Download Attenuating GABAA Receptor Signaling in Dopamine Neurons

Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively
Enhances Reward Learning and Alters Risk Preference in Mice
Jones G. Parker,1 Matthew J. Wanat,2 Marta E. Soden,2 Kinza Ahmad,1 Larry S. Zweifel,2 Nigel S. Bamford,3,4
and Richard D. Palmiter1
Presented by Andrew Bubak
Goal
 Contribution of
GABAA-R in DA
neurons to behavior
 Decision making & risk
preference
 β3-KO mice
How did they do it?
 Locomotion
 Switching Task
 Rotarod Performance
 Contextual Fear
 T-maze
Conditioning
 Two-way Active Avoidance
 Instrumental Conditioning
 Probabilistic Selection Task
DA neurons in midbrain slices from β3-KO mice
have reduced GABAA-R signaling
Whole-cell voltage-clamp
recordings from VTA of
midbrain slices (~45% decrease
in freq.)
GABAA-R Function Testing Results
More significant at
larger amplitudes
Sensitivity of DA neurons to GABAergic
signaling is significantly decreased
Basal locomotor activity and rotarod performance are
normal while morphine-induced locomotion is enhanced in
β3-KO mice
Morphine = Enhancement in DA release
DA neurons have normal mEPSCs but non-DA neurons in the VTA of β3-KO
mice smaller mIPSCs
Marked decrease in amplitude of
inhibitory events in non-DA
neurons of β3-KO
Suggest compensatory changes
in non-DA neurons of VTA in
β3-KO
β3-KO mice have increased DA release in the NAc in response to PPTg
stimulation
Excitation of DA neurons by Glu and ACh is modulated by GABAA-R
Attenuating GABAA-R signaling disrupts inhibitory input to DA neurons
and augments excitability
β3-KO mice have enhanced acquisition but normal reversal or extinction during
appetitive learning
Fixed Rew+ or Rew- arms
10 trials/day for 10days
β3-KO mice have enhanced acquisition but normal reversal or extinction during
appetitive learning cont.
Unrewarded Lever Pressing
Given 7 days
High and Low Switched
β3-KO mice exhibit normal aversive learning
Shown that DA is required for
learning in active avoidance test
β3-KO mice are more risk-preferring in a probabilistic selection task
Final Thoughts
 Information encoding reward probability is relayed to DA
neurons, in part, through GABAergic inputs
 Attenuating the sensitivity of DA neurons to GABA signaling
may have disrupted the proper integration of information
about reward probability at the level of DA neurons and
increased the risk preference of β3-KO mice.
fin