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Control of Sleep-to-Wake
Transitions
fast aminoacid vs slow neuropeptide
Thiago S Mosqueiro
PhD candidate
BioCircuits Inst...
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
...
Take-home message
3
GABA
HCRT
LC
INP
GABAA is not sufficient
to control bursts of
LC activity
An Inhibitory Neuropeptide
co...
Summary
• Previous research on Hypocrexin (HCRT) and Locus Coeruleus (LC)
• Modeling neural populations with conduction mo...
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
GABA
GABAA
HCRT
LC
AMPA
HCRT
AMPA
1.0
1.0
0.5
0.5
0.5
...
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
5...
GABAA-induced
EXCITATION
Varying GABA Conductance
• Hypothesis: GABA hold back LC
• IPSP generated by GABAA in a LC cell
• Amplitude ~ 0. - 4. mV
1...
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
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 L...
SLOW
NEUROPEPTIDE
Inhibitory Neuropeptide (INP)
19
Since GABAA cannot control LC activity,

would a Inhibitory Neuropeptide be able to?
GABA...
Activity With INP group
Also…
i. A faster rise up of activity on
the onset of HCRT activation

ii. LC activity dies out fa...
Activity With INP group
Also…
i. A faster rise up of activity on
the onset of HCRT activation

ii. LC activity dies out fa...
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(...
CONCLUDING
REMARKS
Concluding remarks
✓ We have modeled two possible mechanisms of LC activity regulation
✓ At least the LC model fitted befor...
Secondary remarks…
• GABAA-slow is capable of suppressing overloads of LC activity, but…
• it cannot control LC activity a...
Thanks for your attention :)
Control of sleep-to-wake transitions
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Control of sleep-to-wake transitions

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Full text: http://iopscience.iop.org/1367-2630/16/11/115010/article

Talk about a paper we published on New Journal of Physics regarding mechanisms of controlling sleep-to-wake transitions using fast amino acid and slow neuropeptide transmission. Quality of the slides may be reduced, you can download the slides to get them in "full quality".

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Control of sleep-to-wake transitions

  1. 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
  2. 2. Courtesy of Milena Carvalho
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. PREVIOUS OBSERVATIONS
  7. 7. Locus Coeruleus (LC) 6 Scammell & Saper `2007 Nat Med Carter et al `2010 Nat Neurosci.
  8. 8. …and Hypothalamus 7 Carter et al `2012 PNAS
  9. 9. HCRT-mediated wake transition 8 Carter et al `2012 PNAS The LC relays the sleep-to-wake transition message from HCRT
  10. 10. MODELING
  11. 11. Compartmental model 10 Hindmarsh & Serban `2007 Scholarpedia CVODE
  12. 12. Compartmental model 10 Hindmarsh & Serban `2007 Scholarpedia CVODE
  13. 13. GABAA model 11 Cl -Cl - PostsynapticPresynaptic
  14. 14. 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
  15. 15. 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
  16. 16. GABAA-induced EXCITATION
  17. 17. 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
  18. 18. 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
  19. 19. 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…
  20. 20. SLOW NEUROPEPTIDE
  21. 21. 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
  22. 22. 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
  23. 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 -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
  24. 24. 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
  25. 25. CONCLUDING REMARKS
  26. 26. 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
  27. 27. 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
  28. 28. Thanks for your attention :)

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