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Basic Wiring Diagram of the Brain — from cells to Cajal to connectome — Larry W. Swanson

Discover the neural system underlying drinking, eating, eye movements, and other behaviors through the basic wiring diagram of the brain. Explore the foundational importance of accurate structural data and the historical revolutions in neuroscience.

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Basic Wiring Diagram of the Brain — from cells to Cajal to connectome — Larry W. Swanson

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  1. Basic Wiring Diagram of the Brain — from cells to Cajal to connectome — Larry W. Swanson University of Southern California …

  2. Stevenson (1969) Reeves & Plum (1969)

  3. Drinking to angiotensin II (peptide) or carbachol (classical) (threshold dose in 100 nl) Response Angiotensin II CarbachoI No response Adapted from Swanson & Sharpe, Amer. J. Physiol. (1973)

  4. What is the neural system underlying drinking and eating behaviors?? Like: What system controls eye movements, or reaching and grasping?

  5. Limbic forebrain macroconnections (physical axonal projection from one cell group to another) Bota, Dong & Swanson (2003) From gene networks to brain networks. Nature Neuroscience6:795

  6. Phases of basic motivated behaviors Survival of the individual, and of the species (adapted from: Swanson & Mogenson, BRR3:1-34, 1981) • 1. Initiation • • sensory (external, internal) • • cognitive (learning/experience, prioritization) • • behavioral state (sleep/wake, attention) • 2. Procurement • • exploratory/foraging behavior • • anticipation (drive, intention, expectation) • 3. Consummatory • • motor pattern generators • • satiety & reinforcement

  7. Basic plan of nervous system… What are we looking for exactly? Organizing principles: model of how system works as a whole Foundational importance of accurate structural data & model (adequate functional model can’t be based on inaccurate structural data)

  8. Watson & Crick, Nature, April 1953 (genome 50 years later)

  9. Pauling & Corey PNAS February, 1953 c1951 Franklin’s “structural minutiae” critical

  10. “To extend our understanding of neural function to the most complex human physiological and psychological activities, it is essential that we first generate a clear and accurate view of the structure of the relevant centers, and of the human brain itself, so that the basic plan — the overview — can be grasped in the blink of an eye.” — Santiago Ramón y Cajal (Histology of the Nervous System…, 1909) — died October 17, 1934 at age 82

  11. Basic plan of nervous system… (theoretical foundation of systems neuroscience) long history — short overview

  12. The 3-cell theory of NS organization — Aristotle & Galen foundation but medieval theorizing; “psychicpneuma” Gregor Reisch, 1503 Margarita Philosophica (“Pearl of Wisdom”)

  13. A revolution: observation & experimentation added to pure hypothesizing (1543-1628)

  14. Andreas Vesalius (1543) — “I can in some degree follow the brain’s functions in dissections of living animals [experimentation] with sufficient probability and truth, but I am unable to understand how the brain can perform its offices of imagining, meditating, thinking, and remembering…”

  15. “…we were shown a figure from some Philosophic Pearl which presented to the eyes the ventricles so discussed…Such are the inventions of those who never look into our Maker’s ingenuity in the building of the human body! How such people err in describing the brain will be demonstrated in our subsequent discussion.” — Vesalius (1543) Gregor Reisch, 1503 “Pearl of Wisdom”

  16. Robert Fludd, 1617-21 Utriusque cosmi…

  17. René Descartes De homine (1662)

  18. Thomas Willis (1664) 1. Greatly influenced by Harvey’s revolutionary Circulatory System model (replaced Galen’s model): • Psychic pneuma circulation for NS 2. Cerebri anatome was highly original: Shifted focus from ventricles to parenchyma: • Gray matter production (2 sites)/ • White matter conduction [Relegated ventricles to sink for excrementious material] 3. His theory was highly speculative

  19. Willis theory (1664) on Nicolas Steno drawing (1669) — 4 nodes, 12 projections 3 2 5 1 4 6

  20. Another revolution: Thecell theory (Schleiden & Schwann 1839)

  21. Purkinje (1838) Birth of cytoarchitecture: connections? 16. Substantia nigra 17. Thalamus 18. Cerebellum 19. Inferior olive

  22. How do nerve cells interact? • “Great enigma of 19th c. neurology” • Cajal’s genius at cell level (Golgi’s method) — • Axon termination mode demonstrated in adult CNS (1888): “Articulation” • Dendritic spine (1888) • Neuron doctrine elaborated (1888-): Nervous system not syncytium • Functional polarity theory refined (1889-): Axon is output (structure = function) • Growth cone (1890) • Chemotactic theory of synapse specificity (1892) • Learning theory based on selective synapse strengthening (1892) Self-portrait @ 18 Cajal, 1870

  23. A third revolution: Cajal’s wiring diagram for systems neuroscience (two systems control behavior) In: El nuevo concepto de la histología de los centros nerviosos (1892)

  24. Cajal cellular model (1892) • Nerves don’t come from ventricles • Voluntary control of muscle starts in cerebral cortex not cerebral nuclei (basal ganglia) • Much more accurate physical model (not perfect) Magendie concept, Golgi method

  25. Cajal’s 3-subsystem structure-function nervous system model — “Grasped in the blink of an eye...”

  26. Four subsystem model • Network (not hierarchical) model with feedback • B=Mo=f(ri + si + vi) Adopted from Swanson, Brain Architecture, 2003

  27. Motor subsystem hierarchy — Basically Grillner model (locomotion analysis) Swanson, J. Comp. Neurol.493: 122, 2005

  28. 26 from Swanson 1998-99

  29. Ingestive Behavior Controller (PVH): Inputs Swanson (2000) [Sawchenko collaboration]

  30. Sawchenko & Swanson

  31. Ingestive Behavior Controller (PVH): Outputs Swanson (2000)

  32. Adapted from Swanson, J. Comp. Neurol.493: 122, 2005 [Saper; Köhler, Simerly, Watts, Canteras; Risold, Thompson, Hahn]

  33. Triple descending cerebral projection to motor system — From eye movements to eating… Cerebral nuclei Adapted from Swanson, J. Comp. Neurol.493: 122, 2005

  34. Cerebrum to BCC: — Topograpic inputs (specific) (general) Adapted from Swanson, Brain Res.886:113-164, 2000 [also Petrovich, Dong]

  35. The next phase… • A systematic, high resolution, global structural analysis: • (data like W&C had to construct their model>genome) • Scope of problem: • Boundary conditions for mammalian brain? • New approaches: • Data generation (fast)vs. • Analysis & modeling (slow bottleneck)

  36. Brain comparison estimates: (order of magnitude) Human Mouse Weight Neurons Synapses 1500 g 1011 1014 0.5 g 108 1011 adapted from Swanson 1995, Williams 2000

  37. Nicolaus Steno (1669) — “Because the brain is a machine [Descartes, 1662], we needn’t hope to discover its plan by methods other than those used for other machines — dismantle all its components, piece by piece, and consider what they can do individually and as a whole.”

  38. What are the basic parts? • How does each work? • (local organization) • How are they interconnected? • (rules from Connectome*) *Connectome = complete connection matrix — Sporns, Tononi & Köttler (2005)

  39. Projection 1 Cajal 1899 Projection 2 Region 2 Pathway Region 1 A. cell types, B. local circuitry, C. extrinsic connections A. cell types, B. local circuitry, C. extrinsic connections

  40. Boundary conditions: • 500-1,000 Regions (nodes) • 2,500-5,000 Neuronal cell types • 10-20 Projections (meso) / cell type • 25,000-100,000 Mesoconnections in brain adapted from M. Bota, H.-W. Dong & L.W. Swanson From gene networks to brain networks Nature Neuroscience6:795-799 (2003)

  41. Some possible solutions?

  42. [15B PYs for EM synapses — Luo, Callaway & Svoboda (Neuron 57:644, 2008]

  43. Next generation of approaches (structural skeleton for functional hypotheses) • Parts(gray matter region local organization): • Array tomography: Micheva & Smith Neuron ’07 • EM 3D reconstructions: Briggman & Denk CON ’06 • Brainbow mice: Lichtman et al. Nat. Rev. NS.’08 • Connections between parts (projections between regions) • Conventional and genetic intra-axonal pathway tracing • Double coinjection network tracing: Thompson/Swanson

  44. Double coinjection network analysis strategy — e.g., closed chain hypothesis with four nodes: Coinjection 1 Coinjection 2

  45. DCI strategy on Willis: — complete evaluation! (4 regions, 12 projections)

  46. Next generation of approaches (structural skeleton for functional hypotheses) • Data collection (fast): • Hi-throughput hi-resolution digital photography • Data extraction (slow): • Pattern recognition software • Data manipulation (sporadic): • Discovering organizing principles (intuitive, mathematical) • Combine structural Connectome information with: • fMRI connection correlation networks • Genome-wide expression patterns (AIBS, GENSAT) • Neuroinformatics (ultimately “Google Earth”) • BAMS (Mihai Bota)

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