Download Frankland lecture FINAL

PSY5101H: The neurobiology of engrams
Agenda for today
1. Introductions
2. Short lecture
3. Course organization
PSY5101H: The neurobiology of engrams
Cavdaroglu
Dong
Jacob
Kivisik
Kramer
Lidhar
Ramsaran
Riaz
Sivaselvachandran
Vankampen
Bilgehan
Nan
Alexander
Taavi
Emily
Navdeep Kaur
Adam
Sadia
Sivaani
Lyn
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Richard Semon (1859-1916)
-- wanted to introduce precise terminology to describe
memory representations and processes:
engram = “…the enduring although primarily latent
modifications in the irritable substance produced by a
stimulus…”
i.e., the physical basis of memory, with engraphy
equivalent to encoding or memory formation
ecphory = “… the process that awakens the mnemic
trace or engram out of its latent state into one of
manifested activity”
i.e., equivalent to memory retrieval
4 defining characteristics (building on Semon)
persistence = persistent change in the brain that results from a specific
experience or event
ecphory = engram has potential to be expressed behaviorally via
interaction with retrieval cues (e.g., sensory input, voluntary goals)
content = content of engram reflects what transpired at encoding and
predicts what can be recovered during subsequent retrieval
dormancy = engram may exist in dormant state between the two active
processes of encoding and retrieval (i.e., an engram is not yet a memory but
provides the physical conditions for a memory to emerge)
From: Josselyn et al (2015) Nature Reviews Neuroscience, 16, 521-534.
What does an engram look like?
Donald Hebb (1904-1985):
-- Canadian psychologist (McGill) introduced two core
ideas:
-- learning strengthens synaptic connections between
neurons (‘neurons that fire together, wire together’)
-- synaptic strengthening provides basis for formation of
cell assemblies (i.e., collections of neurons that fire
together at time of learning and during retrieval)
What does an engram look like?
an engram thought to involve strengthened synaptic
connections between populations of neurons (or
ensembles) that are active during encoding
increased synaptic strength between these neurons
increases likelihood that same spatiotemporal pattern of
activity that occurred at encoding is recreated at later
times (i.e., retrieval)
Levels of engram analysis
an engram thought to involve
strengthened synaptic connections
between populations of neurons (or
ensembles) that are active during
encoding
but changes can be described at
multiple levels from network
epigenome
Finding engrams: 3 types of evidence
observing the engram: examination of experience-induced
changes in the brain (at level of molecules, synapses,
neurons, neuronal ensembles, networks) that may reveal the
location of the engram
 Historical roots in work of Ramon y Cajal
erasing the engram: chronic removal or acute disabling of
one or more engram components to prevent expression of
the engram
 Historical roots in work of Karl Lashley
artificially expressing the engram: typically, a memory
emerges when a latent engram is ‘reawakened’ by an
external retrieval cue (i.e., ecphory). Artificial expression
studies ask whether stimulation of the neuronal components
of the engram is sufficient to induce its artificial expression
 Historical roots in work of Wilder Penfield
Observing the engram (Cajal)
Ramon y Cajal (1852-1934)
-- Spanish neuroanatomist
-- studied the microanatomy,
organization and development of the
brain
-- Used Golgi’s new methodology to
label neurons and their processes to
make two key observation:
1) Neurons-- composed of cell body,
dendrites and axon– were not fused
together and so represent discrete
functional units in the brain
2) Flow of information from dendrite
cell body  axon
-- together formed the neuron doctrine
for which he was awarded Nobel in 1906
with Golgi
Observing the engram: ‘cerebral gymnastics’
Less recognized were his idea’s was about brain plasticity:
-- thought that after development the numbers of neurons were fixed
-- but connections between neurons were modifiable (‘cerebral gymnastics’)
-- “Mental exercise facilitates greater development of …. nervous collaterals in the
part of the brain in use. In this way, pre-existing connections between neurons
could be reinforced”
-- changes occur at spines as he correctly hypothesized that these protrusions
represent the connection point between axon terminal and neuron
Contemporary observation studies
Moser et al (1994) PNAS
-- spatial training results in increase in spine density in CA1
Contemporary observation studies
Observation studies include:
anatomical
-- changes in spine density following learning
biochemical
-- post-translational modification of kinases (e.g., phosphorylation of α-CaMKII)
-- activation of transcriptional machinery (e.g., CREB)
electrophysiological recording in rodents
-- detection of replayed patterns of activity
blood flow (humans)
-- detection of replay in human subjects in resting state via fMRI
Erasing the engram (Lashley)
Karl Lashley (1890-1958)
-- American physiologist
-- popularized the term engram
Frequency of term
“engram” in the
20th century
Erasing the engram (Lashley)
-- trained rats, and then ablated
different amounts of cortex
Erasing the engram (Lashley)
-- trained rats, and then ablated
different amounts of cortex
-- deficits corresponded with size,
but not location, of lesion
-- led to two influential
conclusions:
1) Mass action: memory function
is distributed (i.e., opposite of
functional specialization). The
efficiency of memory function
reduced proportionately to
amount of tissue damage
2) Equipotentiality: The
apparent capacity of any intact
part of a functional brain to
carry out… the [memory]
functions which are lost by the
destruction of [other parts]
Criticisms of Lashley
-- over-training (therefore memory is more resistant to damage)
Criticisms of Lashley
-- over-training (therefore memory is more resistant to damage)
-- wrong place? Spatial task, and so in looking for engram in the cortex Lashley
may have been looking in the wrong place. Reanalysis of lesions by Peter Milner
revealed that deficits correlated to amount of hippocampal damage…
Criticisms of Lashley
-- specificity of lesion
approach
-- knife cuts, thermocautery 
lots of collateral damage
-- need an approach that
targets only engram cells…
Contemporary erasure studies
Susumu Tonegawa
Steve Ramirez @okaysteve
Expressing the engram (Penfield)
Wilder Penfield (1891-1976)
Expressing the engram (Penfield)
-- goal was to treat patients with
intractable epilepsy by lesioning
source of seizure
-- to localize this tissue, Penfield
electrically stimulated and
functionally mapped local
topography of surrounding brain
regions in awake (but sedated)
patients
-- stimulation of motor cortex
induced movements of different
limbs (e.g., finger, arm, toe)
-- this approach eventually led to
definition of motor humunculus
Expressing the engram (Penfield)
-- stimulation of temporal lobe also occasionally triggered “ an experience which
the patient could easily recognize and identify as being part of a previous
experience”
-- so, in the absence of any internal retrieval effort or sensory cue, Penfield was
able to re-awaken the engram
-- criticisms:
-- couldn’t predict which memory (random)
-- evoked memories were rare (<10% of stimulation sites)
-- were memories real? For instance, one of Penfield’s patients reported a
stimulation-induced experience that took place in a lumberyard---despite never
having visited a lumberyard
Expressing the engram (Penfield)
-- contemporary example: Andres Lozano
-- deep brain stimulation, morbidly obese patient
-- aimed for lateral hypothalamus, hit the fornix (input to hippocampus)
-- similarly evoked ‘memories’:
“Unexpectedly, the patient reported sudden sensations that he
described as “deja vu” with stimulation of the first contact tested…He
reported the sudden perception of being in a park with friends, a
familiar scene to him. He felt he was younger, around 20 years old. He
recognized his epoch-appropriate girlfriend among the people. He did
not see himself in the scene, but instead was an observer. The scene
was in color; people were wearing identifiable clothes and were talking,
but he could not decipher what they were saying. As the stimulation
intensity was increased from 3.0 to 5.0 volts, he reported that the
details in the scene became more vivid.” (p. 119).
Contemporary Penfield experiments
Course organization
All course information can be found on my lab website: www.franklandlab.com
Classes
Tuesdays 2-4 pm in Sidney Smith Hall, room 560A
Format
Students will present and discuss recent ‘engram’ papers. For each class, 2 papers have been selected.
For each paper a presenter will be assigned, as well as a discussant. The presentation should be 30-40
minutes followed by 10-15 minutes of discussion.
Non-presenters will read the papers before the class and submit a 0.5-1 page summary of each paper,
including 3-4 discussion points/comments/questions. These are to be emailed to the instructor
([email protected]) no later than 11:59 pm on Monday evening.
Course organization
1. What is the question?
-- place question in broader context of the field; why is this an important question to
address;
-- does the study generate a new hypothesis, provide evidence for an old hypothesis;
contradict existing dogma?
2. Methods
-- describe methods used to address the question (transgenic mouse, electrophysiology,
behavioral testing)
-- are these methods novel? would alternative methods have been better?
3. Results
-- describe each figure, also show relevant supplemental material
-- are the results clear, statistical analyses sound
-- control experiments
4. Discussion/conclusions
-- are all conclusions supported by data? Are there alternate accounts of the results that
have not been considered? How do the results fit in with the existing literature?
5. BE POSITIVE!!!!
-- place equal weight on what is good/cool about the study vs. what you view as its
limitations
Course organization
All course information can be found on my lab website: www.franklandlab.com
Evaluation
1) Presentations (30%). Student will get to present twice during the course. Each presentation is worth
15% of the final grade.
2) Participation in class discussions (40%). This grade will be based on the weekly summaries (20%) as
well as ability to lead and participate in class discussions (20%).
3) Assignments (30%). There will be two assignments. Students will write “New and Views” style
commentaries (~1000 words) on recent engram papers. The first is due during reading week. The second
is due at the end of term. Both contribute 15% to the final grade.
Course organization
Date
Paper 1
Presenter
Discussant
Paper 2
Presenter
Discussant
Jan 19
Guzowski
Emily
Navdeep
Reijmers
Adam
Sadia
Jan 26
Singer
Sivaani
Bilgehan
Tambini
Lyn
Nan
Feb 2
Zhou
Alex
Taavi
Nabavi
Navdeep
Adam
Feb 9
Tayler
Sadia
Emily
Denny
Bilgehan
Lyn
Feb 23
Tanaka
Nan
Sivaani
Wheeler
Taavi
Alex
Mar 1
Ramirez
(2015)
Liu
TBD
De Lavilleon
Mar 22
Ramirez
(2013)
Han
Mar 29
Tse (2)
Richards
Mar 8
Mar 15
Kim
Yiu