Drosophila connectome

A Drosophila connectome is a list of neurons in the Drosophila melanogaster (fruit fly) nervous system, and the chemical synapses between them. The fly's nervous system consists of the brain plus the ventral nerve cord, and both are known to differ considerably between male and female.^[1][2] Dense connectomes have been completed for the female adult brain,^[3] the male nerve cord,^[4] and the female larval stage.^[5] The available connectomes show only chemical synapses - other forms of inter-neuron communication such as gap junctions or neuromodulators 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.^{[citation needed]} 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 the almost full connectomes that exist today.^{[citation needed]}

Connectome research (connectomics) 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,^[6] small enough to be currently reconstructed.^[7]
• 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.^{[citation needed]}
• The genetics of the fruit fly are well understood, and many (tens of thousands) of genetic variants are available.^{[clarification needed]}
• There are many electrophysiological, calcium imaging, and other studies ongoing with Drosophila.^{[citation needed]}

The one fully-reconstructed adult female fruit fly brain contains about 128,000 neurons and roughly 50 million chemical synapses, and the single reconstructed male nerve cord has about 23,000 neurons and 70 million synapses. These numbers are not independent, since both the brain and the nerve cord contain portions of the several thousand ascending and descending neurons that run through the neck of the fly. The one female larval brain reconstructed contains roughly 3,000 neurons and 548 thousand chemical synapses. All of these numbers are known to vary between individuals.^[8]

Drosophila connectomics started in 1991 with a description of the circuits of the lamina.^[9] 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,^[10] and is available online.^[11] New techniques such as digital image processing began to be applied to detailed neural reconstruction.^[12]

Reconstructions of larger regions soon followed, including a column of the medulla,^[13] also in the visual system of the fruit fly, and the alpha lobe of the mushroom body.^[14]

In 2017 a paper introduced an electron microscopy image stack of the whole adult female brain at synaptic resolution. The volume was available for sparse tracing of selected circuits.^[15][16]

In 2020, a dense connectome of half the central brain of Drosophila was released,^[17] along with a web site that allows queries and exploration of this data.^[18] The methods used in reconstruction and initial analysis of the 'hemibrain' connectome followed.^[19]

In 2023, using the data from 2017 (above), the full brain connectome (for a female) was made available, containing roughly 5x10^7 chemical synapses between ~130,000 neurons.^[3] A projectome, a map of projections between regions, can be derived from the connectome. In parallel, a consensus cell type atlas for the Drosophila brain was published, produced based on this 'FlyWire' connectome and the prior 'hemibrain'.^[20] 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.

In 2022, a group of scientists mapped the motor control circuits of the ventral nerve cord of a female fruit fly using electron microscopy.^[21] In 2023, a dense reconstruction of the male fly ventral nerve chord was released.^[22]

In 2023, Michael Winding et al. published a complete larval brain connectome.^[23][5] This connectome was mapped by annotating the previously collected electron microscopy volume.^[24] 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 neurons (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 (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.

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.^[25][26] 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.^[27][28]

A natural question is whether the connectome will allow simulation of the fly's behavior. However, the connectome alone is not sufficient. Additional information needed includes gap junction varieties and locations, identities of neurotransmitters, receptor types and locations, neuromodulators and hormones (with sources and receptors), the role of glial cells, time evolution rules for synapses, and more.^[29][30]

• Virtual Fly Brain
• Pigment dispersing factor
• Ganglion mother cell
• OpenWorm

• "FlyWire".
• "FlyCircuit Database".
• "Fruit Fly Brain Observatory".
• "Janelia Research Campus". Howard Hughes Medical Institute.