Download Event memory

- Features of the memory trace (engram),
- Memory types, memory systems
Richard Semon (1859-1918) and the concept
of engram” (engramme, memory trace)
1904 - Die Mneme
1) Engram is a persistent alteration in the brain as a result of a specific
event.
2) The content of the engram is linked to the information perceived during
encoding and predict what can be recalled later.
3) A major feature of engram is ecphory, the ability to change behavior when
reactivated with the appropriate keys.
4) The engram is in a dormant state between encoding and retrieval.
“ Engram is the enduring though primarily latent modifications in the
irritable substance produced by a stimulus…”
“Ecphory awakens the engram out of its latent state into
one of manifested activity… “
Synaptic (LTP)
(pre-, postsyn.
receptors etc)
Plasticity and the substrate of
engram at different levels of
organization
Nuclear
(CREB,hiszton,
c-fos, Arc,
synaptic tag)
Dendritic spines
(size, shape,
longevity)
Neuronal networks
(subnetworks
sparse, dense code)
Brain regions, memory systems
The “life cycle” of the engram
Josselyn et al., 2015 NRN
The engram in case of fear memory
Neuronal representations of engrams
Nat Rev Nsci
5:361
Nakazawa,
1) Persistent, linked to a
special event
2) Linked to the perceived
information
3) Able to change
behavior
4) Gets into a dormant
state (sleep replay only
for 24 hours)
Running
5
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During
sleep
Neuron
36:1183
Lee, Wilson
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0,15 mp
Replay of the engram during sleep and memory consolidation
1. After encoding the engram reactivates spontaneously during
sleep
2. The degree of reactivation is correlated with the degree of
engram retention (memory)
3. Inhibiting reactivation impairs the memory trace
4. Sensory stimuli present during encoding may recall the engram
at a later phase.
Specificity of coding and recalling the engram in humans
The dormant state of the engram
How can we study or demonstrate the existence of the dormant engram?
(sleep replay only for 24 hours)
Labeling (dormant) engram cells
Activity dependent neuronal labeling:
immediate early genes – c-fos, Arc, zinc finger 268
linked to markers which are expressed permanently
- GFP, LacZ, Channelrhodopsin!!! Halorhodopsin
How can we label the specific cell population which participates in
coding a given engram?
Tet Tag method
1) tetracyclin response element (TRE) – regulates the transcription of an
immediate early gene (IEG)
2) tetracyclin transactivator protein (tTA) – binds and activates to TRE
3) !! BUT NOT in the presence of tetrecyclin!!
Condition A - tetracyclin provided (in the drinking water) – no IEG transcription
Condition B - tetracyclin removed – IEG (and the marker) will be expressed in a
GIVEN time window. Subject the animal to a learning situation
THE RESULT: SPECIFIC MARKERS ARE EXPRESSED IN THE CELL
POPULATION WHICH WAS ACTIVATED DURING THE LEARNING SITUATION
Optogenetic activation and inactivation of labeled engram cells
Context specific
excitation/inhibition of engram
cells alters behavior
Ecphory (engram criteria 3!)
Labeling the dendritic spines!! which are involved in coding an engram
Hayashi-Tagaki et al., Nature 2015
Elimination of only those
spines which are involved
in coding an engram
Hayashi-Tagaki et al., Nature 2015
The effect of eliminating
the spines involved in the
engram in case of motor
learning
Ctr
Venus
Venus
Venus
Allocation – insert given neurons to the engram
Basic idea
Neurons which are spontaneously more depolarized than the average during the
learning situation are more likely to participate in establishing the engram
If we are able to slightly depolarize a given cell population we can
promote their participation in the engram
STEP FUNCION OPSINS AND
DREADDs
Designer Receptors Exclusively Activated by Designer Drugs
DREADD – and the chemogenetic activation
Designer Receptors Exclusively Activated by Designer Drugs
Designer receptor (DR): A G protein coupled receptor which has no ligand in the
mammalian nervous system (excitatory/inhibitory, M2/M4)
Designer Drug (DD): A drug which can be injected systematically, crosses the
bold-brain barrier and acts on DRs at nanomolecular concentration
Experiment:
1) Express DR in a well-defined cell population
2) Inject DD
3) Subject the animals to a learning situation
Labeled cell will more (or less) likely to participate in the engram
The effect of excitation and inhibition of the cells allocated to the engram
SUMMARY
Studying Semon’s four postulates of engrams in the 21st century
1) Strucutral basis of engram
Long term Ca-imaging, electron microscopy
2) Content of the engram
recording the activity of neuronal networks, fMRI
3) Ecphory , the effect of engram on behavior
Opto- and chemogenetic experiments
4) Sleeping engram
Opto- and chemogenetic experiments
All memory works according to these principles?
How many types of memory we have?
Memory impairments of HM bilateral temporal lobectomy (1953)
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•
•
•
•
New events, autobiographic data
New words, new persons
Spatial navigation, new places
Recognition tests (longer than 5 min)
Retrogád amnesia (11 years)
”...forgetting of the events of daily life as quickly as they occur”
(Scoville and Millner, 1957)
HM - Henry Gustav Molaison
MRI of HM
The lobectomy involved the
majority of hippocampus parts
of the amygdala and entorhinal
cortex.
The selectivity of memory impairments in case of H.M:
Impaired:
Intact:
Memory of events
Mirror drawing
Intact - Perceptual Priming –
Two versions of recalling words
After reading 20 words
Free recall:
What did you read?
Complex, contextual learning
Hippocamal lesion - Impaired
Perceptual priming:
What word comes to your mind?
Simple association
Hippocampal lesion - Intact.
Ép marad – Rövid távú memória
Different types of memory?
Different memory systems?
• Motor memory (Procedural, Implicit) • Event memory (Declarative,
explicity)
 Requires training, practice
 Can be recalled in situation identical to
the learning situation (rigid)
 Can be distructed by learning similar
things
 Can display plasticity in case of brain
damage
Sport, typing, driving, dancing, priming,
operant and classic conditioning
 Requires a single event
 Can be recalled in various
situations
 More difficult to distruct
 No recovery after damage
Personal events, persons, data,
spatial navigation, words
• Fear memory, reward memory
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

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In case of significant events single association may be sufficient
Can be recalled in situation identical to the learning situation
Highly pronounced vegetative responses (heart, breathing, sweat)
foot shock, kokain
Motor memory circuit
Event memory circuit
Temporális kéreg
Hippokampusz
Frontal cortex
Thalamus
Thalamus
Basal
ganglia/
Cerebellum
Iplastic synapses
Mammillary
body
Fear memory
Prefrontal
cortex
Thalamus
Amygdala
Autonom
centers
MEMORY SYSTEMS – 1.
Hippokampus
Event memory circuit, Papez-circuit
Mamillary body
Anterior talamus
Parahippocampal,
perirhinal and
posterior cingulate
cortices
...and Dracula
The effect of anterior thalamic lesion on hippocampus dependent spatial
memory task
4 arm maze
Fewer arm entry – better performance
SHAM - kontroll lesions
AM/AV/AD- anterior thalamic nuclei
Aggleton et al,. 1996
MEMORY SYSTEMS – 2.
Motor memory circuits (Reward memory)
MEMORY SYSTEMS – 3.
Fear memory
midline thalamus
medial prefrontal
cortex
amygdala (lateral,
basolateral, central)
Synaptic (LTP)
(pre-, postsyn.
receptors etc)
Plasticity and the substrate of
engram at different levels of
organization
Nuclear
(CREB,hiszton,
c-fos, Arc,
synaptic tag)
Dendritic spines
(size, shape,
longevity)
Neuronal networks
(subnetworks
sparse, dense code)
Brain regions, memory systems