BURSTING - PowerPoint Presentation

Slide1

BURSTING

Hasaeam

Cho

Bio-

NanoStructure

Lab

of Prof. MC Choi.Slide2

I will summary the paper …Slide3

Contents

Introduction

Bursting midbrain DA neurons – beyond RPE signal

Primate studies

Rodent studiesBeyond phenomenology – how bursts and pauses are generated in DA neurons

Afferent inputs controlling bursts in DA neuronsAfferent inputs controlling pausesIntrinsic conductances in DA neurons as gates for burst and pause controlIn vitro dynamic clamp approaches to channel function in DA bursting

Conclusions

References

1

2

3

4

5

6Slide4

STEP 1

INTRODUCTIONSlide5

DA midbrain neurons

Dopamine (DA) midbrain neurons

project to several striatal and cortical target areas

Are essentially involved in important brain functions such as

Action selectionMotor performance

MotivationReward-based learningWorking memoryCognitionSlide6

Reward Prediction Error RPE

The reward prediction error (RPE)

The difference between expected and actually delivered rewards

Prediction Error = actual reward – expected rewardSlide7

RPE

The reward prediction error (RPE)

The difference between expected and actually delivered rewards

It’s

Positive when the reward

> expectationPositive RPE is expressed as a phasic increase of firing above the tonic background rate.

It’s

Negative

when the reward

< expectation or not delivered at all (reward omission)

Negative RPE is expressed as a transient reduction of firing frequency below

background rate or even by a period of complete electrical silence (a pause)Slide8

RPE

Midbrain DA neurons

Short (<500

ms

) bursts of high-frequency

In vivo, occur time-locked (>50-300 ms after) to either unexpected reward delivery or, after learning, sensory cues that predict upcoming reward delivery within the next few seconds.Quantitative analysis revealed

the cue-related intra-burst firing frequency was associated with both

the expected reward amplitude and expected probability of delivery,

and the intra-burst frequency after reward delivery, RPE.

Schultz, 2007Slide9

Reinforcement-learning theory

The reinforcement

-learning

theory

Both negative and positive RPEs act as teaching signals.

Most likely

by changing synaptic

weights

of glutamatergic cortico-striatal synapses on the

most prominent target neurons of midbrain DA neuronsVia altering the occupancy and signaling of postsynaptic D1- and D2-type receptors.Slide10

Excitation, Inhibition, Disinhibition

Excitation

Excitatory postsynaptic potential (EPSP)

Causes depolarization

Inhibition

Inhibitory postsynaptic potential (IPSP)Causes hyperpolarizationDisinhibitionA temporary loss of inhibitionSlide11

STEP 2

BURSTING MIDBRAIN DA NEURONS – BEYOND RPE SIGNAL

Burst firing of DA neurons under diverse behavioral contexts in awake animals.Slide12

Primate studies

Burst

firing

was

induced by additional cues.As aversive, a blow of cold air to the eyes that triggers a protective blink response

In many previous studies have characterized dopamine neurons as a functionally homogeneous population.However, the largest population 40% of DA neurons did not

show phasic response to ACS

(ACS = air-puff-predictive conditioned stimulus).

But, displayed typical responses to reward-predicting cues.

An even smaller 10% responses to unexpected

airpuffsdorsolateral DA subpopulation showed large and relatively short (100

ms) phasic burst.Slide13

Primate studies

Matsumoto and

Hikosaka

, 2009Slide14

Primate studies

The midbrain DA population might be indeed relatively

uniform

in their responses to unexpected reward and reward-predicting cues,

But displays a topographically organized diversity in response to other salient events.

which might not directly instruct RPE-learning but initiate. E.g. orienting responses.Slide15

Primate studies

The recent wave of studies in awake primates

have significantly widened the functional context for burst firing

among different types of DA neurons as well as within the burst firing itself.

However, have remained descriptive and phenomenological

Because pharmacological or even optogenetic tools have not yet been used.Slide16

Rodent studies

SFB% : the percentage of spikes within a spike train

that were fired within bursts spikes fired in

bursts

The

degree of “burstiness” of DA neuronThe start (ISI < 80 ms) and stop conditions (ISI > 160

ms

) of burst firing, suggested by Grace and

Bunney

.With this criterion, bursting became quantifiable.Therefore, alternative burst detection methods have been introduced in recent years relate burst firing and pauses to the stochastic properties of the spike train

are independent of the absolute firing frequency.Also, DA recordings in awake rodents, either freely moving or head fixed are increased.Slide17

Rodent studies

In summary,

Cue- and reward-associated burst firing is present in some,

b

ut never all

in recent awake rodent studies even when ruled out by cell type-specific optogenetic tagging.Thus, functional diversity among DA VTA neurons appears to be the norm.Burst firing have also been recorded in behavioral settings not directly related to reward-driven classic or operant conditioning paradigms.

Recordings in awake rodents identified

a diverse phenomenology of burst firing associated with salient sensory cues, delivery of reward and the control of action sequences.

Ventral tegmental area; VTA, substantia

nigra

(pars compacta); SN(C)Slide18

STEP 3

BEYOND PHENOMENOLOGY – HOW BURSTS AND PAUSES ARE GENERATED IN DA NEURONS

Burst firing of DA neurons by synaptic excitation and GABAergic disinhibition.Slide19

Beyond phenomenology

The behavioral importance of bursts and pauses

Can only be appreciated from studies done in awake behaving animals

Most underlying mechanisms arise from studies

in anesthetized rodents

or in vitro brain slice studies.DA neurons exhibit spontaneous bursts, even in anesthetized animal.Much of studies of these spontaneous bursts.

Mechanisms in anesthetized preparations and in awake behaving animals

No guarantee that they are identical.

S

ome evidence that they might be very similar.Spontaneous bursts are indistinguishable

from reward related bursts in duration, firing frequency, and other structural features.The firing ratesOf single spike (

non-bursting), about 0-10 Hz.During bursts in vivo, rates up to 50 Hz.Slide20

Afferent inputs controlling bursts in DA neurons

Excitatory synaptic

input

in vivo

is necessary for bursting in DA neurons.

The synaptic inputs to midbrain DA neuronsPenduculopontine nucleus (PPN)/Lateral dorsal tegmentum (LDT)In vivo disinhibition of PPN increased the burst firing of putative DA neurons in the SN and VTA by about 50%.PPN inhibition reduced burst firing by about 50%

Subthalamic

nucleus (STN)

GABA-mediated disinhibition of the STN leads to increased burst firing in a subpopulation of DA neurons in an NMDA-sensitive manner.

In contrast to excitatory input, it has been estimated that

70% of all afferents to DA neurons are inhibitory

.Slide21

Zweifel

et al., 2009Slide22

Afferent inputs controlling pauses

in vivo

, IPSPs generated by GABAergic synaptic inputs are the obvious candidate afferents.

IPSPs are capable of delaying action potentials in a time-dependent way.

The powerful somatic oscillatory

currents drive the single-spike firing.The cell will fire again unless there is strong inhibition of long duration.Pauses are

only

possible with a synchronized increase in inhibition from significant GABAergic input or a decrease in tonic excitatory input.Slide23

Afferent inputs controlling pauses

Cohen et al., 2012Slide24

STEP 4

INTRINSIC CONDUCTANCES IN DA NEURONS AS GATES FOR BURST AND PAUSE CONTROL

Control of burst firing by distinct potassium channels in DA neurons.Slide25

Gates for burst and pause control

Two complementary approaches

used to study functional contribution of postsynaptic channels to DA bursting.

In vivo

extracellular

approachis to pharmacologically or molecularly modulate channel activityand then analyze the related changes in burst firing parameters.

I

n vitro

intracellular

brain slice approachprovides a high level of experimental controlis to induce bursts in DA neurons by stimulation of afferents

and then assess underlying channel mechanisms.Slide26

Gates for burst and pause control

ATP-sensitive potassium (K-ATP) channels

Necessary for bursting in vivo

for a medial subpopulation of SNC neurons.

In vitro

, selective opening of K-ATP channels in the presence of tonic NMDA receptor stimulation is sufficient to switch medial SNC neurons to a burst-firing mode.Enable

NMDA-mediated bursting of medial DA SN neuron

in vitro

and in vivo

.Slide27

Schiemann

et al., 2012Slide28

Schiemann

et al., 2012Slide29

Gates for burst and pause control

T

he bio-physical mechanisms is

not yet

clearhow K-ATP channel opening enables burst firing

which in vivo upstream mechanism controls K-ATP channel open probabilities in DA neurons Behavioral data suggest that K-ATP channel-mediated bursting in medial DA SN neurons is important for explorative behavior.Slide30

STEP 5

IN VITRO

DYNAMIC CLAMP APPROACHES TO CHANNEL FUNCTION IN DA BURSTING

Realistic burst firing dissected by dynamical clamp techniques.Slide31

Dynamic Clamp technique

A method that uses computer simulations to introduce virtual

conductances

into real neurons.

representing a hybrid between computational models and biological neurons.

can be used to study specific parameters of NMDA, AMPA, GABA, and other channel conductances in shaping bursts and pauses in DA neurons.Slide32

In vitro

dynamic clamp approaches to channel function

NMDA receptor

conductance

is capable of following the activity of DA neurons at bursting

rates.undergoes

block

, following each AP within a burst

.

helps to remove sodium channel inactivation.

allows full hyperpolarization during the repolarization following each AP within a burst.unblocks during the depolarizing phase prior to the next AP, increasing the speed of depolarization.Therefore, the voltage dependence of NMDA receptors allows dopaminergic neurons to fire at rates higher than those possible.N-methyl-D-aspartate (NMDA) Slide33

In vitro

dynamic clamp approaches to channel function

Deister

et al., 2009Slide34

In vitro

dynamic clamp approaches to channel function

Lobb

et al., 2010Slide35

In vitro

dynamic clamp approaches to channel function

Dynamic clamp experiments show that

Realistic burst

firings

the NMDA receptor conductance is capable of following the activity of DA neurons at bursting rates .Intrinsic cellular dynamics are an important part of bursting in the dopaminergic neuron.Future studiesMore complete burst mechanism by incorporating synaptic kinetics with the ion channel kinetics

how specific excitatory inputs may differentially affect the firing pattern of DA neurons.

more data regarding dendritic ion channel distributions.Slide36

In vivo study

In vivo studies show that

local

application of a variety of GAB

antagonists

by

pressure ejection onto the recorded neuron shifts the firing pattern of the DA neuron from a single-spiking mode to a bursting

one

tonic

GAB

receptor activation suppresses burst firing.However, it would need to overcome a substantially increased conductance and block.These limitations can be overcome by a mechanism whereby bursting is controlled by disinhibition, and pausing is controlled by phasic removal of excitation. Slide37

STEP 6

CONCLUSIONSlide38

Highlights

STEP 2

Burst firing of DA neurons under diverse behavioral contexts in awake animals.

STEP 3

Burst firing of DA neurons by synaptic excitation and GABAergic disinhibition.

STEP 4Control of burst firing by distinct potassium channels in DA neurons.STEP 5Realistic burst firing dissected by dynamic clamp techniques.Slide39

CONCLUSION

Transient changes of firing in midbrain DA neurons have received great attention.

Recent work broadened the behavioral framework of these changes both in non-human primates and rodents.

However, up to now most mechanistic studies are currently limited to

in vitro

preparations.Future in vivo studies are likely to advance mechanistic understanding.With the advent of optogenetic tagging of distinct DA neurons in the midbrain and the potential to selectively drive synaptic inputs,

However, intracellular

in vivo

recordings of DA neurons are needed to improve our mechanistic understanding of burst and pause firing of defined DA neurons in awake behaving animals.Slide40

REFERENCES

Figure 1

Generating bursts (and pauses) in the dopamine midbrain neurons, C. A.

Paladini

and J. Roeper

, Neuroscience (2014)Step 1 Introduction - Figure 1, 2, 3, 4, 5, 6, 7http://www.medizinische-fakultaet-hd.uni-heidelberg.de/Simon.102039.0.htmlPPTs of Brain Science FundamentalFigure 2 of Schultz, 2007a

Step 2 - Figure 7, 8

Figure 1, 2 of

Matsumoto and

Hikosaka, 2009Step 3 – Figure 9Figure 3 of

Cohen et al., 2012Step 4 – Figure 10, 11Figure 2, 3 of Schiemann et al.,

2012Figure 12http://blog.gametize.com/2014/03/7-smart-ways-to-improve-learning-with-gamification-part-2/boring/Step 5 The dynamic clamp – Figure 13, 14, 15, 16http://rtxi.org/docs/tutorials/2014/12/05/dynamic-clamp/Figure 1 of Dynamic clamp with StdpC software, Ildiko Kemenes et al., 2011, Nature ProtocolsFigure 6 of Diester et al., 2009Figure 1 of Lobb et al., 2010Slide41

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