associative learning by single cells dr. chrisantha fernando systems biology centre university of...

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

associative learning by single cells dr. chrisantha fernando systems biology centre university of...

Documents

current slide

response slide

essential slide

ampa slide

positive feedback slide

general mechanism slide

ciliary ca

mpk pkk