" THINK BIG, "
Brains have [big number] neurons that make around [stupendously big number] connections, or synapses, with each other. How do genomes with ~10^4 genes direct the development of such complex structures? This is the so-called ‘wiring problem’.
The consensus resolution to the compression issue, i.e. the information mismatch between the genome and the brain, involves combinatorics and target reduction. Single genes do not match up neurons; sets of genes do. And, the same sets of genes can be re-used for different neurons provided they are separated in space and/or in time.
What we have not had a chance to approach is the quality control issue: The brain is a highly stereotyped structure; specific synaptic connections between distinct neurons are required to ensure proper function of constituent circuits and systems. How are these strict tolerances safeguarded against the biological noise inherent in the collective genetic output of a [big number] of cells?
The brain continues to develop after birth; both in early life and in the adult, synaptic connections can be altered and circuits refined in response to experience-dependent neuronal activity. Notably, neuronal activity independent of experience or stimulus is a well-known feature of mammalian brain development. In the visual system, disrupting this activity leads to disorganized synaptic contacts between the retina and higher visual centers.
The consensus resolution to the compression issue, i.e. the information mismatch between the genome and the brain, involves combinatorics and target reduction. Single genes do not match up neurons; sets of genes do. And, the same sets of genes can be re-used for different neurons provided they are separated in space and/or in time.
What we have not had a chance to approach is the quality control issue: The brain is a highly stereotyped structure; specific synaptic connections between distinct neurons are required to ensure proper function of constituent circuits and systems. How are these strict tolerances safeguarded against the biological noise inherent in the collective genetic output of a [big number] of cells?
The brain continues to develop after birth; both in early life and in the adult, synaptic connections can be altered and circuits refined in response to experience-dependent neuronal activity. Notably, neuronal activity independent of experience or stimulus is a well-known feature of mammalian brain development. In the visual system, disrupting this activity leads to disorganized synaptic contacts between the retina and higher visual centers.
Stimulus-independent activity in the developing fruit fly visual system. All neurons are expressing the genetically encoded calcium indicator, GCAMP6s.
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We discovered comparable stimulus-independent activity in the developing brain of the fruit fly—the first observation of such a phenomenon in an invertebrate. Molecular mechanisms of brain development are remarkably similar between vertebrates and the fly. In many cases, families of homologous genes whose point of origin stretch back some five hundred million years are used to the same effect. In others, common developmental demands appear to have produced convergent solutions from different starting points. Such parallels, which also extend to the organization of neuronal circuits, particularly in the visual systems, point to intrinsic constraints evolution must contend with in building complex brains. Now that stimulus-independent neuronal activity also appears to be a shared feature of development, it is tempting to ask if this phenomenon also exists to address a common biological constraint.
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We do not have a full understanding of the functional significance of stimulus-independent activity to brain development in any system. At its onset in the fly, stimulus-independent activity is coordinated across the entire central nervous system, suggesting that an early collection of synapses, or connectome, is present at this time. This early connectome would be built through local, largely contact-dependent interactions. While the level of organization achieved through such mechanisms is astonishing, the early connectome may still be a coarse approximation of what is required in the adult. By coordinating communication at temporal and spatial scales inaccessible to earlier signaling mechanisms, neuronal activity has the potential to connect cells that never came into contact through development. Perhaps stimulus-independent activity represents simulated experience, which exercises and refines nascent circuits as a final quality check on brain assembly.
We have the fly to thank for inspiring us to think big. We will also depend on it to work small.
We have the fly to thank for inspiring us to think big. We will also depend on it to work small.