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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. Project Leader: Katie Kavanagh. What brain mechanisms underlie sensory specific satiety in hind limb unloaded rats?. Questions:.

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Project Leader: Katie Kavanagh

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  1. Effects of Lateral Hypothalamic Injections of Glutamate Receptor Antagonist (D-AP5) and Agonist (ATPA) on Food Intake in Rats Under Simulated Microgravity Project Leader: Katie Kavanagh

  2. What brain mechanisms underlie sensory specific satiety in hind limb unloaded rats? Questions: • Specifically, are lateral hypothalamic glutamate receptors regulating sensory specific satiety?

  3. 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.

  4. Neural Model Sensory Inputs Sight, Smell, Taste (via Nucleus Accumbens, etc.) Lateral Hypothalamus Motor Output: Glutamate release LH Injection of D-AP5 at 1g EAT X EAT LESS • 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

  5. Neural Model Sensory Inputs Sight, Smell, Taste (via Nucleus Accumbens, etc.) Lateral Hypothalamus Motor Output: Glutamate release EAT LH Injection of ATPA at 1g • ATPA = glutamate receptor agonist EAT MORE • 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?

  6. dorsal / ventral anterior / posterior medial / lateral Getting to the Lateral Hypothalamus:Stereotaxic Surgery (Paxinos and Watson, 1998)

  7. Procedure= Inject 0.3 mL of: aCSF (control) D-AP5 (10 nmol) n= 9 male Sprague-Dawley rats aCSF (control) ATPA (1 nmol) n= 8 male Sprague-Dawley rats needle Methods: Central Microinjections ATPA Study (unilaterally) D-AP5 Study (bilaterally)

  8. Experimental Procedures 18 hr. food deprivation Pre-injection meal – 90 minutes Rat Chow Lateral Hypothalamic injection – aCSF, ATPA, or D-AP5 Post-injection meal – 60 minutes Rat Chow or Froot Loops®

  9. Experimental Time Line Rest (in standard cages) Hindlimb Unload Food Deprive Experiment FRI WED THURS SUN SAT MON TUES Counterbalanced 4 times Rats had ad libitum access to food and water except on experimental days. Light cycle was 12 hr /12hr light/dark.

  10. 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

  11. Results for D-AP5, a glutamate receptor antagonist X LH Injection of D-AP5 EAT LESS

  12. D-AP5: pre-injection meal data Rats satiate on chow in pre-injection meal

  13. D-AP5: post-injection meal food intake at 30 minutes **p<0.001 ~99% Injection

  14. D-AP5: latency to eat in post-injection meal p=0.13 *p<0.05 Injection

  15. 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.

  16. LH Injection of ATPA EAT MORE Results for ATPA,a glutamate receptor agonist

  17. ATPA: pre-injection meal data Rats satiate on chow in pre-injection meal

  18. ATPA: post-injection meal food intake at 60 minutes p=0.31 *p<0.05 Injection

  19. ATPA: latency to eat post-injection meal *p<0.001 ~75% p=0.3 Injection

  20. 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.

  21. Conclusions: Lateral Hypothalamus Sensory Inputs (via Nucleus Accumbens, etc.) Sight, Smell, Taste Motor Output: Glutamate release LH Injection of D-AP5 in HU EAT X EAT LESS • D-AP5 = glutamate receptor antagonist LH Injection of ATPA in HU • ATPA = glutamate receptor agonist EAT MORE RAT CHOW

  22. Application: Lateral Hypothalamus Sensory Inputs (via Nucleus Accumbens, etc.) Sight, Smell, Taste Motor Output: Glutamate release Future Directions: Looking at the link between nucleus accumbens and SSS. EAT • Although pharmacological interventions are not plausible, it appears that offering astronauts a more palatable food as second course is sufficient to ensure adequate intake.

  23. Chow Froot Loops® Results: DAP-5 Suppresses Overeating During Sensory Specific Satiety Cumulative Food Intake (grams)

  24. Results: Rats are Fed to Satiety on Rat Chow Cumulative Rat Chow Intake (grams) @ 60 min @ 90 min Meal Duration

  25. D-AP5: Pre-injection meal food intake at 60 and 90 minutes

  26. ATPA: Pre-injection meal food intake at 60 and 90 minutes

  27. D-AP5: post-injection meal food intake at 60 minutes **p<0.001 ~75%

  28. ATPA: Post-injection meal food intake at 30 minutes p=0.06 *p<0.05

  29. 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

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