Connectomics in the Lee Lab

video: Wei-Chung Allen Lee is working in a new field of neuroscience referred to as connectomics that aims to comprehensively map connections between neurons.
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Credit score: Catherine Caruso, Stephanie Dutchen, and Tyler Sloan

Many of us have seen microscopic photographs of neurons within the mind — every neuron showing as a glowing cell in an unlimited sea of blackness. This picture is deceptive: Neurons don’t exist in isolation. Within the human mind, some 86 billion neurons type 100 trillion connections to one another — numbers that, mockingly, are far too massive for the human mind to fathom.

Wei-Chung Allen Lee, Harvard Medical College affiliate professor of neurology at Boston Youngsters’s Hospital, is working in a new field of neuroscience referred to as connectomics, which aims to comprehensively map connections between neurons within the mind.

“The brain is structured so that each neuron is connected to thousands of other neurons, and so to understand what a single neuron is doing, ideally you study it within the context of the rest of the neural network,” Lee defined.

Lee lately spoke to Harvard Medication Information in regards to the promise of connectomics. He additionally described his personal analysis, which mixes connectomics with info on neural exercise to discover neural circuits that underlie habits.

Harvard Medication Information: To start out with a fundamental query, what’s connectomics?

Lee: We outline connectomics as understanding how particular person neurons are linked to each other to type purposeful networks. The aim is to create connectomes, or detailed structural maps of connectivity the place we will see each neuron and each connection. What’s distinctive is the comprehensiveness of connectivity: In an ideal connectome, we’d know the way each neuron was linked to each different neuron.

We consider that the connectivity of neurons is prime to how they perform, since they need to obtain info from one another so as to use this info. Having complete knowledge about connectivity permits us to take a look at higher-order interactions between populations of neurons which might be necessary for mind perform and habits. It’s difficult to research higher-order interactions with out connectomics.

Some have argued that you’re your connectome. Once you go to sleep at evening, your mind exercise dramatically adjustments, interrupting your ideas and emotions — however whenever you get up, you resume your ideas and emotions with none break in your sense of self. That is probably as a result of your mind connectivity has remained largely intact via the evening. In essence, the construction of how our neurons are wired is our “self,” and connectomics is the important thing to understanding this construction.

HMNews: What are you learning throughout the context of connectomics?

Lee: My lab is occupied with understanding how computations come up within the mind, or the overall ideas by which neural circuits arrange themselves into purposeful networks. To do that, we intention to comprehensively map how particular person neurons are linked to each other in complicated networks. On the identical time, we wish to perceive how these neurons are energetic throughout the functioning circuit. We do that within the context of habits, starting from making choices to executing actions.

We try to couple connectomics with recordings of neural exercise to do what we name purposeful connectomics. Basically, we take the map of the place each neuron is and the way it’s linked to each different neuron, and we layer on details about the exercise of these neurons in a dwelling animal. We additionally use genetic engineering approaches to label particular cell varieties, which is further info that we will layer on high of connectivity.

HMNews: What instruments do scientists use to map connectomes?

Lee: We’re growing and making use of high-throughput microscopy, computational approaches, and machine studying to generate connectomes and translate these detailed maps of neural connectivity into organic and computational insights. One key part of our strategy is serial transmission electron microscopy, or EM, which has unsurpassed spatial decision, signal-to-noise ratio, and velocity relative to different serial EM strategies. This system permits us to establish excitatory and inhibitory neurons, in addition to the synapses, or small gaps the place neurons join to one another. We will additionally study connectivity patterns of neurons, and research the group of synaptic connections.

Traditionally, high-resolution EM has been sluggish and tedious, however we’ve engineered a high-speed EM platform that enables us to seize the entire nervous system of an grownup fruit fly in a couple of months, producing 5 to 10 terabytes of knowledge a day. We’ve got additionally developed computational infrastructure and instruments that allow us to deal with and visualize the big quantities of knowledge that we’re producing. For instance, we use synthetic deep neural networks to extract details about cells and their connectivity from these large datasets.

HMNews: What fashions do you utilize in your analysis?

Lee: We’ve got primarily labored with mice and fruit flies, that are highly effective and well-studied mannequin programs. The field has refined genetic instruments that enable us to label completely different populations of neurons throughout the central nervous programs of these species. In fruit flies, we will use the applied sciences we’ve been growing for connectomics to seize your entire mind and nervous system at synapse decision. Within the mouse, we will goal related neural circuits or subcircuits. We’re utilizing these fashions to research the essential ideas of how neural circuits are constructed and function — mainly how neural networks are linked to one another to carry out completely different computations that underlie habits.

We additionally work in nontraditional mannequin programs such because the mosquito. Mosquito brains are about the identical measurement as fruit fly brains, however the genetics is more difficult. Scientists have used genetics to entry the first-order neurons that begin carrying info into the mosquito mind, however the remainder of the mind is a black field in lots of respects. We don’t know a lot about its basic neurobiology, together with how the mosquito mind integrates completely different sensory modalities to drive habits.

For instance, grownup feminine mosquitoes which might be attempting to reproduce combine info on human odors, warmth, and carbon dioxide. We all know that these completely different sensory cues enter the mind, however we don’t know the way they’re built-in and converge onto neural circuits that drive mosquitoes’ host-seeking habits.

We hope that mapping the entire mosquito mind will present a new basis for understanding how sensory integration and motion choice works for innate habits. Moreover, the particular mosquito species we research is a vector for ailments similar to malaria, West Nile, Zika, yellow fever, and dengue fever, so there’s a medical and public well being side of this that makes it a very necessary mannequin system.

HMNews: You latterly printed a paper in Nature on mind connectivity and sample affiliation in mice. What was the premise of the research?

Lee: This was a collaboration with Wade Regehr, professor of neurobiology at HMS. The paper focuses on info processing within the cerebellum, which is a mind area that, amongst different issues, is necessary for easy, coordinated motion. One of the issues the cerebellum is assumed to do is make fine-scale error corrections in motion by evaluating patterns from meant and executed actions. For instance, in case you strive to contact your nostril and also you miss, there may be info coming out of your motor system that tells your cerebellum what the meant motion was, and there may be sensory info coming out of your finger about what truly occurred, together with the situation of your finger in area. The cerebellum is assumed to compute the distinction between the meant motion and the precise motion, and to assist right the error.

We studied the cerebellar cortex, which is packed full of small neurons referred to as granule cells that make up greater than half the neurons within the mind. These granule cells every have, on common, 4 dendrites, or branching constructions that obtain info from different neurons. On this case, the dendrites join to neurons referred to as mossy fibers that deliver info into the cerebellum. The granule cells then course of this info and talk it to different neurons referred to as Purkinje cells, with every Purkinje cell integrating info from 100,000 to 200,000 granule cells, and sending this info to different mind areas. These three cell varieties make up the “feedforward” circuit we needed to higher perceive.

HMNews: What was your key discovering within the Nature paper?

Lee: Beforehand, scientists and computational fashions assumed that the dendrites on granule cells randomly linked to completely different mossy fibers, and this randomness contributed to the complexity and encoding capability of the knowledge communicated to Purkinje cells. Nonetheless, utilizing connectomics, we mapped the connections between mossy fibers, granule cells, and Purkinje cells. We discovered that the dendrites on granule cells don’t join to mossy fibers in a random method. As an alternative, they join to mossy fibers selectively, with extra granule cells connecting to the identical mossy fibers than anticipated. This selectivity ought to lower the encoding capability of the knowledge that may be conveyed — however it seems that for less than a really small lower in capability, you get extra robustness in sample affiliation. We predict it is because there may be extra redundancy within the connections between granule cells and mossy fibers, and granule cells could also be connecting to more-informative mossy fibers.

This can be a discovering that leverages connectomics to set up extra complete circuit construction by permitting us to take a look at how massive populations of neurons are linked to one another in the identical circuit. We want this connectivity info to make detailed and complete fashions of how info flows via the community. This paper demonstrates how connectomics can be utilized to present knowledge to check long-standing theories about info processing and sophisticated neural networks.

HMNews: What else do you assume connectomics may also help scientists work out?

Lee: One thing that I feel goes to be actually highly effective within the close to future is what persons are calling “comparative connectomics,” or evaluating completely different connectomes. I’m notably enthusiastic about taking a look at how behavioral variations throughout people correlate with variations of their connectomes. I’m additionally occupied with evaluating connectomes for various species to see what ideas are conserved in several sorts of brains. As well as to discovering conserved ideas that may be generalized throughout species, I would like to discover differentiating ideas that make people distinctive. Finally, our widespread humanity could lie within the shared construction of how our brains are wired.

HMNews: Why do you assume connectomics is such a rising field?

Lee: Progress has been partially pushed by advances in expertise, together with advances in mechanical engineering that enable us to scale knowledge acquisition, in addition to advances in genetic engineering that enable us to label particular cell varieties. Moreover, the field has been remodeled by machine studying, which can be utilized to analyze these datasets to extract organic perception. The connectomics field is an attention-grabbing convergence of neurobiology, engineering, computing energy, and synthetic intelligence.

We’ve been growing rather a lot of completely different applied sciences for scaling up knowledge era and knowledge evaluation that I feel shall be helpful in different scientific disciplines. We’re producing some of the largest picture datasets on the earth proper now, and there are extra to come. For instance, the NIH has a aim of mapping an entire mouse mind connectome within the subsequent 10 years, which might be a couple of zettabyte of knowledge, or a trillion gigabytes. Researchers additionally need to map human and nonhuman primate brains.

We’ve solely scratched the floor of understanding how neurons are linked to each other to type purposeful networks, however connectomics is arguably remodeling neuroscience. I consider we’re on the cusp of understanding circuit mechanisms underlying how neurons and networks of neurons compute. We’re on the precipice of understanding the essential constructing blocks of neural networks, together with the foundations by which they join to each other and the foundations that underlie the computations they perform. To me, that’s actually, actually thrilling.

Authorship, funding, disclosures

Extra authors on the paper embrace Tri Nguyen, Jeffrey Rhoades, Xintong (Cindy) Yuan, Logan Thomas, Ilaria Ricchi, and David Hildebrand of HMS; and Jan Funke and Arlo Sheridan of the Howard Hughes Medical Institute.  

Assist for the analysis was offered by the Nationwide Institutes of Well being (R21NS085320; RF1MH114047; R01MH122570; R35NS097284), the Bertarelli Program in Translational Neuroscience and Neuroengineering, The Stanley H and Theodora L Feldberg Basis, and the Edward R. and Anne G. Lefler Middle.

This interview was edited for size and readability.

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Structured cerebellar connectivity helps resilient sample separation

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The Obsessed Guy
Hi, I'm The Obsessed Guy and I am passionate about artificial intelligence. I have spent years studying and working in the field, and I am fascinated by the potential of machine learning, deep learning, and natural language processing. I love exploring how these technologies are being used to solve real-world problems and am always eager to learn more. In my spare time, you can find me tinkering with neural networks and reading about the latest AI research.


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