Learning and Memory

Dr. Atomu Sawatari

Systems Neuroscience Lab
atomu@medsci.usyd.edu.au
 Learning and Memory
• What is memory?
• Different categories

• Memory Processes

• Memory Mechanisms
• Neural evidence
• LTP
• Different types
• Possible outcomes
 Relevant brain areas
• Declarative
• Cortex, medial temporal lobe, medial diencephalon, basal
ganglia

• Nondeclarative
• Cortex, basal ganglia, cerebellum, amygdala

• Working
• Cortex, medial temporal lobe (?), basal ganglia (?)
Figure 1. Basic Anatomy of the Basal Ganglia and Schematic of Frontostriatal Circuitry(A) Locations of basal ganglia structures are
outlined on coronal slices (caudate, putamen, and nucleus accumbens [NAcc]); GPe, external segment of the globus pallidus; GPi, ...

Jason M. Scimeca, David Badre

Striatal Contributions to Declarative Memory Retrieval
null, Volume 75, Issue 3, 2012, 380–392
http://dx.doi.org/10.1016/j.neuron.2012.07.014
 Memory processes
Focus on explicit memory
• Encoding
• Formation of a representation of knowledge
• Consolidation
• Conversion to long- term persistent memory
• Storage
• Persistent memory “transferred” over time to permanent
storage “location” – not consciously aware
• Retrieval
• Process of accessing stored memory to subserve
behavior
 Memory mechanisms
• Engrams
• Cells within the dentate gyrus

Susumu Tonegawa, Xu Liu, Steve Ramirez, Roger Redondo

Memory Engram Cells Have Come of Age

null, Volume 87, Issue 5, 2015, 918–931

http://dx.doi.org/10.1016/j.neuron.2015.08.002
 Memory mechanisms
• Retrieval?

• Frontal cortex: ACC

 Memory mechanisms
• Retrieval?

• Hippocampus

• “Dynamics of retrieval strategies for remote memories”

(Goshen, et al., 2011)
The hippocampus is involved in memory

A)Formation and consolidation

B)Storage
C)Retrieval
D)All of the above
 Memory mechanisms
• What’s the mechanism?
• Hebb’s Rule:

“When an axon of cell A is near enough to excite cell B and

repeatedly and persistently takes part in firing it, some
growth process or metabolic change takes place in one or
both cells such that A’s efficiency, as one of the cells firing
B, is increased” (Hebb, 1949)

“Cells that fire together, wire together.”

• Mechanism would require some form of persistent,

activity dependent change in synaptic strength
 Memory mechanisms
• What is the mechanism?
• Long term potentiation (LTP): possible candidate

• Bliss and Lomo, 1973

• Stimulation of the perforant
pathway resulted in
potentiated field epsp’s in
granule cell layer of DG

From Bliss and Lomo, 1973

 Memory mechanisms
• How does it work?
• Explored mostly in vitro
• Induced
• Tetanic stimulation (e.g. multiple stimulation at 100Hz for
1sec)
• Low frequency stimulation can result in LTD
• natural spike trains
• theta
• STDP
• Occurs in various brain areas
• In vivo:
• Rogan, Staubli, and Le Doux, 1997- Fear conditioning potentiates responses in
the amygdala of awake behaving rats
• Xiong, Znameskiy, and Zador, 2014 – Acquisition of an acoustic discrimination
task induces corticostriatal plasticity
_______ can induce LTP in vitro.

A)Low frequency stimulation (1Hz)

B)Natural spike trains
C)Tetanic stimulation
D)B and C
 Memory mechanisms
• How does it work?
• “Classical” properties of LTP

• Cooperative
• Greater drive, greater likelihood of potentiation
 Memory mechanisms
• How does it work?
• “Classical” properties of LTP

• Cooperative
• Greater drive, greater likelihood of potentiation

• Associative
• Pre-post co-activation leads to increased likelihood of
potentiation
 Memory mechanisms
• How does it work?
• “Classical” properties of LTP

• Cooperative
• Greater drive, greater likelihood of potentiation

• Associative
• Pre-post co-activation leads to increased likelihood of
potentiation
• Specific
• Potentiation specific to activated synapses
 Memory mechanisms
• How does it work?
• “Classical” properties of LTP

• Cooperative
• Greater drive, greater likelihood of potentiation

• Associative
• Pre-post co-activation leads to increased likelihood of
potentiation
• Specific
• Potentiation specific to activated synapses

• All share an increase in intracellular calcium concentration

in key compartments of pre- and/or post-synaptic cells
 Relevant brain areas
Sub

CA1

CA3

DG

Other Areas Entorhinal

Perirhinal Parahippocampal

Association Areas
Adapted from Squire and Dede, Cold Spring Harb Perspect Biol 2015;7:a021667
 Memory mechanisms
• Hippocampus
• EC (superficial) to dentate gyrus
(DG) via Perforant path

• DG to CA3 via the Mossy fibres

• CA3 to CA1 via the Schaffer

collaterals

• CA1 projects out of the

hippocampus or to the subiculum
 Memory mechanisms
• How does it work?
• Hippocampus

• NMDA receptor dependent

• Occurs at CA3 to CA1 synapse

• Associative: requires both pre- and post-synaptic activation
• Both ligand (glutamate) and voltage dependent
• Voltage dependent release of Mg++ block necessary to open channel-may
require back-propogating AP
• Allows Ca++ to enter post synaptic terminal
 Memory mechanisms
• How does it work?
• Hippocampus

• NMDA receptor independent

• Occurs at (e.g.) Mossy fibre-CA3 synapse

• Non-associative: Does not require simultaneous pre- and pos-synaptic activation
• Pre-synaptic voltage gated Ca++ channels (VGCC) allow direct influx of Ca++:
Ca-Calmodulin-cAMP-PKA
• At the Mossy fibre synapse, LTP dependent on the increase in Ca++
concentration in the pre-synaptic terminal
 Memory mechanisms
• How does it work?
• Hippocampus

• NMDA receptor independent

• Class I mGluRs:
• activates phospholipase C (PLC)
• yields diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3)
• modulate channel activity via protein kinase C (PKC)
• open intracellular stores of Ca++ respectively – leads to induction
of LTP
LTP at the Mossy fibre to CA3 synapse is

A)NMDA independent
B)Non-associative
C)Predominantly due to changes at the pre-synaptic level
D)All of the above
 Memory mechanisms
• How does it work?
• General

• Spike time dependent plasticity (STDP)

• Dependent on timing of pre and post synaptic spiking

• Positive (potentiating) vs. negative (depressing) timing vs. window
• May vary between cell types (excitatory vs. inhibitory)

• Mechanism
• NMDA for potentiating
• NMDA desensitization, mGluR, pre-synaptic NMDA for depressing

• In vivo
Generally, positive timing (pre- prior to postsynaptic spiking) to

A)Potentiation
B)Depression
 Memory mechanisms
• How does it work?
• Different mechanisms
• Early LTP
• 1 to 3 hours
• Elevated intracellular Ca++ levels
• May be regulated by increased probability of transmitter release
at the pre-synaptic terminal
• Does not require new protein synthesis
• Late LTP
• At least 24 hours
• Requires new RNA and protein synthesis
• Over the long term, LTP activates adenylyl cyclase, which in turn
activates a cAMP dependent kinase that translocates to the cell
nucleus, phosphorylating CREB. CREB activates targets that
eventually lead to structural changes.
• Not set in stone
 Memory mechanisms
• How does it work?
• Different possible outcomes

Pre-
• Increased probability of release
• Increased number of pre-synaptic release sites
• Increase in the number of available vesicles
Post-
• Increased receptor sensitivity
• Increased number of functional receptors
Both
• Pre- and post-synaptic morphological changes
Protein synthesis is generally associated with

A)Early LTP
B)Late LTP
 Memory mechanisms
• How does it work?
• General

• Circuit level plasticity

• Developmental critical periods

• Heightened plasticity
• Offset maturation of excitatory and inhibitory networks

• Inhibitory networks
• Help to establish oscillatory networks, synchronize activity
• Regulate circuit level plasticity

• Always a good thing?

• “Neocortical excitation/inhibition balance in information processing and social
dysfunction.” (Yizhar, et al., 2011)