Presented by Andrew Bubak 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 β3-KO mice Decision making & risk preference β3-KO mice

How did they do it? Locomotion Rotarod Performance T-maze Instrumental Conditioning Probabilistic Selection Task Switching Task Contextual Fear Conditioning Two-way Active Avoidance

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.

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