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Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice

Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice.

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Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice

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  1. Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice Yuki Kobayashi, Yoshitake Sano, Elisabetta Vannoni, Hiromichi Goto, Toshio Ikeda, Hitomi Suzuki, Atsuko Oba, Hiroaki Kawasaki, Shigenobu Kanba, Hans-Peter Lipp, Niall P. Murphy,David P. Wolfer and Shigeyoshi Itohara Presented by: Justin P. Smith

  2. Fineberg Review • Impulsivity- a predisposition toward rapid, unplanned reactions to internal or external stimuli with diminished regard to the negative consequences of these reaction to the impulsive individual or to others

  3. Fineberg Fig 1

  4. IPN

  5. Table 1

  6. Role of 5-HT (Table 2)

  7. Heldt and Ressler • Habenula (Hb) modulates DA and 5-HT • Lesioned Hb • Tested ± DA agonist (apomorphine) or DA/5-HT antagonist (clozapine) • Fear-potentiated startle • Freezing • Conditioned fear • Prepulse inhibition (PPI) • Locomotion

  8. Heldt and Ressler • No stress = no difference • Following Conditioned Stress (lesioned animals) • ↓ PPI, normalized with DA/5-HT antag (clozapine) • DA agonist (apomorphine) = hyperlocomotion • Hb involved in stress-dependent regulation of monoamine systems

  9. Heldt Ressler Fig 3

  10. Main paper • Created genetic ablation of mHb • Subdivide Hb into medial (mHb) & lateral (lHb) • mHb- nicotinic acetylcholine R’s • α3,α5& β4 subunits • mHb-interpeduncular nucleus (IPN) pathway  • Behavioral role- ↓ cognition-dependent executive fxns

  11. Behavior • Males for classic tests • Females for IntelliCage study • Nicotine subcu groups • 0, 0.35, 1.05, 3.5, 10.5, and 35 μg/kg • once daily, • 10 min prior to the task

  12. α5 subtype in mHb cells role limiting mHb–IPN pathway & nicotine intake

  13. Fig 1 Characterization of mHb-specific Cre expression transgenic mice Show us they have targeted the mHb

  14. mHb-selective lesions in mHb:DTA mice Fig 2 Successful genetic lesion of mHb

  15. Monoamines and metabolites

  16. Behavior • Locomotor activity in home cage • mHb:DTA mice had no new environment habitation • 5-choice serial reaction time task (5-CSRTT) • Prepulse Inhibition • Open field • EPM

  17. Fig 3 Locomotor activity 5-CSRTT PPI Open field EPM

  18. Delayed and Effort based decision making (ish) • T-maze • ↑ reward (HRA; 10 pellets), ↓reward (LRA;1 pellet) • Delay-trained to wait (5, 10 then 15s) for HRA • Effort- small 15cm obstacle in HRA, LRA open

  19. Fig 4: Delay top, Effort bottom Black = control

  20. Learning and memory tests • Morris water maze • Fear conditioning • Radial arm maze

  21. Fig 5 Morris water maze Fear conditioning Radial arm maze

  22. IntelliCage (females) • Activity and Adaptation • Visits to water bottle • Week 1 all doors were open, access 8 drinking bottles (free adaptation) • week 2 doors closed, opened with 5 s nose-poke (nose-poke adaptation) • 3rd week fixed drinking schedule (drinking session adaptation) opening to nose-pokes between the hours of 11am–noon and 4pm–5pm

  23. IntelliCage • Corner avoidance task (Avoidance and preference) • Trained to drink from specific corners • Air puff to face if incorrect

  24. Fig 6: IntelliCage reversal

  25. Flexibility • Chain task reward • water same corner for 14 sessions (corner preference), • 14 sessions water in opposite corner (corner reversal) • 8 sessions learn new corner during each drinking session (serial reversal) • Cage mates in four subgroups, target corners • water delivered in corner adjacent to most recently visited one • 14 sessions in one direction (chaining acquisition) • 21 sessions in the opposite direction (chaining reversal) • Water in the corner adjacent to the last rewarded corner (patrolling acquisition) clockwise or counter clockwise • 21 sessions in opposite direction (patrolling reversal)

  26. Reaction time and Saccharin preference • Reaction time • Nose poke with light cue and allow drinking • Nose poke during delay = premature response • Saccharin preference • Preference for sweet water • Must wait timeout period (increases per day)

  27. Patrolling Patrolling Chaining Chaining Reaction Time Saccharin preference Saccharin delay

  28. Fig 7: Lack of susceptibility to nicotine in mHb:DTA mice on 5-CSRTT performance and adaptation to a new environment • Effects of nicotine on the new environment adaptation task • Nicotine failed to induce any effect • Mhb-IPN central pathway on inhibitory and environmental adaptation

  29. c-Fos expression • Measure of activity • Sampled from 5-CSRTT • Reflect differences in the genotype • Suggest a crucial involvement • ACC and hippocampus in the behavioral abnormalities of mHb-DTA mice

  30. Fig 8

  31. Take home • mHb-IPN pathway involved • inhibitory control (impulsive and compulsive behaviors) • Executive functions • mHb:DTA resemble phenotypes with bilateral lesions habenular complex • mHb:DTA lack susceptibility systemic nicotine • supports mHb–IPN pathway, expresses a ↑level of unique nicotinic acetylcholine receptors (α3,α5& β4) • mHb–IPN–monoaminergic centers & lHb-mediated pathway essential for controlling monoaminergic centers (mech unknown)

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