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Dopamine D3 receptor modulation of
prefrontal cells and circuits
N E U R O S C I E N C E T H E S I S S E M I N A R
F R I D A Y , S E P T E M B E R 2 2 , 2 0 1 7
R E B E C C A C L A R K S O N
B E N D E R L A B
Prefrontal cortex supports high level cognitive processes
Adapted from Arias-Carrión et al., 2010
Prefrontal
cortex
• Working memory
• Attention
• Decision-making
Adapted from Arias-Carrión et al., 2010
Prefrontal
cortex
Prefrontal cortex is a central hub in a distributed system
• Prefrontal circuits integrate
information about internal and
external conditions to guide
decision-making.
Adapted from Arias-Carrión et al., 2010
Nucleus
accumbens
Thalamus
Amygdala
Prefrontal
cortex
Spinal cord
VTA
Prefrontal cortex is a central hub in a distributed system
• Prefrontal circuits integrate
information about internal and
external conditions to guide
decision-making.
• Prefrontal cortex is extensively
interconnected with other brain
regions.
Prefrontal dopamine is critical for normal cognitive function
• Dopaminergic input is essential for
both fear and reward-related
learning.
Adapted from Arias-Carrión et al., 2010
VTA
Prefrontal
cortex
source of prefrontal
dopamine input
fibers that release dopamine
Dysfunctional prefrontal
dopamine signaling à
• Schizophrenia
• Depression
• Parkinson’s
• Drug addiction
Prefrontal dopamine is critical for normal cognitive function
Adapted from Arias-Carrión et al., 2010
VTA
Prefrontal
cortex
source of prefrontal
dopamine input
fibers that release dopamine
PFC pyramidal neurons receive dense dopaminergic input
VTA
Adapted from Arias-Carrión et al., 2010
source of prefrontal
dopamine input
fibers that release dopamine
Neurons: highly specialized
cells within the brain that
communicate with each other
Prefrontal
cortex
VTA
Prefrontal
cortex
PFC pyramidal neurons receive dense dopaminergic input
PFC pyramidal neurons receive dense dopaminergic input
PFC pyramidal neurons receive dense dopaminergic input
PFC pyramidal neurons receive dense dopaminergic input
Pyramidal neurons have many kinds of receptors
Dopamine acts via D1-family and D2-family receptors
Dopamine Receptors
D1-family D2-family
Dopamine acts via D1-family and D2-family receptors
Dopamine Receptors
D1-family D2-family
Gas/olf Gai/o
Dopamine acts via D1-family and D2-family receptors
Dopamine Receptors
D1-family D2-family
Gas/olf Gai/o
Adenylyl cyclase
Dopamine Receptors
D1-family and D2-family both have multiple subtypes
D1-family D2-familyPharmacology
Dopamine Receptors
D1-family and D2-family both have multiple subtypes
D1-family D2-familyPharmacology
D1 D5 D2 D3 D4
Dopamine Receptors
D1-family D2-family
D1 D5 D2 D3 D4
D1-family and D2-family both have multiple subtypes
Genetically-modified
“transgenic” mice
Dopamine Receptors
D1-family D2-family
D1 D5 D2 D3 D4
Dopamine receptor subtypes in PFC
Genetically-modified
“transgenic” mice
Dopamine Receptors
D1-family D2-family
D1 D5 D2 D3 D4
Dopamine receptor subtypes in PFC
Genetically-modified
“transgenic” mice
D3R role in prefrontal function
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
D3Rs
Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
D3R role in prefrontal function
• Many antipsychotics have equal affinity for
D3R and D2R
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
D3R role in prefrontal function
• Many antipsychotics have equal affinity for
D3R and D2R
• Pro-cognitive effect of decreased prefrontal
D3R activation
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
D3R role in prefrontal function
• Many antipsychotics have equal affinity for
D3R and D2R
• Pro-cognitive effect of decreased prefrontal
D3R activation
• Very high D3R affinity for dopamine (>20x
higher than D2R)
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
D3R role in prefrontal function
• Many antipsychotics have equal affinity for
D3R and D2R
• Pro-cognitive effect of decreased prefrontal
D3R activation
• Very high D3R affinity for dopamine (>20x
higher than D2R)
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
The cellular mechanisms by which
D3Rs modulate prefrontal function
remain unclear Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
D3R role in prefrontal function
Dysfunction in prefrontal D3R signaling may play a major role in
neuropsychiatric disorders
Thalamus
Amygdala
Spinal cord
VTA
Nucleus
accumbens
• Many antipsychotics have equal affinity for
D3R and D2R
• Pro-cognitive effect of decreased prefrontal
D3R activation
• Very high D3R affinity for dopamine (>20x
higher than D2R)
The cellular mechanisms by which
D3Rs modulate prefrontal
OUTPUT remain unclear Schwartz et al., 2000; Newman et al., 2012;
Joyce and Millan, 2005; Gross et al., 2013;
Glickstein et al., 2005; Loiseau and Millan,
2009; Watson et al., 2012
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
Electrophysiology = electrical properties of
biological cells and tissues
Action potentials (APs)
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
3) What are the downstream targets of these D3+ neurons?
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
3) What are the downstream targets of these D3+ neurons?
4) How do D3Rs modulate prefrontal neurons?
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
3) What are the downstream targets of these D3+ neurons?
4) How do D3Rs modulate prefrontal neurons?
5) What are the functional consequences of D3R signaling
on neural activity?
D3Rs
Key questions remain concerning mPFC D3R function
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of D3R-
expressing neurons?
3) What are the downstream targets of these D3+ neurons?
4) How do D3Rs modulate prefrontal neurons?
5) What are the functional consequences of D3R signaling
on neural activity?
What do we already know
about D1R and D2R
expression?
Orientation to mouse prefrontal cellular anatomy
Orientation to mouse prefrontal cellular anatomy
Orientation to mouse prefrontal cellular anatomy
Coronal section
Orientation to mouse prefrontal cellular anatomy
Coronal section
Coronal brain slice
Orientation to mouse prefrontal cellular anatomy
medial prefrontal
cortex (mPFC)
Coronal brain slice
Orientation to mouse prefrontal cellular anatomy
medial prefrontal
cortex (mPFC)
Coronal brain slice
Orientation to mouse prefrontal cellular anatomy
Prefrontal cortical circuits contain diverse cell types
Prefrontal cortical circuits contain diverse cell types
Pyramidal neurons send
excitatory projections across
the brain
Nucleus
accumbens
Prefrontal
cortex Thalamus
Amygdala
Spinal cord
VTA
Two major classes of prefrontal projection neuron
Pyramidal neurons send
excitatory projections
throughout the brain
Spinal cordAmygdala
StriatumCortex
Two major classes of prefrontal projection neuron
Two major classes:
Pyramidal neurons send
excitatory projections
throughout the brain
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT) = subcortical
Two major classes:
Pyramidal neurons send
excitatory projections
throughout the brain
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT)
2) Intratelencephalic (IT) = cortical
Two major classes:
Pyramidal neurons send
excitatory projections
throughout the brain
1) Pyramidal tract (PT) = subcortical
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT)
2) Intratelencephalic (IT)
Two major classes:
Pyramidal neurons send
excitatory projections
throughout the brain
What do we know about D1R and D2R expression in L5 PFC?
D1
D1
Contralateral cortex
D1R is expressed on
callosally-projecting (IT)
pyramidal neurons
Gee, Ellwood et al., 2012
Projection targets of D1R- and D2R-expressing L5 neurons
Thalamus
D2
D2
D2R is expressed on
subcortically-projecting (PT)
pyramidal neurons
Gee, Ellwood et al., 2012
Projection targets of D1R- and D2R-expressing L5 neurons
D1R- and D2R-dependent modulation in PFC
D1R- and D2R-expressing
neuron populations are
electrophysiologically distinct
D2
D2
D1
D1 D1+ D2+
Gee, Ellwood et al., 2012
D1R- and D2R-dependent modulation in PFC
D1R- and D2R-expressing
neuron populations are
differentially affected by
dopamine
D2
D2
D1
D1
D1R- and D2R-dependent modulation in PFC
D1-receptor dependent:
• Increase in AP firing
• Depolarization
• Increase in input resistance
Seong and Carter 2012
D1
D1
D1R- and D2R-dependent modulation in PFC
D2-receptor dependent:
• Increase in AP firing
• Requires synaptic stimulation
Gee, Ellwood et al., 2012; Robinson and Sohal 2017
D2
D2
D1R/D2R
D1R and D2R role in prefrontal cortex
1) Where are they in the prefrontal cortex?
2) What are their electrophysiological properties?
3) What are their downstream targets?
4) How do these receptors modulate prefrontal neurons?
5) What are the functional consequences?
D1R/D2R
D1R and D2R role in prefrontal cortex
1) Where are they in the prefrontal cortex?
2) What are their electrophysiological properties?
3) What are their downstream targets?
4) How do these receptors modulate prefrontal neurons?
5) What are the functional consequences?
Layer 5
Distinct properties
IT vs PT
Increase AP firing via different
mechanisms
1 How are D3Rs distributed
anatomically?
Results Outline
D3R DISTRIBUTION
1 How are D3Rs distributed
anatomically?
2
ELECTROPHYSIOLOGICAL
PROPERTIES OF
D3R-EXPRESSING NEURONS
Results Outline
What are the electrophysiological
characteristics of these neurons? Do
they differ from neighboring neurons?
D3R DISTRIBUTION
3
Are D3Rs expressed on a
specific class of projection
neuron?
PROJECTION
PATTERNS
3
4
Are D3Rs expressed on a
specific class of projection
neuron?
PROJECTION
PATTERNS
D3R-DEPENDENT
MODULATION
Do D3R-expressing pyramidal
neurons undergo subtype-
specific modulation?
3
4
5
Are D3Rs expressed on a
specific class of projection
neuron?
PROJECTION
PATTERNS
Do D3R-expressing pyramidal
neurons undergo subtype-
specific modulation?
What are the functional
consequences of D3R
modulation?
D3R IMPACT ON
NEURONAL
OUTPUT
D3R-DEPENDENT
MODULATION
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
Dopamine receptor distribution in mPFC
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
mPFC
Dopamine receptor distribution in mPFC
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing cells in mPFC
D3-Cre transgenic mouse
Experimental method:
mPFC
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing cells in mPFC
D3-Cre transgenic mouse
+ Cre-dependent virus with
fluorescent marker
Experimental method: DIO-EYFP
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing cells in mPFC
D3-Cre transgenic mouse
+ Cre-dependent virus with
fluorescent marker
Experimental method: DIO-EYFP
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing cells in mPFC
D3-Cre transgenic mouse
+ Cre-dependent virus with
fluorescent marker
Experimental method: DIO-EYFP
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing cells in mPFC
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
Dopamine receptor distributions (D1R/D2R/D3R)
D1R-expressing
(whole brain)
D2R-expressing
(mPFC)
D3R-expressing
(mPFC)
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
L5 distribution differs between D1R+/D2R+/D3R+ cells
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
L5 distribution differs between D1R+/D2R+/D3R+ cells
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
L5 distribution differs between D1R+/D2R+/D3R+ cells
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
L5 distribution differs between D1R+/D2R+/D3R+ cells
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
L5 distribution differs between D1R+/D2R+/D3R+ cells
Distinct L5 laminar profiles suggests separate neuronal populations
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Berger et al., 2001, 2003
[HCN = hyperpolarization-activated cation]
Receptor expression correlated with intrinsic properties
Hyperpolarizing (negative) current
injection can activate HCN channels,
revealing “h-current”
h-current affects neuronal functional properties:
• Synaptic integration
• AP backpropagation
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
Rebound
Sag
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
Type 2
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
Type 2
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
Type 2
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
D2+ cells can be distinguished by “h-current”
Type 2 Type 1 or Type 3
Sorting D1+ and D3+ cells is a little trickier…
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Sorting D1+ and D3+ cells is a little trickier…
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Cannot be distinguished by latency to peak rebound
D1+ and D3+ neurons have overlapping sag/rebound properties
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
1) Are these separate populations?
Cannot be distinguished by latency to peak rebound
D1+ and D3+ neurons have overlapping sag/rebound properties
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
1) Are these separate populations?
2) Can we use electrophysiology to predict dopamine receptor
expression in unlabelled neurons?
Cannot be distinguished by latency to peak rebound
D1+ and D3+ neurons have overlapping sag/rebound properties
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Dt
D1+ and D3+ neurons have overlapping sag/rebound properties
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
DmV (exp. fit)
D1+ and D3+ neurons have overlapping sag/rebound properties
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Sag and rebound
properties significantly
differ, but have a lot of
overlap
D1+ and D3+ neurons have overlapping sag/rebound properties
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Using AP firing properties to distinguish D1+ and D3+ neurons
ISI 1 ISI 2
ISI = inter-spike interval
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Action potential
threshold
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Action potential
threshold
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Action potential
threshold
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
• AP bursting
• Spike train shape
• AP waveform shape
Can AP firing properties
help distinguish D1R- and
D3R-expressing pyramidal
neurons?
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Using AP firing properties to distinguish D1+ and D3+ neurons
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Rate of rise
Using AP firing properties to distinguish D1+ and D3+ neurons
No single variable completely separates the populations
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
No single variable completely separates the populations
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
1) Are these separate populations?
2) Can we use electrophysiology to predict dopamine receptor
expression in unlabelled neurons?
No single variable completely separates the populations
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Combining information from all 5
variables might be more effective at
discriminating D1+ and D3+ neuronal
phenotypes…
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
Supervised machine learning for classification
Multiple
Electrophysiological
Features
D1 or D3 receptor expression
?
Use Linear Discriminant Analysis to see if classification can
be done through a linear combination of features.
1
2
3
4
5
ELECTROPHYSIOLOGICAL
PROPERTIES
Feature 1
Feature2
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
D1
D3
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
Feature 1
Feature2
With only two features, we can
easily visualize the separation
between two classes…
But what about five features?
D1
D3
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
Feature 1
Feature2
With only two features, we can
easily visualize the separation
between two classes…
But what about five features?
D1
D3
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
D1
D3
Feature 1
Feature2
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
Type 1 Type 3
D1
D3
Feature 1
Feature2
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Results of linear discriminant analysis
D1
D3
Type 1 Type 3
Feature 1
Feature2
D1+/D2+/D3+ neurons classified as T1/T2/T3
D1+ (n = 92) D2+ (n = 35) D3+ (n = 157)
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
D1+/D2+/D3+ neurons classified as T1/T2/T3
D1+ (n = 92) D2+ (n = 35) D3+ (n = 157)
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
Given some electrophysiological
overlap, can we confirm D1+/D3+
separation another way?
Breeding strategy: D3-Cre mice x D1-tdtomato mice
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5x
D3-Cre D1-tdTomato
D3-Cre x D1-tdTomato
Anatomical segregation consistent with electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
D1R-expressing
D3R-expressing
Anatomical segregation consistent with electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
D1R-expressing
D3R-expressing
Anatomical segregation consistent with electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
D1R-expressing
D3R-expressing
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing pyramidal neurons
comprise a distinct cell class from
D1R- and D2R-expressing neurons:
Recap: mPFC D3R distribution and electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing pyramidal neurons
comprise a distinct cell class from
D1R- and D2R-expressing neurons:
• Different L5 laminar distribution
Recap: mPFC D3R distribution and electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing pyramidal neurons
comprise a distinct cell class from
D1R- and D2R-expressing neurons:
• Different L5 laminar distribution
• Distinct electrophysiological phenotype
(Type 3 vs. Type 1/Type 2)
Type 1
Type 3
Recap: mPFC D3R distribution and electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing pyramidal neurons
comprise a distinct cell class from
D1R- and D2R-expressing neurons:
• Different L5 laminar distribution
• Distinct electrophysiological phenotype
(Type 3 vs. Type 1/Type 2)
• Anatomically separate from D1R+ neurons
Recap: mPFC D3R distribution and electrophysiology
ELECTROPHYSIOLOGICAL
PROPERTIES
1
2
3
4
5
DOPAMINE RECEPTOR
DISTRIBUTION
D3R-expressing pyramidal neurons
comprise a distinct cell class from
D1R- and D2R-expressing neurons:
• Different L5 laminar distribution
• Distinct electrophysiological phenotype
(Type 3 vs. Type 1/Type 2)
• Anatomically separate from D1R+ neurons
What are the projection patterns of
D3R-expressing pyramidal neurons?
Recap: mPFC D3R distribution and electrophysiology
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT)
2) Intratelencephalic (IT)
D1
D1
D2
D2
• Subcortical projections:
• Thalamus
• Brainstem
• Spinal cord
• Cortical projections
• Contralateral cortex
• Amygdala
• Striatum
1
2
3
4
5
PROJECTION
PATTERNS
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT)
2) Intratelencephalic (IT)
D1
D1
D2
D2
PT
IT
• Subcortical projections:
• Thalamus
• Brainstem
• Spinal cord
• Cortical projections
• Contralateral cortex
• Amygdala
• Striatum
1
2
3
4
5
PROJECTION
PATTERNS
Two major classes of prefrontal projection neuron
1) Pyramidal tract (PT)
2) Intratelencephalic (IT)
D1
D1
D2
D2
• Subcortical projections:
• Thalamus
• Brainstem
• Spinal cord
• Cortical projections
• Contralateral cortex
• Amygdala
• Striatum
1
2
3
4
5
PROJECTION
PATTERNS
D3
?
PT
IT
Experimental technique: Orthograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
AAV-DIO-ChR2-EYFP
Inject into prefrontal cortex
D3-Cre::Ai14 transgenic mouse
+ Cre-dependent virus with
fluorescent marker
Experimental technique: Orthograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
D3-Cre::Ai14 transgenic mouse
+ Cre-dependent virus with
fluorescent marker
AAV-DIO-ChR2-EYFP
Inject into prefrontal cortex
Experimental technique: Orthograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
D3-Cre::Ai14 transgenic mouse
+ Cre-dependent virus with
fluorescent marker
AAV-DIO-ChR2-EYFP
Inject into prefrontal cortex à
D3R-expressing cells are infected
Experimental technique: Orthograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
D3-Cre::Ai14 transgenic mouse
+ Cre-dependent virus with
fluorescent marker
AAV-DIO-ChR2-EYFP
Inject into prefrontal cortex à
D3R-expressing cells are infected
Virus is trafficked down the axonal fibers
Prefrontal D3+ cells are transfected with DIO-ChR2-EYFP
PROJECTION
PATTERNS
1
2
3
4
5
Prefrontal D3+ cells are transfected with DIO-ChR2-EYFP
PROJECTION
PATTERNS
1
2
3
4
5
Prefrontal D3+ neurons project to contralateral cortex
PROJECTION
PATTERNS
1
2
3
4
5
Prefrontal D3+ neurons have cortical and subcortical targets
PROJECTION
PATTERNS
1
2
3
4
5
Prefrontal D3+ cells are transfected with DIO-ChR2-EYFP
PROJECTION
PATTERNS
1
2
3
4
5
Cells transfected across cortical layers
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
D3-Cre::Ai14 transgenic mouse
Ctb-488
Inject into cortical or subcortical region
Amygdala
+ retrograde tracer in downstream
brain regions
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
Ctb-488
Inject into cortical or subcortical region
Amygdala
D3-Cre::Ai14 transgenic mouse
+ retrograde tracer in downstream
brain regions
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
Ctb-488
Inject into cortical or subcortical region
Amygdala
D3-Cre::Ai14 transgenic mouse
+ retrograde tracer in downstream
brain regions
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
Ctb-488
Inject into cortical or subcortical region
Virus is trafficked from axon terminal to cell body
Amygdala
D3-Cre::Ai14 transgenic mouse
+ retrograde tracer in downstream
brain regions
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
mPFC coronal brain slice
D3-Cre::Ai14 transgenic mouse
+ retrograde tracer in downstream
brain regions
Experimental technique: Retrograde viral tracing
PROJECTION
PATTERNS
1
2
3
4
5
mPFC coronal brain slice
D3-Cre::Ai14 transgenic mouse
+ retrograde tracer in downstream
brain regions
PROJECTION
PATTERNS
1
2
3
4
5
Verify targeting in 4 potential downstream targets
Contralateral
mPFC
Nucleus
accumbens
core
Basolateral
amygdala
Mediodorsal
thalamus
PROJECTION
PATTERNS
1
2
3
4
5
Projection neurons in mPFC: Overlap with D3R+ neurons
Contralateral mPFC
Nucleus
accumbens core
Basolateral
amygdala
Mediodorsal
thalamus
Injection
location
mPFC
coronal
section
L1
L2/3
L5a
L5b
L6
D3-Cre::Ai14
Ctb-488 (retrogradely-labeled)
PROJECTION
PATTERNS
1
2
3
4
5
Contralateral mPFC
Nucleus
accumbens core
Basolateral
amygdala
Mediodorsal
thalamus
Injection
location
mPFC
coronal
section
L1
L2/3
L5a
L5b
L6
Projection neurons in mPFC: Overlap with D3R+ neurons
D3-Cre::Ai14
Ctb-488 (retrogradely-labeled)
PROJECTION
PATTERNS
1
2
3
4
5
Contralateral mPFC
Nucleus
accumbens core
Basolateral
amygdala
Mediodorsal
thalamus
Injection
location
mPFC
coronal
section
Projection neurons in mPFC: Overlap with D3R+ neurons
L1
L2/3
L5a
L6
L5b
PROJECTION
PATTERNS
1
2
3
4
5
Contralateral mPFC
Nucleus
accumbens core
Basolateral
amygdala
Mediodorsal
thalamus
Injection
location
mPFC
coronal
section
Projection neurons in mPFC: Overlap with D3R+ neurons
L1
L2/3
L5a
L6
L5b
PROJECTION
PATTERNS
1
2
3
4
5
Contralateral mPFC
Nucleus
accumbens core
Basolateral
amygdala
Mediodorsal
thalamus
Injection
location
mPFC
coronal
section
Projection neurons in mPFC: Overlap with D3R+ neurons
L1
L2/3
L5a
L6
L5b
PROJECTION
PATTERNS
1
2
3
4
5
L5 D3R-expressing neurons are an IT population
D1
D1
D2
D2
IT PT
IT
D3
• Contralateral cortex
• Nucleus accumbens
D1
D1
D2
D2
PT IT
IT
D3R-dependent modulation in prefrontal cortex
D2
D2
D1
D1
1
2
3
4
5
D3R
MODULATION
Do D3R-expressing
pyramidal neurons undergo
subtype-specific modulation?
D3
D3
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
D3
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Axon initial segment (AIS):
Site of action potential
initiation
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Experimental Method
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Experimental Method
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Experimental Method
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Experimental Method
1
2
3
4
5
D3R
MODULATION
D3R-dependent modulation in D3R-expressing neurons
Experimental Method
AP-evoked AIS calcium
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
Wash on quinpirole (D2-
family receptor agonist)
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
Wash on quinpirole (D2-
family receptor agonist)
Reduction in AIS Ca
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
This modulation also occurs in Type 3 neurons
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
Mice lacking the D3R do not show this effect
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
D3R-dependent modulation in D3R-expressing neurons
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
D3R modulation does not occur in neighboring cells
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
D3R modulation does not occur in neighboring cells
1
2
3
4
5
D3R
MODULATION
D2
D2
D1
D1
D3R modulation does not occur in neighboring cells
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Does D3R modulation at the AIS affect neuronal output?
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Does D3R modulation at the AIS affect neuronal output?
Experimental methods:
Evoke APs in D3R-expressing neurons à
1) Bath application of quinpirole (D2-family agonist)
2) Local application of Ni to AIS (approximates modulatory affect)
OR
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Does D3R modulation at the AIS affect neuronal output?
Experimental methods:
Evoke APs in D3R-expressing neurons à
1) Bath application of quinpirole (D2-family agonist)
2) Local application of Ni to AIS (approximates modulatory affect)
OR
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Simulated
synaptic input
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Simulated
synaptic input
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
Simulated
synaptic input
D3R IMPACT ON
NEURONAL
OUTPUT
Functional impact of D3R modulation
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
Selective suppression of high frequency AP bursts
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
Selective suppression of high frequency AP bursts
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
Selective suppression of high frequency AP bursts
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
Selective suppression of high frequency AP bursts
1
2
3
4
5
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of
D3R-expressing neurons?
3) What are the downstream targets of these D3+
neurons?
4) How do D3Rs modulate prefrontal neurons?
5) What are the functional consequences of D3R
signaling on neural activity?
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
Superficial cortical
layers, in particular
L2/3 and L5a
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of
D3R-expressing neurons?
• Low sag and rebound
• No initial doublet
• Broad, slow APs
• Steadily depolarizing AP threshold
during train
Electrophysiologically-distinct phenotype from
D1R- and D2R-expressing neurons
D1
D1
D2
D2
PT IT IT
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of
D3R-expressing neurons?
3) What are the downstream targets of these D3+
neurons?
D3
IT cell type
• Projections to contralateral
cortex and nucleus accumbens
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of
D3R-expressing neurons?
3) What are the downstream targets of these D3+
neurons?
4) How do D3Rs modulate prefrontal neurons?
Decrease in AP-evoked
calcium influx at the AIS
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
1) Where is the D3R in the prefrontal cortex?
2) What are the electrophysiological properties of
D3R-expressing neurons?
3) What are the downstream targets of these D3+
neurons?
4) How do D3Rs modulate prefrontal neurons?
5) What are the functional consequences of D3R
signaling on neural activity?
Selective reduction in high
frequency AP bursting
Conclusions
1
2
3
4
5
D3R IMPACT ON
NEURONAL
OUTPUT
PROJECTION
PATTERNS
D3R
MODULATION
ELECTROPHYSIOLOGICAL
PROPERTIES
DOPAMINE RECEPTOR
DISTRIBUTION
This provides a framework for understanding
cellular and subcellular substrates of prefrontal
dopaminergic modulation
How do antipsychotic drugs impact prefrontal
function (and output) via both D3R and D2R?
How does regulation of D3+ bursting
impact intracortical processing?
Thank you!
Bender lab
Kevin Bender
Current Members
Jiggy Athilingam
Roy Ben-Shalom
Ken Burke
Caroline Keeshen
Anna Lipkin
Perry Spratt
Former Members
Alayna Liptak
Gina Rinetti Vargas
Sungchil Yang
Funding sources: NSF, NIDA, NIMH
Sohal Lab
Steven Gee
Thesis Committee
Stephan Lammel
Roger Nicoll
Vikaas Sohal

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