Download - Control of sleep-to-wake transitions
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
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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
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PREVIOUS OBSERVATIONS
Locus Coeruleus (LC)
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Scammell & Saper `2007 Nat Med
Carter et al `2010 Nat Neurosci.
…and Hypothalamus
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Carter et al `2012 PNAS
HCRT-mediated wake transition
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Carter et al `2012 PNAS
The LC relays the sleep-to-wake transition
message from HCRT
MODELING
Compartmental model
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Hindmarsh & Serban `2007 Scholarpedia
CVODE
Compartmental model
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Hindmarsh & Serban `2007 Scholarpedia
CVODE
GABAA model
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Cl-Cl-
PostsynapticPresynaptic
Populations
• Each population has 20 neurons in most simulations
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GABAGABAA
HCRT
LC
AMPAHCRT
AMPA
1.0
1.0
0.5
0.5
0.5
Hyphotalamus
sublateraldorsal periLC
brainstem
HCRT Excitation Protocol
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-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
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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
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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
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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 :)