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Genetic dissection of medial habenula–interpeduncular nucleus
pathway function in miceYuki 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
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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
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Fineberg Fig 1
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IPN
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Neurocognitive domain Definition Task Neural system Neurochemistry
Impulsivity
Motor impulsivity Prepotent motor disinhibition
Stop signal reaction time task (SSRT)
Right inferior frontal cortex and subcortical
connectionsNorepinephrine
Decision-making impulsivity
Difficulty in delaying gratification and
choosing immediate small rewards despite
negative long-term consequences
Decision making or gambling tasks (eg
Cambridge Gambling Task (CANTAB), Iowa
gamble task)
Orbitofrontal cortex and subcortical
connections
Cortex—serotonin Subcortical circuitry-serotonin/dopamine
Reflection impulsivity
Insufficient information sampling before making a choice
Reflection task, 5-CSRTT Not known Not known
Table 1
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Role of 5-HT (Table 2)
Compulsivity (reversal learning task)
Impulsivity (5CSRTT)
5-HT2C antagonist (SB24284)
ReducedIncreased
5-HT2A antagonist (M100907)
Increased Reduced
Hypothesized- mediating neuroanatomy
Neural projections from OFC to the caudate nucleus (dorsomedial striatum in the rat)
Neural projections from VMPFC (area 25) to the shell of the nucleus accumbens
Impulsivity (5CSRTT)
5-HT2C antagonist (SB24284) Increased
5-HT2A antagonist (M100907) Reduced
Hypothesized- mediating neuroanatomy
Neural projections from VMPFC (area 25) to the shell of the nucleus
accumbens
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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
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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
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Heldt Ressler Fig 3
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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
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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
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α5 subtype in mHb cells role limiting mHb–IPN pathway & nicotine intake
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Fig 1
Characterization of mHb-specific Cre expression transgenic mice
Show us they have targeted the mHb
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Fig 2 mHb-selective lesions in mHb:DTA mice
Successful genetic lesion of mHb
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Monoamines and metabolites
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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
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Fig 3
Locomotor activity
PPI Open fieldEPM
5-CSRTT
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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
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Fig 4: Delay top, Effort bottom Black = control
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Learning and memory tests
• Morris water maze• Fear conditioning• Radial arm maze
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Fig 5
Morris water maze
Fear conditioning
Radial arm maze
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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
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IntelliCage
• Corner avoidance task (Avoidance and preference)
• Trained to drink from specific corners• Air puff to face if incorrect
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Fig 6: IntelliCage
reversal
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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)
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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)
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Chaining Chaining Patrolling Patrolling
Reaction Time
Saccharin preference Saccharin delay
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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
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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
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Fig 8
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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)