Neural circuit reconstruction is the reconstruction of the detailed circuitry of the

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

(or a portion of the nervous system) of an animal. It is sometimes called EM reconstruction since the main method used is the

electron microscope An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

(EM). This field is a close relative of

reverse engineering Reverse engineering (also known as backwards engineering or back engineering) is a process or method through which one attempts to understand through deductive reasoning how a previously made device, process, system, or piece of software accompli ...

of human-made devices, and is part of the field of

connectomics Connectomics is the production and study of connectomes: comprehensive maps of connections within an organism's nervous system. More generally, it can be thought of as the study of neuronal wiring diagrams with a focus on how structural connectivi ...

, which in turn is a sub-field of

neuroanatomy Neuroanatomy is the study of the structure and organization of the nervous system. In contrast to animals with radial symmetry, whose nervous system consists of a distributed network of cells, animals with bilateral symmetry have segregated, defin ...

Model systems

Some of the model systems used for circuit reconstruction are the fruit fly, the

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, and the

nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

''.

Sample preparation

The sample must be fixed, stained, and embedded in plastic.

Imaging

The sample may be cut into thin slices with a

microtome A microtome (from the Greek ''mikros'', meaning "small", and ''temnein'', meaning "to cut") is a cutting tool used to produce extremely thin slices of material known as ''sections''. Important in science, microtomes are used in microscopy, allow ...

, then imaged using

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 ...

. Alternatively, the sample may be imaged with a scanning electron microscope, then the surface abraded using a

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 s ...

, or trimmed using an in-microscope microtome. Then the sample is re-imaged, and the process repeated until the desired volume is processed.

Image processing

The first step is to align the individual images into a coherent three dimensional volume. The volume is then annotated using one of two main methods. The first manually identifies the skeletons of each

neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...

. The second techniques uses computer vision software to identify voxels belonging to the same neuron, which are then corrected in the process of ''proofreading''.

Notable examples

*The connectome of ''

'' was the seminal work in this field. This circuit was obtained with great effort using manually cut sections and purely manual annotation on photographic film. For many years this was the only circuit reconstruction available. *The central brain of the fruit fly ''Drosophila Melanogaster'' was released in 2020. This data release introduced the first on-line tools to query the connectome.

Querying the connectome

Connectomes of higher organism's brains requires considerable data. For the fruit fly, for example, roughly 10 terabytes of image data are processed, by humans and computers, to generate several gigabyte of connectome data. Easy interaction with this data requires an interactive query interface, where researchers can look at the portion of data they are interested in without downloading the whole data set, and without specific training. A specific example of this technology is the ''NeuPrint'' interface to the connectomes generate at HHMI. This mimics the infrastructure of genetics, where interactive query tools such as

BLAST Blast or The Blast may refer to: * Explosion, a rapid increase in volume and release of energy in an extreme manner *Detonation, an exothermic front accelerating through a medium that eventually drives a shock front Film * ''Blast'' (1997 film) ...

are normally used to look at genes of interest, which for most research comprise only a small portion of the genome.

Limitations and future work

Understanding the detailed operation of the reconstructed networks also requires knowledge of

gap junctions Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

(hard to see with existing techniques), the identity of

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

s and the locations and identities of

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

s. In addition,

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 second m ...

s can diffuse across large distances and still strongly affect function. Currently these features must be obtained through other techniques.

Expansion microscopy Expansion microscopy (ExM) is a sample preparation tool for biological samples that allows investigators to identify small structures by expanding them using a polymer system. The premise is to introduce a polymer network into cellular or tissue sa ...

may provide an alternative method.

References

{{Reflist Brain Emerging technologies Neural coding Neuroimaging Neuroinformatics