Control of Sleep-to-Wake Transitions

fast aminoacid vs slow neuropeptide

Thiago S MosqueiroPhD candidate

BioCircuits Institute, UCSD (USA) Institute of Physics of São Carlos, USP (BR)

08/28/2014

thmosqueiro.vandroiy.com

Courtesy of Milena Carvalho

Take-home message

3

GABA

HCRT

LC

INP

GABAA is not sufficient to control bursts of

LC activity

Mosqueiro, de Lecea & Huerta New Journal of Physics, v16 p115010

Take-home message

3

GABA

HCRT

LC

INP

GABAA is not sufficient to control bursts of

LC activity

An Inhibitory Neuropeptide could implement this

control very well

Mosqueiro, de Lecea & Huerta New Journal of Physics, v16 p115010

Summary

• Previous research on Hypocrexin (HCRT) and Locus Coeruleus (LC)

• Modeling neural populations with conduction models

• GABAA-induced excitation (?)

• Control of LC activity through a slow neuropeptide

• Concluding remarks and ideas

4

PREVIOUS OBSERVATIONS

Locus Coeruleus (LC)

6

Scammell & Saper `2007 Nat Med

Carter et al `2010 Nat Neurosci.

…and Hypothalamus

7

Carter et al `2012 PNAS

HCRT-mediated wake transition

8

Carter et al `2012 PNAS

The LC relays the sleep-to-wake transition

message from HCRT

MODELING

Compartmental model

10

Hindmarsh & Serban `2007 Scholarpedia

CVODE

Compartmental model

10

Hindmarsh & Serban `2007 Scholarpedia

CVODE

GABAA model

11

Cl-Cl-

PostsynapticPresynaptic

Populations

• Each population has 20 neurons in most simulations

12

GABAGABAA

HCRT

LC

AMPAHCRT

AMPA

1.0

1.0

0.5

0.5

0.5

Hyphotalamus

sublateraldorsal periLC

brainstem

HCRT Excitation Protocol

13

-55

-50

-45

-40

-35

-30

-25

-20

-15

50 60 70 80 90 100 110

V (

mV

)

t (s)

HCRTLCIdc

0

5

10

15

50 60 70 80 90 100 110

F (

Hz)

t (s)

HCRTGABA

LC

LC

HCRT

GABA

GABAA-inducedEXCITATION

Varying GABA Conductance

• Hypothesis: GABA hold back LC

• IPSP generated by GABAA in a LC cell

• Amplitude ~ 0. - 4. mV

15

-60

-40

-20

0

20

9.0

V (

mV

)

t (s)Varying GABAA conductance

Suppress overloads of LC activity

16

0

5

10

15

gGABA = 800nS

HCRTGABA

LC

0

5

10

15

gGABA = 200nS

0

5

10

15

65 70 75 80 85 90 95 100

F (

Hz)

t (s)

gGABA = 0nS

17

0

5

10

15

20

50 75 100 125 150

F (

Hz)

t (s)

10

15

20

25

30

102 103

F (

Hz)

gGABA (a.u.)

GABALC

GABA is increasing the LC firing frequency!Changing the number of GABA neurons won’t change anything

Assessing the asymptotic firing frequency…

SLOW NEUROPEPTIDE

Inhibitory Neuropeptide (INP)

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Since GABAA cannot control LC activity,would a Inhibitory Neuropeptide be able to?GABA

HCRT

LC

INP Feedback from LC: overload of activity means more inhibition

HCRT is the gauge:Both LC and INP activities are basically triggered by HCRTs

INP model ~~ HCRT

Activity With INP group

Also…

i. A faster rise up of activity on the onset of HCRT activation

ii. LC activity dies out faster when HCRT stimulation stops…

LC activity successfully decreased

20

-60

-50

-40

-30

-20

-10

50 60 70 80 90 100 110

V (

mV

)

t (s)

HCRTLCIdc

0

5

10

0.05 0.06 0.07 0.08 0.09 0.1 0.11

F (

Hz)

t (s)

HCRTINPLC

INP seems to increase the precision of LC activity as well

Activity With INP group

Also…

i. A faster rise up of activity on the onset of HCRT activation

ii. LC activity dies out faster when HCRT stimulation stops…

LC activity successfully decreased

20

-60

-50

-40

-30

-20

-10

50 60 70 80 90 100 110

V (

mV

)

t (s)

HCRTLCIdc

0

5

10

0.05 0.06 0.07 0.08 0.09 0.1 0.11

F (

Hz)

t (s)

HCRTINPLC

INP seems to increase the precision of LC activity as well

-55

-50

-45

-40

-35

-30

-25

-20

-15

50 60 70 80 90 100 110

V (

mV

)

t (s)

HCRTLCIdc

0

5

10

15

50 60 70 80 90 100 110

F (

Hz)

t (s)

HCRTGABA

LC

LC

HCRT

GABA

Synaptic input + Frequency

21

INP time scale does not need to match exactly HCRT’s

LC

HCRT

INP

-10

0

10

20

30

40

80 100

I (p

A)

t (s)

HCRTINP

INP+HCRT

5

10

15

20

0 100 200 300

F (

Hz)

g (kS)

INPLC

INP activity decreases as LC is requesting less inhibition

CONCLUDINGREMARKS

Concluding remarks

✓ We have modeled two possible mechanisms of LC activity regulation

✓ At least the LC model fitted before is not controlled

✓ A slow and inhibitory neuropeptide is capable

✓ Possibilities for this inhibitory neuropeptide: MCH and opioids

✓ Questions:Should we search for such neuropeptide? How?

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of controlling LC activity with unexpected precision

by GABAA inhibition

Secondary remarks…

• GABAA-slow is capable of suppressing overloads of LC activity, but…

• it cannot control LC activity as well as we have shown with INP

• Also, it’s not likely to have GABAA-slow from thephysiological point of view…

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Thanks for your attention :)