project leader: katie kavanagh effects of lateral hypothalamic injections of glutamate receptor...
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Project Leader: Katie Kavanagh
Effects of Lateral Hypothalamic Injections of Glutamate Receptor Antagonist (D-AP5) and Agonist
(ATPA) on Food Intake in Rats Under Simulated Microgravity
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•What brain mechanisms underlie sensory specific satiety in hind limb unloaded rats? •Specifically, are lateral hypothalamic glutamate receptors regulating sensory specific satiety?
Questions:
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Why is this important?
•We hope to determine what brain mechanisms regulate SSS and whether they operate similarly in microgravity as they do on Earth.
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Sensory Inputs Sight, Smell, Taste
(via Nucleus Accumbens, etc.)
EAT
Motor Output:
Neural Model
Glutamate release
Lateral Hypothalamus
EAT LESS
LH Injection of D-AP5 at 1g
X•D-AP5 = glutamate receptor antagonist
•Hypothesis 1: D-AP5 will suppress food intake and increase latency to feed during a SSS paradigm in hind limb unloaded rats
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Sensory Inputs Sight, Smell, Taste
(via Nucleus Accumbens, etc.)
EAT
Motor Output:
Neural Model
Glutamate release
Lateral Hypothalamus
EAT MORE
LH Injection of ATPA at 1g•ATPA = glutamate receptor agonist
•Hypothesis 2: ATPA will boost food intake and decrease latency to feed during a SSS paradigm in hind limb unloaded rats•How do we target glutamate receptors in the lateral hypothalamus?
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Getting to the Lateral Hypothalamus:Stereotaxic Surgery
medial / lateral
dorsal / ventral
ante
rior /
post
erio
r
(Paxinos and Watson, 1998)
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Methods: Central MicroinjectionsProcedure= Inject 0.3 L of:
– aCSF (control)– D-AP5 (10 nmol)
n= 9 male Sprague-Dawley rats
– aCSF (control)– ATPA (1 nmol)
n= 8 male Sprague-Dawley rats
D-AP5 Study (bilaterally) ATPA Study (unilaterally)
needle
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Experimental Procedures18 hr. food deprivation
Pre-injection meal – 90 minutesRat Chow
Lateral Hypothalamic injection – aCSF, ATPA, or D-AP5
Post-injection meal – 60 minutesRat Chow or Froot Loops®
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HindlimbUnload
WED
Experiment
FRI
FoodDeprive
THURS MON
Rest(in standard cages)
TUESSAT SUN
Rats had ad libitum access to food and water except on experimental days. Light cycle was 12 hr /12hr light/dark.
Experimental Time Line
Counterbalanced 4 times
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Statistical Analysis
•Two way repeated measures ANOVA•Student-Newman-Keuls post hoc test
How SSS was measured…• Cumulative Food Intake (grams):
– pre-injection meal at 60 and 90 minutes– post-injection meal at 30 and 60 minutes
• Latency to Eat (minutes):– post-injection meal
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EAT LESS
LH Injection of D-AP5
X
Results for D-AP5, a glutamate receptor antagonist
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Time Post Presentation
60 min 90 min
Cu
mu
lati
ve C
ho
w In
take
(g
ram
s)
0
1
2
3
4
5p = 0.61
Rats satiate on chow in pre-injection meal
D-AP5: pre-injection meal data
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D-AP5: post-injection meal food intake at 30 minutes
**p<0.001
~99%
Injection
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D-AP5: latency to eat in post-injection meal
*p<0.05
p=0.13
Injection
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Summary : D-AP5
• D-AP5, a glutamate receptor antagonist, suppresses Froot Loops ® intake and increases latency to feed when injected into the lateral hypothalamus.
Conclusion•D-AP5 suppresses intake of a highly palatable food suggesting that glutamate receptors in the lateral hypothalamus are part of the neural pathway underlying SSS.
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Results for ATPA,a glutamate receptor agonist
EAT MORE
LH Injection of ATPA
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ATPA: pre-injection meal data Rats satiate on chow in pre-injection meal
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ATPA: post-injection meal food intake at 60 minutes
p=0.31
*p<0.05
Injection
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ATPA: latency to eat post-injection meal
p=0.3
*p<0.001~75%
Injection
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Summary : ATPA
• ATPA, a glutamate receptor agonist, boosts rat chow but not Froot Loops® intake when injected into the lateral hypothalamus.
Conclusion• Offering Froot Loops® or injecting with ATPA appear
to be equally effective in increasing food intake. This suggests that access to a highly palatable food is sufficient to saturate this neural pathway.
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Sensory Inputs (via Nucleus Accumbens, etc.)
Sight, Smell, Taste
EAT
Motor Output:
Conclusions:
Glutamate release
Lateral Hypothalamus
EAT LESS
LH Injection of D-AP5 in HU
X•D-AP5 = glutamate receptor antagonist
EAT MORE RAT
CHOW
LH Injection of ATPA in HU•ATPA = glutamate receptor agonist
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Application:• Although pharmacological interventions are not
plausible, it appears that offering astronauts a more palatable food as second course is sufficient to ensure adequate intake.
Sensory Inputs (via Nucleus Accumbens, etc.)
Sight, Smell, Taste
EAT
Motor Output:
Glutamate release
Lateral Hypothalamus
Future Directions: Looking at the link between nucleus accumbens and SSS.
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Results: DAP-5 Suppresses Overeating During Sensory Specific Satiety
Cum
ulat
ive
Foo
d In
take
(gr
ams)
ChowFroot Loops®
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Cu
mu
lati
ve R
at C
ho
w I
nta
ke (
gra
ms)
@ 60 min @ 90 min
Results: Rats are Fed to Satiety on Rat Chow
Meal Duration
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D-AP5: Pre-injection meal food intake at 60 and 90 minutes
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ATPA Injected into LH
Meal 1 Food Intake
Time Post Presentation
60 min 90 min
Cu
mu
lati
ve F
oo
d In
take
(g
ram
s)
0
1
2
3
4
5
6
a CSF Chow ATPA Chow aCSF FL ATPAFL
ATPA: Pre-injection meal food intake at 60 and 90 minutes
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D-AP5: post-injection meal food intake at 60 minutes
**p<0.001
~75%
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ATPA: Post-injection meal food intake at 30 minutes
*p<0.05
p=0.06
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Summary : aCSF
• Our results confirm that rats exhibit SSS during hind limb unloading
Conclusion• The same mechanisms responsible for SSS in
horizontal rats appear to be operating in hind limb unloading