1. Control of Sleep-to-Wake
Transitions
fast aminoacid vs slow neuropeptide
Thiago S Mosqueiro
PhD candidate
BioCircuits Institute, UCSD (USA)
Institute of Physics of São Carlos, USP (BR)
08/28/2014
thmosqueiro.vandroiy.com

3. Courtesy of Milena Carvalho

4. 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

5. 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

6. 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

7. PREVIOUS
OBSERVATIONS

8. Locus Coeruleus (LC)
6
Scammell & Saper `2007 Nat Med
Carter et al `2010 Nat Neurosci.

9. …and Hypothalamus
7
Carter et al `2012 PNAS

10. HCRT-mediated wake transition
8
Carter et al `2012 PNAS
The LC relays the
sleep-to-wake transition
message from HCRT

11. MODELING

12. Compartmental model
10
Hindmarsh & Serban
`2007 Scholarpedia
CVODE

13. Compartmental model
10
Hindmarsh & Serban
`2007 Scholarpedia
CVODE

14. GABAA model
11
Cl
-Cl
-
PostsynapticPresynaptic

15. Populations
• Each population has 20 neurons in most simulations
12
GABA
GABAA
HCRT
LC
AMPA
HCRT
AMPA
1.0
1.0
0.5
0.5
0.5
Hyphotalamus
sublateraldorsal
periLC
brainstem

16. HCRT Excitation Protocol
13
-55
-50
-45
-40
-35
-30
-25
-20
-15
50 60 70 80 90 100 110
V(mV)
t (s)
HCRT
LC
Idc
0
5
10
15
50 60 70 80 90 100 110
F(Hz)
t (s)
HCRT
GABA
LC
LC
HCRT
GABA

17. GABAA-induced
EXCITATION

18. 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

19. 16
0
5
10
15
g
GABA
= 800nS
HCRT
GABA
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

20. 17
0
5
10
15
20
50 75 100 125 150
F(Hz)
t (s)
10
15
20
25
30
10
2
10
3
F(Hz)
gGABA
(a.u.)
GABA
LC
GABA is increasing the LC firing frequency!
Changing the number of GABA neurons won’t change anything
Assessing the asymptotic firing frequency…

21. SLOW
NEUROPEPTIDE

22. Inhibitory Neuropeptide (INP)
19
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

23. 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)
HCRT
LC
Idc
0
5
10
0.05 0.06 0.07 0.08 0.09 0.1 0.11
F(Hz)
t (s)
HCRT
INP
LC
INP seems to increase the
precision of LC activity as well

24. 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)
HCRT
LC
Idc
0
5
10
0.05 0.06 0.07 0.08 0.09 0.1 0.11
F(Hz)
t (s)
HCRT
INP
LC
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)
HCRT
LC
Idc
0
5
10
15
50 60 70 80 90 100 110
F(Hz)
t (s)
HCRT
GABA
LC
LC
HCRT
GABA

25. 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(pA)
t (s)
HCRT
INP
INP+HCRT
5
10
15
20
0 100 200 300
F(Hz)
g (kS)
INP
LC
INP activity decreases as LC is requesting
less inhibition

26. CONCLUDING
REMARKS

27. 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?
23
of controlling LC activity with unexpected precision
by GABAA inhibition

28. 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 the
physiological point of view…
24

29. Thanks for your attention :)