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Unprecedented Mapping of Mouse Brain Achieved: A Milestone in Neuroscience
The complexity of the human brain presents a formidable challenge to scientific understanding. Even a minuscule fragment of neural tissue, roughly the size of a grain of sand, can house hundreds of thousands of cells intricately connected through extensive neural pathways. In 1979, Nobel laureate Francis Crick postulated that the detailed anatomy and activity within just a cubic millimeter of brain matter might forever elude complete comprehension.
“Requesting the impossible is futile,” Dr. Crick famously stated.
Overcoming the Impossible: Mapping a Cubic Millimeter of Brain Tissue
However, forty-six years later, a collaborative effort involving over 100 researchers has seemingly achieved this ‘impossible’ feat. They have successfully documented cellular activity and meticulously mapped the neural framework within a cubic millimeter of a mouse brain – a volume representing less than one percent of the organ’s total size. This landmark accomplishment generated an immense volume of data, totaling 1.6 petabytes, equivalent to approximately 22 years of continuous high-definition video.
“This represents a significant milestone,” commented Davi Bock, a neuroscientist at the University of Vermont, who was not affiliated with the study. Published in ‘Nature’, the research, according to Dr. Bock, signifies advancements that pave the way for a more ambitious objective: mapping the complete neural circuitry of an entire mouse brain.
“It is entirely feasible, and in my view, a profoundly worthwhile undertaking,” he asserted.
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Historical Perspective: Unraveling Neural Structures
More than 130 years ago, Spanish neuroscientist Santiago Ramón y Cajal first observed individual neurons under a microscope, discerning their unique, branched morphologies. Subsequent generations of scientists elucidated many mechanisms of neuronal communication, including how a neuron transmits an electrical signal along its axon. Each axon forms connections with dendrites of adjacent neurons, with some neurons stimulating their neighbors and others inhibiting them.
The Enigma of Human Cognition
Human thought originates from this complex interplay of neuronal excitation and inhibition. However, the precise processes remain largely enigmatic, primarily due to the historical limitations of studying only a small number of neurons concurrently.
Technological Advancements Enable Comprehensive Brain Mapping
Recent decades have witnessed technological leaps that have enabled scientists to embark on mapping entire brains. In 1986, British researchers published the complete wiring diagram of a tiny worm, comprising just 302 neurons. Following this pioneering work, researchers mapped more complex brains, including that of a fly with approximately 140,000 neurons.
Could Dr. Crick’s seemingly unattainable aspiration be realized? In 2016, the U.S. government initiated a $100 million project to scan a cubic millimeter of a mouse brain. This initiative, known as Machine Intelligence from Cortical Networks (MICrONS), brought together researchers from the Allen Institute for Brain Science, Princeton University, and Baylor College of Medicine.
The MICrONS researchers concentrated on a specific region of the mouse brain responsible for processing visual input. Initially, the team recorded neuronal activity in this area as mice viewed various landscape videos.
MICrONS Project: Detailed Neural Reconstruction
Subsequently, the researchers dissected the mouse brain and subjected the cubic millimeter sample to hardening chemicals. They then meticulously sliced the tissue block into 28,000 ultra-thin sections, imaging each one. Sophisticated computer algorithms were employed to identify cell boundaries in each image and reconstruct three-dimensional representations. In total, the team mapped approximately 200,000 neurons and other brain cells, along with an astonishing 523 million neural connections.
Nuno da Costa, a biologist at the Allen Institute and a lead investigator of the project, described witnessing the cells materialize on his computer screen as awe-inspiring. “These neurons are truly remarkable – they are a source of profound aesthetic pleasure,” he expressed.
To decipher the functional organization of this neuronal network, Dr. da Costa and his colleagues analyzed the neuronal activity data recorded while the mouse watched the videos.
“Imagine attending a gathering of 80,000 individuals where you can overhear every conversation, yet lack the knowledge of who is speaking to whom,” Dr. da Costa illustrated. “Now, envision possessing the capacity to know who is interacting with whom, but without understanding the content of their dialogues. Having both perspectives allows for a significantly richer understanding of the event.”
Insights into Brain Wiring Organization
Analyzing the extensive dataset, the researchers uncovered previously unknown patterns in brain circuitry. For example, they distinguished specific types of inhibitory neurons that selectively connected to particular neuron subtypes.
“The initial stages of brain research can feel overwhelming due to the sheer volume of connections and complexity,” remarked Mariela Petkova, a biophysicist at Harvard, who was not involved in the MICrONS project. “The identification of wiring principles is a major advancement. The brain exhibits a greater degree of order than previously assumed,” she noted.
Mapping the Entire Mouse Brain and Beyond
Many MICrONS researchers are now contributing to an even more ambitious endeavor: mapping the entire mouse brain. With a volume of 500 cubic millimeters, charting a complete brain using current techniques would require decades, potentially centuries. Scientists will need to devise innovative strategies to accomplish this within a decade.
“Their achievements thus far are already extraordinary,” acknowledged Gregory Jefferis, a neuroscientist at the University of Cambridge, who also was not involved in the MICrONS project. “However, significant challenges remain.”
Forrest Collman, a MICrONS project member at the Allen Institute, expressed optimism. He and his team have recently developed methods for creating microscopically thin sections from an entire mouse brain. “Some of the major obstacles are beginning to diminish,” Dr. Collman stated.
However, he cautioned that the human brain, approximately a thousand times larger than a mouse brain, presents a far greater undertaking. “Mapping the human brain currently seems beyond our reach,” he added. “It is not a near-term prospect.”
Sebastian Seung, a neuroscientist at Princeton and a MICrONS project participant, emphasized that similarities between mouse and human brains suggest that research in mice could yield crucial insights for developing treatments for psychological disorders, potentially with fewer adverse effects.
“Our current methods for nervous system manipulation are remarkably crude,” Dr. Seung explained. “Administering a drug results in widespread distribution throughout the system. However, the capability to precisely target and manipulate a specific cell type represents a leap forward in precision.”
Concerns Over Funding Cuts for Brain Research
The ongoing efforts to map a whole mouse brain are supported by the National Institutes of Health’s BRAIN Initiative. However, the future of this research is uncertain. Recent governmental actions include a significant reduction in funding for the BRAIN Initiative, raising concerns about the long-term viability of such ambitious projects.
Dr. Bock emphasized that large-scale brain-mapping projects like MICrONS require considerable time, partly due to the necessity of developing new technologies and software.
“Consistent and predictable science funding is essential to realize these long-term scientific objectives,” Dr. Bock concluded.