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Associative Learning by Single Cells

Associative Learning by Single Cells. Dr. Chrisantha Fernando Systems Biology Centre University of Birmingham. Questions. How can associative learning be implemented in single cells? How can we go about trying to find if these implementations exist?

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Associative Learning by Single Cells

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  1. Associative Learning by Single Cells Dr. Chrisantha Fernando Systems Biology Centre University of Birmingham

  2. Questions • How can associative learning be implemented in single cells? • How can we go about trying to find if these implementations exist? • How can we make associative learning devices and what are they good for?

  3. Coincidence detectors Pre-Synaptic (Eccles) Post-Synaptic (Hebb)

  4. Coincidence Detection and Memory • Pre-synaptic AC coincidence detection • 5-HT (G-protein) + Ca2+/Calmodulin (Eccles) • Post-synaptic NMDA coincidence detection • Ca2+ + Glutamate (Hebbian) • Short and Long Term State Storage • AC --> cAMP [15mins] --> PKA --> Decreased K+conductance • MAPK, Prion like CREB --> CRE gene expression • Increased NMDA localization to membrane,PKC --> AMPA

  5. A Model of Pre-Synaptic AC based Learning • Gingrich and Byrne (J. Neurophys. 1987)

  6. Paramecia Exhibit Classical Conditioning • Todd Hennessey et al • Shock (UCS) + Vibration (CS) classical conditioning of ‘avoidance response’ in paramecia. UCS = Shock CS = Vibration R = Avoiding Response

  7. Sensory Mechanisms in Paramecia • Mechano: Eckert, Naitoh and Friedman. J. Exp. Biol. (1972) Ca2+ current K+ current

  8. MACHEMER & ECKERT 1973 Applying depolarization produces reversal

  9. Ca2+ channels are on the membrane surrounding the cilia Voltage gated Ca2+ channels are essential Shaving cilia abolishes Ca2+ current, until they grow back.

  10. Behaviour of voltage gated Ca2+ channels can be modulated Vibration??

  11. Ciliary Ca2+-Calmodulinactivates ciliary AC. Is AC acting as a coincidence detector in classical conditioning in paramecia? How is AC activity influenced by vibration? Is spatial distribution of membrane de/hyper-polorization relevant?

  12. Possible Associative Learning Mechanisms in Paramecia • Is learning occurring by a mechanism analogous to pre-synaptic facilitation in Aplysia, i.e. using an AC coincidence detector, and cAMP dependent state changes mediating memory?

  13. Gene mediated memory Reduced CDI PKA Ca2+ Ca2+ channel ATP cAMP Vibration AC Ciliary beat reversal Depolorization

  14. An Intra-cellular “Hebbian” Learning Mechanism • I propose an abstract organization for an intra-cellular “Hebbian” mechanism, i.e. that depends on the extent of ciliary activity (“post-synaptic” effect) and not just on the coincidence between shock and vibration. • This can be implemented for example using a PK, PKK cascade with positive feedback.

  15. mPK*2 mPK mPK*1 mPK PKK + u1 PKKu1 10 V U1* PKK + u2 PKKu2 u1 10 u2 U2* oPKK S 0.005 Cilia feedback signal PKK

  16. Existing Components • oPKK activated along with the effecter by at least two iPKs • Two iPKs themselves activated by another mPK only when they are bound to signal molecules or signal molecules themselves are phosp. directly. • The oPKK should bind to signal molecules and specifically activate the appropriate mPK • The mPK should have a very slow equilibrium compared to the other PKs.

  17. Kinase Cascades with Positive Feedback

  18. NS Phosphatase PK*2 PK A more general mechanism PK*1 PK PKK + u1 PKKu1 10 U1* PKK + u2 PKKu2 u1 10 u2 U2* PKK 0.005 Promotor Gene

  19. Constructing an Associative Learning Circuit • Are such components known? • How to go about finding networks in existence? • How to go about making them and seeing if the idea works?

  20. Acknowledgements • T. Hennessey • D. Stekel • E. Szathmary • J. Rowe

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