Transcript Presentation: Kristan-Slides-Banbury-May

The dynamics of decision-making by leech neurons
Neurobiology of Decision-Making
CSH
24 May 2005
Bill Kristan
Section of Neurobiology
Division of Biological Sciences
UC San Diego
La Jolla, CA
We make all kinds of choices:
Choosing whether (respond or ignore)
Choosing what (feed on it, fight it, love it)
Choosing how (direct/indirect, strongly/subtly)
Choosing when (now, later)
Choosing which (regular/diet, large/medium, left/right)
We make all kinds of choices:
Choosing whether (respond or ignore)
Choosing what (feed on it, fight it, love it)
Choosing how (direct/indirect, strongly/subtly)
Choosing when (now, later)
Choosing which (regular/diet, large/medium, left/right)
Leeches crawl in shallow water (3 mm)
QuickTime™ and a
Video decompressor
are needed to see this picture.
Leeches swim in deep water (33 mm)
QuickTime™ and a
Video decompressor
are needed to see this picture.
Anatomy of the leech CNS
Leech preparations
Leech locomotory behaviors
Swimming
Crawling
Elongation (E)
Contraction (C)
G10
C
Dorsal
C
C
G10
E
E
G13
Ventral
C
QuickTime™ and a
decompres sor
are needed to see thi s pic ture.
E
1 sec
C
C
10 sec
Swim initiation by a command neuron, cell 204
10 mV
Cell 204
DE motor neuron
5 sec
Weeks & Kristan, 1978
Invertebrate model of choice: inhibition of command neurons
Command
neurons
Command
neurons
Problem #1: some “command neurons” are activated in incompatible behaviors.
B.
B.
B.
Stimulus
Stimulus
Stimulus
Cell ll204
204
Ce
Ce ll 204
Cell ll61
61
Ce
Ce ll 61
SE1
SE1
SE1
TrTr1 1
Tr 1
Shaw & Kristan, 1997
Problem #2: Some “command neurons” are bifunctional
Semi-intact preparation
Intracellular
Stimulate cell R3b1:
Shallow water
Extracellular
Deep water
Esch,Mesce & Kristan, 2002
Decisions appear to be made interactively
by multiplexed neurons
using a combinatorial code
Leech nervous system can swim or crawl to the same stimulus
Head brain
Use isolated nerve cord
Stimulate (S) one nerve electrically , record (R) from another
• same stimulation elicits different responses:
Imaging
Swimming
Crawling
R
G15
S
Tail brain
Stimulus
Briggman, Abarbanel & Kristan, 2005
Optical activity in motor neurons during swimming
QuickTime™ and a
decompres sor
are needed to see thi s pic ture.
Data of Adam Taylor
Membrane potential trajectories of 144 neurons
Crawl
Swim
Cell number
Cell number
dF/F (%)
Time (msec)
Time (msec)
Briggman, Abarbanel & Kristan, 2005
Discrimination by single neurons
Swim Trials
Crawl Trials
Non-discriminating (ND)
Late Discriminating (LD)
p > 0.000001
p < 0.000001
Nerve DT
Early Discriminating (ED)
Transiently Discriminating (TD)
Single cells with early DTs
Single cell
DT
Briggman, Abarbanel & Kristan, 2005
Principal component analysis, across neurons
PC1
PC2
PC3
Cell Number
Discrimination of single cells vs. neuronal populations
{
{
LDA DTs
Earliest cell DTs
Nerve DTs
Single cell DTs
Cells contributing to Linear Discriminant
Single cells with early DTs
Polarizing cell 208 biases behavioral choice
Intracellular
Stimulation
Hyperpolarized Trials (-1.5 nA)
Depolarized Trials (+1.5 nA)
DP Nerve
Stimulus
Briggman, Abarbanel & Kristan, 2005
Leeches make behavioral choices sequentially
Cell
Active during Command
208
swimming
shortening
“Do something!”
R3b1
swimming
crawling
“Locomote”
204
swimming
28
swimming
“Swim!”
“Bend up (down)”
and dynamically:
z
Swim
CPG
Crawl
CPG
y
x
Decision making
Stimulation
Rest state
CONCLUSIONS
• Many leech neurons take part in both swimming and crawling.
• About half of them have different activity in the two behaviors.
• Only a few differ early (good candidates for being decision-makers).
• Decision-making may depend on dynamic interactions
-- among multiplexed neurons
-- using a combinatorial code.
Cast of characters
KRISTAN LAB:
Brian Shaw
Tim Cacciatore
Adam Taylor
Teresa Esch
Karen Mesce
Kevin Briggman
COLLABORATORS:
David Kleinfeld
Roger Tsien
Tito Gonzalez
Peter Brodfuehrer
Gary Cottrell
Henry Abarbanel
Dyes provided by Vertex Pharmaceuticals
(PanVera) (Aurora Biosciences)
Linear Discriminant Analysis (LDA)
Cell A
LD Direction
LD Direction
c
b
Cell B
Cell C
a
Principal component analysis, by participating neurons:
PC1
PC1
PC2
PC2
PC3
B
A
PC2
Cell Number
PC1
Briggman, Abarbanel & Kristan, 2005
What’s ahead?
Input to decision makers:
p(choice A) = p(any behavior) x p(success of A) x (benefit of A - risks)
p(choice A) =
response
threshold
x
sensory
processing
x
(positive - negative)
modulation
• source of modulation
site of action
• effects of feeding
• classical conditioning: bias to swim or crawl
Cast of characters
KRISTAN LAB:
Brian Shaw
Tim Cacciatore
Adam Taylor
Teresa Esch
Karen Mesce
Kevin Briggman
COLLABORATORS:
David Kleinfeld
Roger Tsien
Tito Gonzalez
Peter Brodfuehrer
Gary Cottrell
Henry Abarbanel
Dyes provided by Vertex Pharmaceuticals
(Aurora Biosciences) (PanVera)
Discrimination by single neurons
Swim Trials
Crawl Trials
Non-discriminating (ND)
Late Discriminating (LD)
p > 0.000001
p < 0.000001
Nerve DT
Early Discriminating (ED)
Transiently Discriminating (TD)
Single cell
DT
(Data of Kevin Briggman)
Discrimination by single neurons
Single cells with early DTs
Swimming…
in 144 neurons
Cell number
dF/F (%)
Time (msec)
Data of Kevin Briggman
Is leech decision-making hierarchical?
Cell
type:
Stimulation
produces:
A
swimming
swimming
shortening
“Do something!”
B
swimming or
crawling
swimming
crawling
“Get out of here!”
C
swimming
swimming
D
bending
swimming
Active during:
Command:
“Swim!”
“Move this
muscle group”
Cell 204 is inhibited during shortening….
Data of Brian Shaw
Record optically from 91 neurons simultaneously
Swim
Shorten
(Data of Kevin Briggman)
Subtract no-swim from swim traces for each neuron
Swim
Shorten
Swim – Shorten
(Data of Kevin Briggman)
Reasonable hypothesis:
Decision-making neurons have different activity trajectories
in different behaviors.
Use principal component analysis (PCA) to detect neurons
with different activity trajectories in different behaviors.
Swimming
Component amplitude
Shapes of the first 3 components:
PCA2
PCA1
PCA3
Crawling
Time
(Data of Kevin Briggman)
Response Variability
Head brain
G12
G15
Tail brain
(Data of Kevin Briggman)
A few neurons have different trajectories in swimming and crawling:
Swim
Crawl
(Data of Kevin Briggman)
Another reasonable hypothesis:
Decision-making neurons have the earliest differences
in their trajectories.
Use PCA analysis to follow the trajectories of neuronal classes over time.
For assemblies of neurons,
we plot their PCA components:
1st Frame
With just 3 neurons, we could
plot their activity on separate axes:
Stimulus delivered
1st Swim Burst
C3
PC 3
C1
C2
PC 2
PC 1
Do we make choices hierarchically? (sequential, linear)
“Choice-makers” will be active in sequence
…..or interactively? (feedback, resetting)
“Choice-makers” activity will bounce back and forth
…..or simultaneously? (nonlinearity, overlapping function)
“Choice-makers” will all be active at the same time
Neuronal circuits for whole-body shortening, swimming
Mechanosensory neurons
Trigger interneurons
Gating interneurons
Oscillator interneurons
Motor neurons
Shortening and swimming circuits overlap
Measuring voltage changes with FRET dyes
(FRET = fluorescence resonance energy transfer)
(Developed by Tito Gonzalez & Roger Tsien)
FRET VSD optical signals
(Figure provided by Tim Cacciatore)
Tr2 terminates swimming
Swimming….
in 90 neurons
Data of Kevin Briggman
QuickTime™ and a
Cinepak decompressor
are needed to see this picture.
FRET-based dyes can detect
synaptic potentials
Tr2 spikes elicit 1-1 EPSPs
Multiple responses to identical stimulation
Head brain
Use isolated nerve cord
Stimulate (S) one nerve electrically, record (R) from another
• same stimulation elicits different responses:
Crawling
R
G15
S
?
Behavioral
state
?
?
?
Swimming
Behavioral
choice
Tail brain
Data of Kevin Briggman
Do we make choices hierarchically?
(implies sequential, linear)
• ”Let’s go out to dinner”
• “Some place new”
• “Italian”
• “Mario’s!”
…..or interactively?
(implies feedback, resetting)
• ”I’m not that hungry; let’s do that new Bistro”
• ”I don’t want to dress up; how about our favorite sushi bar?”
• “The Lakers are playing tonight; maybe we should order in.”
…..or simultaneously?
(suggests nonlinearity, overlapping function)
• {impossible to express verbally}