janelia Research Campus is a scientific research campus of the Howard Hughes Medical Institute that opened in October 2006. The campus is located in Loudoun County, Virginia, near the town of Ashburn. It is known for its scientific research and m ...
using a novel high-throughput serial section
transmission electron microscopy Transmission electron microscopy (TEM) is a microscopy technique in which a beam of electrons is transmitted through a specimen to form an image. The specimen is most often an ultrathin section less than 100 nm thick or a suspension on a g ...
(ssTEM) pipeline. At the time, however, automated methods could not cope with its reconstruction, but the volume was available for sparse tracing of selected circuits. Six years later, in 2023, Sebastian Seung’s lab at
Princeton Princeton University is a private Ivy League research university in Princeton, New Jersey, United States. Founded in 1746 in Elizabeth as the College of New Jersey, Princeton is the fourth-oldest institution of higher education in the Unit ...
used
convolutional neural network A convolutional neural network (CNN) is a type of feedforward neural network that learns features via filter (or kernel) optimization. This type of deep learning network has been applied to process and make predictions from many different ty ...
s (CNNs) to automatically segment neurons, while Jan Funke's lab at Janelia used similar techniques to detect pre- and post-synaptic sites. This automated version was then used as a starting point for a massive community effort among fly neuroscientists to proofread neuronal morphologies by correcting errors and adding information about cell type and other attributes. This effort, called FlyWire, was conducted by Sebastian Seung and Mala Murthy of the Princeton Neuroscience Institute in conjunction with a large team of other scientists and labs called the FlyWire Consortium. The full brain connectome produced by this effort is now publicly available and searchable through the FlyWire Codex. This full brain connectome (of a female) contains roughly 5x10^7 chemical synapses between ~130,000 neurons. Estimated
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
IDs were added, again using techniques from the Funke lab. A projectome, a map of projections between regions, can be derived from the connectome. Members of the fly connectomics community have made an effort to match cell types between FlyWire and the Hemibrain. They have found that at first pass, 61% of Hemibrain types are found in the FlyWire dataset and, out of these consensus cell types, 53% of “edges” from one cell type to another can be found in both datasets (but edges connected by at least 10 synapses are much more consistently found across datasets). In parallel, a consensus
cell type A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
atlas for the ''Drosophila'' brain was published, produced based on this 'FlyWire' connectome and the prior 'hemibrain'. This resource includes 4,552 cell types: 3,094 as rigorous validations of those previously proposed in the hemibrain connectome; 1,458 new cell types, arising mostly from the fact that the FlyWire connectome spans the whole brain, whereas the hemibrain derives from a subvolume. Comparison of these distinct, adult ''Drosophila'' connectomes showed that cell type counts and strong connections were largely stable, but connection weights were surprisingly variable within and across animals.


Adult ventral nerve cord

There are two publicly available datasets of the adult fly
ventral nerve cord The ventral nerve cord is a major structure of the invertebrate central nervous system. It is the functional equivalent of the vertebrate spinal cord. The ventral nerve cord coordinates neural signaling from the brain to the body and vice ve ...
(VNC). The female adult nerve cord (FANC) was collected using high-throughput ssTEM by Wei-Chung Allen Lee’s lab at
Harvard Medical School Harvard Medical School (HMS) is the medical school of Harvard University and is located in the Longwood Medical and Academic Area, Longwood Medical Area in Boston, Massachusetts. Founded in 1782, HMS is the third oldest medical school in the Un ...
. It then underwent automatic segmentation and synapse prediction using CNNs, and researchers at Harvard and the
University of Washington The University of Washington (UW and informally U-Dub or U Dub) is a public research university in Seattle, Washington, United States. Founded in 1861, the University of Washington is one of the oldest universities on the West Coast of the Uni ...
mapped motor neurons with cell bodies in the VNC to their muscular targets by cross-referencing between the EM dataset, a high-resolution nanotomography image volume of the fly leg, and sparse genetic lines to label individual neurons with
fluorescent protein Fluorescent proteins include: * Green fluorescent protein The green fluorescent protein (GFP) is a protein that exhibits green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the ...
s. The rest of the FANC was reconstructed by 2024. The male adult nerve cord (MANC) was collected and segmented at Janelia using FIB-SEM and flood-filling network protocols modified from the Hemibrain pipeline. In a collaboration between researchers at Janelia, Google, the
University of Cambridge The University of Cambridge is a Public university, public collegiate university, collegiate research university in Cambridge, England. Founded in 1209, the University of Cambridge is the List of oldest universities in continuous operation, wo ...
, and the
MRC Laboratory of Molecular Biology The Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) is a research institute in Cambridge, England, involved in the revolution in molecular biology which occurred in the 1950–60s. Since then it has remained a major medical r ...
(LMB), it is fully proofread and annotated with cell types and other properties (in particular predicted neurotransmitter identities), and searchable on neuPrint.


Larval brain

The connectome of a complete
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(connected brain and VNC) of a 1st
instar An instar (, from the Latin '' īnstar'' 'form, likeness') is a developmental stage of arthropods, such as insects, which occurs between each moult (''ecdysis'') until sexual maturity is reached. Arthropods must shed the exoskeleton in order to ...
''D. melanogaster''
larva A larva (; : larvae ) is a distinct juvenile form many animals undergo before metamorphosis into their next life stage. Animals with indirect development such as insects, some arachnids, amphibians, or cnidarians typically have a larval phase ...
has been reconstructed as a single dataset of 3016 neurons. The imaging was done at Janelia using serial section electron microscopy. This dataset was segmented and annotated manually using CATMAID by a team of people mainly led by researchers at Janelia, Cambridge, and the MRC LMB. They found that the larval brain was composed of 3,016 neurons and 548,000 synapses. 93% of brain neurons had a homolog in the opposite hemisphere. Of the synapses, 66.6% were axo-dendritic, 25.8% were axo-axonic, 5.8% were dendro-dendritic, and 1.8% were dendro-axonic. To study the connectome, they treated it as a directed graph with the neurons forming nodes and the synapses forming the edges. Using this representation, Winding et al found that the larval brain neurons could be clustered into 93 different types, based on connectivity alone. These types aligned with the known neural groups including
sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded receptor potentials. This process is called sensory transduc ...
s (visual, olfactory, gustatory, thermal, etc), descending neurons, and ascending neurons. The authors ordered these neuron types based on proximity to brain inputs vs brain outputs. Using this ordering, they could quantify the proportion of recurrent connections, as the set of connections going from neurons closer to outputs towards inputs. They found that 41% of all brain neurons formed a recurrent connection. The neuron types with the most recurrent connections were the
dopaminergic neurons Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first identi ...
(57%), mushroom body feedback neurons (51%), mushroom body output neurons (45%), and convergence neurons (42%) (receiving input from mushroom body and lateral horn regions). These neurons, implicated in learning, memory, and action-selection, form a set of recurrent loops.


Structure and behavior

One of the main uses of the ''Drosophila'' connectome is to understand the neural circuits and other brain structure that gives rise to behavior. This area is under very active investigation. For example, the fruit fly connectome has been used to identify an area of the fruit fly brain that is involved in odor detection and tracking. Flies choose a direction in turbulent conditions by combining information about the direction of air flow and the movement of odor packets. Based on the fly connectome, processing must occur in the “fan-shaped body” where wind-sensing neurons and olfactory direction-sensing neurons cross. A natural question is whether the connectome will allow simulation of the fly's behavior. However, the connectome alone is not sufficient. A comprehensive simulation would need to include
gap junction Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites. Gap junctions were first described as ''close appositions'' alongside tight ...
varieties and locations, identities of
neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotransmitters are rele ...
,
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
types and locations,
neuromodulators Neuromodulation is the physiology, physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic receptor, metabotropic, G protein-coupled rece ...
and
hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...
(with sources and receptors), the role of
glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
, time evolution rules for synapses, and more. However some pathways have been simulated using only the connectome plus neurotransmitter predictions.


See also

* Virtual Fly Brain * Pigment dispersing factor *
Ganglion mother cell Ganglion mother cells (GMCs) are cells involved in neurogenesis, in non-mammals, that divide only once to give rise to two neurons, or one neuron and one glial cell or two glial cells, and are present only in the central nervous system. They are al ...
* OpenWorm


References


Further reading

*


External links

* * * * {{cite web , url = https://www.janelia.org/ , title = Janelia Research Campus , publisher = Howard Hughes Medical Institute Brain Neural coding Neuroimaging Neuroinformatics Drosophila melanogaster Invertebrate nervous system