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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Coincidence detectors
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• 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)
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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)
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K+ current
Ca2+ current
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MACHEMER & ECKERT1973
Applyingdepolarizationproduces reversal
Ca2+ channels are on the membrane surrounding the
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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
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Vibration??
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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?
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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