Yang Ming Lectures on Neuroscience
Feburary 13, 2014
Neural Plasticity:
From Synapse to Cognition
Mu-ming Poo
Neural Plasticity
The ability of the nervous system to adopt a
new functional or structural state in
response to extrinsic and intrinsic factors.
Homeostasis vs. Plasticity
Electrical activity
(sensory/motor/cognitive experience)
Neuronal and synaptic modifications
(plasticity)
Learning/memory and changes in
cognition & behaviors
A Physiological Postulate on Neural Plasticity
“When an axon of cell A is near enough to excite a
cell B and repeatedly or 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.”
Donald O. Hebb
The Organization of Behavior (1949)
Discovery of LTP and LTD
Bliss T.V and Lomo M.
Journal of Physiology 232:331-56 (1973)
Long-lasting potentiation of synaptic transmission in
the dentate area of the anaesthetized rabbit following
high-frequency (100 Hz) stimulation of the perforant
path.
M. Ito and M. Kano
Neuroscience Letters 13;33:253-8 (1982)
Long-lasting depression of parallel fiber-Purkinje
cell transmission induced by conjunctive stimulation
(at 4 Hz) of parallel fibers and climbing fibers in the
cerebellar cortex
Changes in EPSP Amplitude
Long-term potentiation (LTP) and Long-term depression (LTD)
(min)
100 Hz stim. (1 sec)
高频刺激 (1秒)
(min)
1 Hz stim. (a few min)
Time (minutes)
Formation of new spines after LTP-inducing high-frequency
stimulation in hippocampal slice cultures
Engert and Bonhoeffer, Nature (1999)
Spine shrinkage after LTD-inducing low-frequency
stimulation in acute hippocampal slices
Zhou et al. Neuron (2004)
In vivo two-photon imaging of YFP-H mice
100 µm
Hebb’s Learning Rule
1. Correlated pre- and postsynaptic activities
cause synapse strengthening / stabilization
2. Uncorrelated pre- and postsynaptic activities
cause synapse weakening / elimination
(G. Stent)
“Cells that fire together wire together”
Development of Retinotectal Projections
T
N
Retina
(EphA3)
C
R
Tectum
(Ephrin-A2)
development
activity
ganglion
cell
tectal
cell
In vivo whole-cell recording in developing Xenopus tectum
input 1
R
Input 1+input 2
S2
Measured 1+2 (nA)
T
FB
S1
input 2
0.4
0.3
0.2
0.1
0.0
0.0
0.1
0.2
0.3
0.4
Expected 1+2 (nA)
Correlated activation of sub- and suprathreshold inputs
(10 msec intervals between input 1 and 2)
I: supra
I II
I: sub
II: supra
II: sub
2.0
Normalized EPSC Amplitude
II
I
2.0
Input I
Input I
1.5
1.5
1.0
1.0
0.5
-10
0
10
20
30
0.5
-10
0
10
20
30
2.0
2.0
Input II
Input II
1.5
1.5
1.0
1.0
0.5
0.5
-10
0
10
20
Time (min)
30
-10
0
10
20
Time (min)
30
Correlated activation of sub - and supra-threshold inputs
(with 10 msec intervals)
Normalized EPSC Amplitude
I : sub
II : supra
I II
2.0
I : supra
II:: sub
I
2.0
Input I
Input I
1.5
1.5
1.0
1.0
0.5
0.5
-10
0
2.0
10
20
Input II
3
0
-10
10
20
Input II
2.0
1.5
0
II
30
AP5
1.5
1.0
1.0
0.5
-10
0
10
20
Time (min)
30
0.5
-10
0
10
20
Time (min)
30
Change in EPSC Amplitude (%)
A critical window for synaptic modification
100
I
II
III
∆Τ
∆Τ
∆Τ
I
II
III
80
synaptic
inputs
60
current
injection
LTP
40
20
0
-20
-40
LTD
-60
-100 -80 -60 -40 -20
0
20 40 60 80 100
Timing of synaptic input (ms)
Zhang, et. al . Nature (1998); Bi and Poo, J. Neurosci. (1998)
Temporally Specific Hebb’s Learning Rule
Correlated pre- and postsynaptic activities can
induce either strengthening or weakening of the
synapse, depending on the temporal order of spiking.
* Pre before post -- strengthening
* Post before pre -- weakening
“Spike timing-dependent Plasticity (STDP)”
reference
Levy & Steward (83)
Bell et. al. (97)
Zhang et al. (98)
Boettiger & Doupe (01)
Bi & Poo (98); Li et al. (04)
Debanne et al. (98)
Nishiyama et al. (00)
Lin et al. (03)
Markram et al. (98)
Egger et al. (99)
Feldman (01)
Sjostrom et al. (03)
Froemke et al. (05)
Tzounopoulos et al. (04)
reference
Zhang et al (98)
Meliza & Dan (06)
Allen et al (03), Celikel et al (04)
Mehta et al (00)
Schuett et al (01)
Fu et al (02), Yao & Dan (01,04)
Fu et al (04)
Stefan et al (02), Wolters et al (03)
Dan & Poo. Physiol. Rev. 86: 1033-48 (2006)
Name That Tune!
Tune 1
Tune 2
Memory is temporally specific:
• Temporal Sequence of Events
• Time Intervals of Events
Sound track made by Li Zhang
STDP - based strengthening / weakening of connections
following uni-directional sequential excitation
19
Recall of sequential spiking by partial stimulus
following uni-directional modification of connnectivity
20
Neural circuit mechanism for storing
sequence information using STDP
- A study using mouse visual cortex
21
Monitoring neuronal ensemble activity with multi-electrode
arrays in rat primary visual cortex (V1)
Sheng-jin Xu
Wen-chen Jiang
Receptive fields of 16 neurons recorded by multi-electrode array
Sequential spiking triggered
by uni-directional moving spot
Conditioning with moving spot
Recall of sequence spiking with test
spot at “starting” and “end” points
Sequence learning/memory by V1 neuronal ensemble
1. Flashes at “starting point” elicit no sequential spiking before training
2. Sequential spiking induced by uni-directional moving light spot
3. Flashes at “starting point” elicit sequence spiking after training
Sorted cross correlogram showing increased
post-conditioning recall of sequential spiking
Anesthetized
Awake
27
Specificity of cue triggered recall of spike
sequence – Spearman (rank order) CCs
28
Post-conditioning “recall” of sequence spiking
Anesthetized
Awake
29
Spontaneous switch of brain state in awake rats
Ratio 1 = P0-10 Hz / P0 -25 Hz
Ratio 2 = P15-30 Hz / P15-60 Hz
Red (Low state): low frequency dominant , synchronized state
Blue (High state): high frequency dominant, desynchronized state
30
Sequence recall in the synchronized but not
de-synchronized state
Xu, et. al. Nature Neurosci. (2012)
31
Is sequential spiking of V1 neurons sufficient and
necessary for learning of sequence of motion stimuli?
Yan Xing-Jian
Zhang Deng
32
Optogenetic Induction of Sequential Firing
Viral injectionCh
S
PSTH
249
1
E
0
154
2
0
226
3
0
Adeno-associated virus
(AAV)
251
4
8
6 7
5
34
12
hsyn
NpHR-EYFP
0
ChR2-mCherry
2A
277
5
0
232
6
0
244
7
0
192
8
0
0
0.1
0.2
0.3
0.4
0.5
0.6
Time (s)
33
Sequential activation of V1 neurons with optogenetic stimulation
Test
Test starting point / end point at random
Conditioning
Sweeping light (conditioning)
Test starting point / end point at random
Cond
Before
Starting point test
Ch 1
8
0
500 ms
0
500 ms
0
500 ms
Ch 1
8
After
Ch 1
8
34
Sequence firing in V1 is sufficient for sequence learning
Example
Averaged
(n=9)
Starting point
Starting point
End point
End point
35
Many issues remain to be addressed
1. Is sequential spiking of V1 neuron ensembles required for
sequence memory due to conditioning with the moving spot?
2. Are there indeed spike timing-dependent LTP & LTD of intracortical
connections due to repetitive sequential spiking as predicted by
STDP?
3. Do brain states affect the learning/memory of sequential spiking?
How could persistent memory be imprinted?
4. Can non-linear (arbitrarily chosen) neuronal ensembles store
memory of sequence spiking?
5. Where are the “real” long-term storage sites for sequence memory?
36
Three levels of cognition
1. Cognition about the outside world
- Perception, concept and categorization
- Many animals have it
2. Cognition about oneself – self-awareness
- Limited to human and a few primates
3. Cognition of language
- Unique to humans
37
Self-Awareness and Mirror Self-Recognition
1. Only humans and a few species of great apes are known to be
capable of recognizing themselves in the mirror
2. Human babies acquire the ability of mirror self-recognition by
two years of age
3. Some psychiatric and autistic patients are impaired in selfawareness
Monkeys cannot recognize themselves in the mirror
Training of visual-somatosensory
association in the monkey chair
Neng Gong
Liangtang Chang
Test of visual-somatosensory association
41
Test of visual-somatosensory association
with a mirroring video image
42
Mark test with a low-power laser light
on the training chair
43
Standard mark test with dye mark
on the training hair
44
Mark tests with low-powered laser light
in the home cage
45
Standard dye mark tests in the home cage
46
Does the monkey really recognize himself? --Mirror/glass wall experiments
47
Mirror-induced Spontaneous Behavior
Trained (green)
naïve (yellow)
Mirror-induced Spontaneous behaviors
Trained (green)
Trained (red)
Mirror-induced Spontaneous behaviors
Trained (green)
naïve (yellow)
Mirror-mediated self-directed
behaviors
M1: Red
M2: Green
51
Implications
1. Rhesus monkey can learn mirror self-recognition
2. Human babies may acquire the ability of mirror selfrecognition via learning during the first two years
3. Impairment in self-awareness (mirror self-recognition)
in humans may be treated by training of visualsomatosensory association in front of a mirror
Acknowledgement
UCSD & Berkeley :
Li Zhang
Qiang Zhou
Huizhong Tao
German Sumbre
Guo-qiang Bi
Institute of Neuroscience, Shanghai:
Shanjin Xu
Deng Zhang
Wen-cheng Jiang
Neng Gong
Xinjian Yan
Liangtang Chang
Collaborators :
Bill Harris
Christine Holt
Yang Dan