What is memory? Memory is an organism's ability to store, retain, and recall Knowledge Behaviors Values or Preferences contextual (explicit) or non‐contextual (implicit) resulting from single or repeated presentation of stimuli facilitated by motivation and emotion consciously or without conscious awareness
Pavlovian conditioning
Ring!
Ivan Pavlov (1849‐1936) Ring!
Classification of memory in Neuroscience • Declarative memory formation • Procedural memory formation • Emotional memory formation
How can you detect memory formation in the brain? Changes in neural activity detected with BOLD (blood‐oxygen‐level‐dependent) contrast in fMRI magnetic fields in MEG electric activity in EEG radioactivity of chemicals in PET multi‐unit recording, extracellular field potential recording intracellular recording (voltage clamp, current clamp) in vivo calcium or voltage imaging Changes in neural structure real‐time in vivo imaging one‐shot imaging by (immuno)histochemistry in LM and EM Changes in biochemical activity real‐time in vivo imaging with various fluorescence reporters one‐shot analyses of amount, phosphorylation or other modifications
Synaptic Connections in Neuronal Cells
What is neuronal substrates of memory? Molecular alterations expression/trafficking of receptors/ion channels phosphorylation of receptors or enzymes
Structural alterations in neuronal cells depletion of vesicles spine/synapse enlargement/shrinkage synaptic formation and elimination
Synaptic Connections in Neuronal Cells
Ionotropic glutamate receptors
Synaptic Connections in Neuronal Cells
Voltage‐gated calcium channels
Synaptic Connections in Neuronal Cells
Voltage‐gated pottassium channels
LTP and LTD: necessary for learning? • Hebb predicted strengthening of specific synaptic connection after associative learning (1949). • Bliss and Lømo discovered long‐term potentiation of hippocampal field excitatory postsynaptic potentials after tetanus (1973). • Lynch and Baudry proposed NMDA receptor hypothesis (1984).
NMDA receptor‐dependent LTP in CA1 Useful for exploring how patterns of synaptic activity drive changes in efficiency of neuronal communication
Motor Learning ------- Repetition of Training Short-term Memory
Long-Term memory
Acquisition of Motor Skill
Consolidation
Autonomic Behavior (Unconscious)
小脳皮質 Granule cell layer
分子層
白質
Purkinje cell
Granule cell
Long‐Term Depression of Parallel Fiber EPSP in Cerebellar Slices
Conjunctive stimulation of parallel and climbing fibers
(Karachot et al., 2001)
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
Molecules Involved in Long‐Term Depression at Parallel Fiber‐Purkinje Cell Synapses
PKG
Depolarization
CaMK
LTD is not essential for motor learning
(Schonewille et al., Neuron 2011)
Adaptation of HOKR
HOKR: Horizontal OptoKinetic Response
HOKR training induces adaptation
Short‐term (STA)
Long‐term (LTA)
Neural circuit of the HOKR Screen Movement
FL PF
LTD MF CF Vestibular complex
IV III
RtTg
Retinal slip signal Inferior olive
Pretectal area
CF: Climbing fibre FL: Flocculus HOKR: horizontal optokinetic response RtTg: Reticulotegmental nucleus of the pons MF: mossy fibre PF: parallel fibre III: the third cranial nerve IV: the fourth cranial nerve
Neural circuit of the HOKR Screen Movement
FL PF
LTD MF CF Vestibular complex
IV III
RtTg
Retinal slip signal Inferior olive
Pretectal area
CF: Climbing fibre FL: Flocculus HOKR: horizontal optokinetic response RtTg: Reticulotegmental nucleus of the pons MF: mossy fibre PF: parallel fibre III: the third cranial nerve IV: the fourth cranial nerve
Neural circuit of the HOKR Screen Movement
FL PF
LTD MF CF Vestibular complex
IV III
RtTg
Retinal slip signal Inferior olive
Pretectal area
CF: Climbing fibre FL: Flocculus HOKR: horizontal optokinetic response RtTg: Reticulotegmental nucleus of the pons MF: mossy fibre PF: parallel fibre III: the third cranial nerve IV: the fourth cranial nerve
Anatomy of flocculus
FL PFL internal control
1mm
1mm
FL Synapses from control (A) or trained (B) animal 15 nm gold for GluR2 5 nm gold for pan AMPAR Parallel Fibre Parallel Fibre A: Control
Purkinje cell spine
B: Trained
Purkinje cell spine
Density of AMPA receptor particles: 771.68547 /m2
530.70547 /m2
Neural substrate for STA ‐ Quantification of AMPAR density by SDS freeze‐fracture replica labeling (FRL) Massed 1h training
AMPAR density in FL transiently reduces after 1 hr HOKR training Wang et al
Selective decrease of PF‐PC synapses in FL after long‐term adaptation
‐33.3%
Spine Density Analysis on Golgi Stained Sections by Ultra High Voltage EM Control
FL
PF‐PC synapse density negatively correlates with LTA
CONCLUSION Regulation of different AMPA receptor subunits dynamics in synapses may underlie short‐ and long‐term memory in the hippocampus. Regulation of AMPA receptor dynamics in synapses and presynaptic release may underlies some kinds of long‐ term memory in the amygdala. Regulation of AMPA receptor dynamics and synapse structure may underlie short‐ and long‐term memory in the cerebellum.
