skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Fast deep neural correspondence for tracking and identifying neurons in C. elegans using semi-synthetic training
Understanding the intricacies of the brain often requires spotting and tracking specific neurons over time and across different individuals. For instance, scientists may need to precisely monitor the activity of one neuron even as the brain moves and deforms; or they may want to find universal patterns by comparing signals from the same neuron across different individuals. Both tasks require matching which neuron is which in different images and amongst a constellation of cells. This is theoretically possible in certain ‘model’ animals where every single neuron is known and carefully mapped out. Still, it remains challenging: neurons move relative to one another as the animal changes posture, and the position of a cell is also slightly different between individuals. Sophisticated computer algorithms are increasingly used to tackle this problem, but they are far too slow to track neural signals as real-time experiments unfold. To address this issue, Yu et al. designed a new algorithm based on the Transformer, an artificial neural network originally used to spot relationships between words in sentences. To learn relationships between neurons, the algorithm was fed hundreds of thousands of ‘semi-synthetic’ examples of constellations of neurons. Instead of painfully collated actual experimental data, these datasets were created by a simulator based on a few simple measurements. Testing the new algorithm on the tiny worm Caenorhabditis elegans revealed that it was faster and more accurate, finding corresponding neurons in about 10ms. The work by Yu et al. demonstrates the power of using simulations rather than experimental data to train artificial networks. The resulting algorithm can be used immediately to help study how the brain of C. elegans makes decisions or controls movements. Ultimately, this research could allow brain-machine interfaces to be developed.  more » « less
Award ID(s):
1845137
PAR ID:
10317769
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
eLife
Volume:
10
ISSN:
2050-084X
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. A major goal in neuroscience is to understand the relationship between an animal’s behavior and how this is encoded in the brain. Therefore, a typical experiment involves training an animal to perform a task and recording the activity of its neurons – brain cells – while the animal carries out the task. To complement these experimental results, researchers “train” artificial neural networks – simplified mathematical models of the brain that consist of simple neuron-like units – to simulate the same tasks on a computer. Unlike real brains, artificial neural networks provide complete access to the “neural circuits” responsible for a behavior, offering a way to study and manipulate the behavior in the circuit. One open issue about this approach has been the way in which the artificial networks are trained. In a process known as reinforcement learning, animals learn from rewards (such as juice) that they receive when they choose actions that lead to the successful completion of a task. By contrast, the artificial networks are explicitly told the correct action. In addition to differing from how animals learn, this limits the types of behavior that can be studied using artificial neural networks. Recent advances in the field of machine learning that combine reinforcement learning with artificial neural networks have now allowed Song et al. to train artificial networks to perform tasks in a way that mimics the way that animals learn. The networks consisted of two parts: a “decision network” that uses sensory information to select actions that lead to the greatest reward, and a “value network” that predicts how rewarding an action will be. Song et al. found that the resulting artificial “brain activity” closely resembled the activity found in the brains of animals, confirming that this method of training artificial neural networks may be a useful tool for neuroscientists who study the relationship between brains and behavior. The training method explored by Song et al. represents only one step forward in developing artificial neural networks that resemble the real brain. In particular, neural networks modify connections between units in a vastly different way to the methods used by biological brains to alter the connections between neurons. Future work will be needed to bridge this gap. 
    more » « less
  2. INTRODUCTION A brainwide, synaptic-resolution connectivity map—a connectome—is essential for understanding how the brain generates behavior. However because of technological constraints imaging entire brains with electron microscopy (EM) and reconstructing circuits from such datasets has been challenging. To date, complete connectomes have been mapped for only three organisms, each with several hundred brain neurons: the nematode C. elegans , the larva of the sea squirt Ciona intestinalis , and of the marine annelid Platynereis dumerilii . Synapse-resolution circuit diagrams of larger brains, such as insects, fish, and mammals, have been approached by considering select subregions in isolation. However, neural computations span spatially dispersed but interconnected brain regions, and understanding any one computation requires the complete brain connectome with all its inputs and outputs. RATIONALE We therefore generated a connectome of an entire brain of a small insect, the larva of the fruit fly, Drosophila melanogaster. This animal displays a rich behavioral repertoire, including learning, value computation, and action selection, and shares homologous brain structures with adult Drosophila and larger insects. Powerful genetic tools are available for selective manipulation or recording of individual neuron types. In this tractable model system, hypotheses about the functional roles of specific neurons and circuit motifs revealed by the connectome can therefore be readily tested. RESULTS The complete synaptic-resolution connectome of the Drosophila larval brain comprises 3016 neurons and 548,000 synapses. We performed a detailed analysis of the brain circuit architecture, including connection and neuron types, network hubs, and circuit motifs. Most of the brain’s in-out hubs (73%) were postsynaptic to the learning center or presynaptic to the dopaminergic neurons that drive learning. We used graph spectral embedding to hierarchically cluster neurons based on synaptic connectivity into 93 neuron types, which were internally consistent based on other features, such as morphology and function. We developed an algorithm to track brainwide signal propagation across polysynaptic pathways and analyzed feedforward (from sensory to output) and feedback pathways, multisensory integration, and cross-hemisphere interactions. We found extensive multisensory integration throughout the brain and multiple interconnected pathways of varying depths from sensory neurons to output neurons forming a distributed processing network. The brain had a highly recurrent architecture, with 41% of neurons receiving long-range recurrent input. However, recurrence was not evenly distributed and was especially high in areas implicated in learning and action selection. Dopaminergic neurons that drive learning are amongst the most recurrent neurons in the brain. Many contralateral neurons, which projected across brain hemispheres, were in-out hubs and synapsed onto each other, facilitating extensive interhemispheric communication. We also analyzed interactions between the brain and nerve cord. We found that descending neurons targeted a small fraction of premotor elements that could play important roles in switching between locomotor states. A subset of descending neurons targeted low-order post-sensory interneurons likely modulating sensory processing. CONCLUSION The complete brain connectome of the Drosophila larva will be a lasting reference study, providing a basis for a multitude of theoretical and experimental studies of brain function. The approach and computational tools generated in this study will facilitate the analysis of future connectomes. Although the details of brain organization differ across the animal kingdom, many circuit architectures are conserved. As more brain connectomes of other organisms are mapped in the future, comparisons between them will reveal both common and therefore potentially optimal circuit architectures, as well as the idiosyncratic ones that underlie behavioral differences between organisms. Some of the architectural features observed in the Drosophila larval brain, including multilayer shortcuts and prominent nested recurrent loops, are found in state-of-the-art artificial neural networks, where they can compensate for a lack of network depth and support arbitrary, task-dependent computations. Such features could therefore increase the brain’s computational capacity, overcoming physiological constraints on the number of neurons. Future analysis of similarities and differences between brains and artificial neural networks may help in understanding brain computational principles and perhaps inspire new machine learning architectures. The connectome of the Drosophila larval brain. The morphologies of all brain neurons, reconstructed from a synapse-resolution EM volume, and the synaptic connectivity matrix of an entire brain. This connectivity information was used to hierarchically cluster all brains into 93 cell types, which were internally consistent based on morphology and known function. 
    more » « less
  3. We investigated the neural representation of locomotion in the nematode C. elegans by recording population calcium activity during movement. We report that population activity more accurately decodes locomotion than any single neuron. Relevant signals are distributed across neurons with diverse tunings to locomotion. Two largely distinct subpopulations are informative for decoding velocity and curvature, and different neurons’ activities contribute features relevant for different aspects of a behavior or different instances of a behavioral motif. To validate our measurements, we labeled neurons AVAL and AVAR and found that their activity exhibited expected transients during backward locomotion. Finally, we compared population activity during movement and immobilization. Immobilization alters the correlation structure of neural activity and its dynamics. Some neurons positively correlated with AVA during movement become negatively correlated during immobilization and vice versa. This work provides needed experimental measurements that inform and constrain ongoing efforts to understand population dynamics underlying locomotion in C. elegans . 
    more » « less
  4. Most animals develop from juveniles, which cannot reproduce, to sexually mature adults. The most obvious signs of this transition are changes in body shape and size. However, changes also take place in the brain that enable the animals to adapt their behavior to the demands of adulthood. For example, fully fed adult male roundworms will leave a food source to search for mates, whereas juvenile males will continue feeding. The transition to sexual maturity needs to be carefully timed. Too early, and the animal risks compromising key stages of development. Too late, and the animal may be less competitive in the quest for reproductive success. Cues in the environment, such as the presence of food and mates, interact with timing mechanisms in the brain to trigger sexual maturity. But how these mechanisms work – in particular where and how an animal keeps track of its developmental stage – is not well understood. In the roundworm species Caenorhabditis elegans, waves of gene activity, known collectively as the heterochronic pathway, determine patterns of cell growth as animals mature. Through further studies of these worms, Lawson et al. now show that these waves also control the time at which neural circuits mature. In addition, the waves of activity occur inside the nervous system itself, rather than in a tissue that sends signals to the nervous system. Moreover, they occur independently inside many different neurons. Each neuron thus has its own molecular clock for keeping track of development. Several of the genes critical for developmental timekeeping in worms are also found in mammals, including two genes that help to control when puberty starts in humans. If one of these genes – called MKRN3 – does not work correctly, it can lead to a condition that causes individuals to go through puberty several years earlier than normal. Studying the mechanisms identified in roundworms may help us to better understand this disorder. More generally, future work that builds on the results presented by Lawson et al. will help to reveal how environmental cues and gene activity interact to control when we become adults. 
    more » « less
  5. Brain simulation techniques have demonstrated undisputable therapeutic effects on neural diseases. Invasive stimulation techniques like deep brain stimulation (DBS) and noninvasive techniques like transcranial magnetic stimulation (TMS) have been approved by FDA as treatments for many drug resist neural disorders and diseases. Developing noninvasive, deep, and targeted brain stimulation techniques is currently one of the important tasks in brain researches. Transcranial direct current stimulation (tDCS) and transcranial alternative current stimulation (tACS) techniques have the advantages of low cost and portability. However, neither of them can produce targeted stimulation due to lacking of electrical field focusing mechanism. Recently, Grossman et al. reported using the down beating signals of two tACS signals to accomplish focused stimulation. By sending two sine waves running at slightly different high frequencies (~2kHz), they demonstrated that they can modulate a “localized” neuron group at the difference frequency of the two sine waves and at the same time avoid excitation of neurons at other locations. As a result, equivalent focusing effect was accomplished by such beating mechanism. In this work, we show neither theoretically nor experimentally the beating mechanism can produce “focusing effect” and the beating signal spread globally across the full brain. The localized modulation effect likely happened right at the electrode contact sites when the electrode contact area is small and the current is concentrated. We conclude that to accomplish noninvasive and focused stimulation at current stage the only available tool is the focused TMS system we recently demonstrated. 
    more » « less