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2nd half of the course
• Spatial Processing
• LTP
Ongoing operation of the hippocampus
and related brain structures
during memory performance
• functional neuroimaging methods in
normal humans
• recording of the activity patterns of
single neurons in animals.
Nature of the task:
• Allocentric (world centered) processing
• Egocentric (body centered) processing
Critical structures in the memory
system of the medial temporal lobe
1
2
the hippocampus
the parahippocampal region
Functional imaging studies of
Human spatial navigation
Hippocampus place cells in rats
Initial report:
fire only when the rat is in a particular location
Recent analysis
Navigation cues:
• external landmarks
• idiothetic (self-motion) cues
Neural mechanisms:
•Cell types
Place cells: hippocampus
head direction cells
•Response properties for both types of cells
Controlled by an interaction
between landmarks and idiothetic cues
Neural mechanisms (Con’t):
Theory
Place cells – cognitive map model
Alterative theories: Eichenbaum “memory space” model
o Place cell not exist and function together
as a simple topography of external space as was originally suspected.
o these cells fire in response to
the complex interaction of multiple cues and
not in response to an internal Cartesian coordinate system.
LONG-TERM POTENTIATION (LTP)
Anatomical background
Hippocampal formation: two interlocking
C-shaped regions (the hippocampus and
the dentate gurus)
main inputs to the hippocampal
formation: entorhinal cortex via axon of
the perforant pathway
Hippocampus has three major afferent
pathways
Mossy fiber
pathway
Perforant
pathway
entorhinal
cortex
subiculum
• Perforant pathway
(subiculum -> granule cells
in dentate gyrus)
• Mossy fiber pathway
(axons of the granule
cells -> pyramidal cells in
the CA3)
• Schaffer collaterals
(pyramidal cells in the
CA3 -> pyramidal cells in
the CA1)
dentate
gyrus
CA3
Schaffer
collaterals
CA1
Underlying molecular mechanisms
• LTP (in area CA1) depends on certain changes at
glutamate synapses
• LTP requires some sort of additive effect of highfrequency stimulation,
•Activation of synapses and depolarization of
the postsynaptic neuron must occur at the
same time
•Types of glutamate receptors
•NMDA receptors
•Non-NMDA receptors
At NMDA receptors
background
1. Controls a calcium ion channel
2. glutamate is neither excitatory nor inhibitory
3. Ion channel is blocked by magnesium ions
DURING INDUCTION
1. Mg2+ removal
2. Ca2+ entry
3. After induction of LTP, transmission at non-NMDA receptors is
facilitated (entry of Na+)
Inside the cell
1. Ca2+ activates some protein kinases (catalyze
phosphorylation)
2. Calcium-calmodulin kinase (CaM kinase)
3. The activated protein kinases also trigger the synthesis of
proteins
1. activate cAMP responsive element-binding protein
(CREB)
2. CREB -> production of the transcription (mRNA) of IEGs
-> regulate the expression of particular late effector
genes (LEGs) -> synthesis of proteins
4. Induction of LTP requires a retrograde signal, from the
postsynaptic neuron to the presynaptic neuron
LINKS BETWEEN LTP AND LEARNING AND MEMORY
Molecular Approaches
NMDAR-dependent LTP - spatial learning in the water maze?
Water maze overall performance (Morris et al, 1986)
Partition of the task into two components (Bannerman et al, 1995)
Non-spatial pretraining and
Spatial training
Gene knockout mutants (NMDAR)
Gene disruption at embryotic stage (early studies)
mutants with effects that are regionally and temporally restricted
Electrophysiological Approaches
Does learning produce LTP-like changes?
skilled learning (Rioult-Pedotti, 1998, 2000)
Does induction of LTP influence learning?
prior to learning (to saturate normal LTP) (Moser, 2000)