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

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?

• How can we make associative learning devices and what are they good for?

Pre-Synaptic (Eccles) Post-Synaptic (Hebb)

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are needed to see this picture.





Coincidence detectors

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are needed to see this picture.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

A Model of Pre-Synaptic AC based Learning

• Gingrich and Byrne (J. Neurophys. 1987)





Paramecia Exhibit Classical Conditioning

• Todd Hennessey et al

• Shock (UCS) + Vibration (CS) classical conditioning of ‘avoidance response’ in paramecia.

UCS = ShockCS = VibrationR = Avoiding Response

Sensory Mechanisms in Paramecia

• Mechano: Eckert, Naitoh and Friedman. J. Exp. Biol. (1972)





K+ current

Ca2+ current



MACHEMER & ECKERT1973

Applyingdepolarizationproduces reversal

Ca2+ channels are on the membrane surrounding the

ciliaQuickTime™ and a

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Shaving cilia abolishes Ca2+

current, until they grow back.

Voltage gated Ca2+

channels are essential

Behaviour of voltage gated Ca2+ channels can be

modulated



Vibration??



Ciliary Ca2+-Calmodulin

activates ciliary AC.

Is AC acting as a coincidence detector in classical conditioningin paramecia? How is AC activity influenced by vibration? Is spatial distribution of membrane de/hyper-polorization relevant?



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?

AC

Depolorization

Ca2+ channelCa2+

ATP cAMP

PKA

Gene mediatedmemory

Reduced CDI

VibrationCiliary beatreversal

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.

u1

u2 U2*

U1*

oPKK

mPK*2 mPK

mPK*1 mPK

PKK + u1 PKKu1

PKK + u2 PKKu2

10

10

0.005

Cilia feedback signal PKK

V

S

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.

Kinase Cascades with Positive Feedback

u1

u2 U2*

U1*

PKK

PK*2 PK

PK*1 PK

PKK + u1 PKKu1

PKK + u2 PKKu2

Promotor Gene

NS Phosphatase

10

10

0.005

A more general mechanism

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?

Acknowledgements

• T. Hennessey

• D. Stekel

• E. Szathmary

• J. Rowe

Documents

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