Expertise:
mouse genetics, mouse behavior,
neurochemistry, neuroanatomy and neuropharmacology
The role of the dopamine system in reward has been well
established. However, how the specific aspects of reward
are mediated by dopaminergic activity remain to be specified.
It is well accepted that a reward has two main properties.
1) A reward acts as a reinforcer that strengthens associative
learning (reinforcement learning). 2) A reward energizes
responses (incentive motivation). It has been suggested that
dopaminergic mechanisms underlie both aspects. According
to the reinforcement learning hypothesis, dopaminergic activity
may code for a so called “prediction error” that
drives the formation of associations between reward and reward-predicting
cues. The incentive salience hypothesis emphasizes that dopamine
mediates the energizing effect of reward or reward-predicting
cues.
Dopamine neurons display two distinct firing modes: tonic
slow irregular firing and phasic burst firing. In an earlier
study in our lab using inducible dopamine transporter knockdown
mice, we found that elevated dopaminergic tone enhanced
motivation with no alteration in reinforcement learning.
However, this result cannot rule out the possibility that phasic dopaminergic
activity may be important for reinforcement learning. It
is dopamine neuron’s phasic bursting activity that
is highly correlated with reinforcement learning
in electrophysiological studies. However, no studies have
shown causality between dopamine neuron bursting
activity and reinforcement learning. In a follow-up study,
we have generated transgenic mice that over-express SK3 channels
under the tyrosine hydroxylase promoter (TH-SK3 mice). SK3
is a well-characterized calcium-dependent potassium channel
that has been shown to play a key role in dopamine neurons'
bursting properties. We are in the process to test the hypothesize
that TH-SK3 mice will have decreased dopamine neuron bursting
activity and will have impaired reinforcement learning.
The molecular basis for dopamine dependent learning may
be very different from other types learning. In the hippocampus,
converged glutamatergic input is sufficient to induce neuroplasticity.
In the striatum/ nucleus accumbens, neuroplasticity requires
converged input from corticostriatal projections (glutamatergic)
and nigrostriatal or mesolimbic dopaminergic projections
(presumably the reward related signal). What makes the striatum/
nucleus accumbens so special? We hypothesize that the type
V adenylyl cyclase plays a key role here. In the hippocampus,
type I adenylyl cyclase can be activated by calcium/calmodulin
and thus lead to increased cAMP and neuroplasticity. In the
striatum/ nucleus accumbens, there is only type V adenylyl
cyclase which cannot be activated by calcium/calmodulin and
can be activated by dopamine D1 receptors. We hypothesize
that this is the mechanism for converged corticostriatal
projections and nigrostriatal/mesolimbic dopaminergic projections
to cause neuroplasticity in dopamine dependent learning.
We have generated mice in which type I adenylyl cyclase is
expressed in the striatum/ nucleus accumbens to test this
hypothesis. We predict that in these mice, striatum/ nucleus
accumbens based learning will be less dependent on reward.
We are also interested in the biochemical basis of dopamine
neuron degeneration in Parkinson's disease. We have made
several transgenic lines to test the hypothesis that dopamine
neuron degeneration is caused by oxidative stress in dopamine
neurons.
Specific research projects:
-- Genetic and behavioral dissection of inhibitory control
Principal Investigator: Xiaoxi Zhuang, Ph.D.
Agency: NIH
Type: R01
--In vivo investigation of DJ-1 function in DJ-1
knockout mice
Principal Investigator: Xiaoxi Zhuang, Ph.D.
Agency: The Michael J. Fox Foundation for Parkinson's Research
Type: Community fast track grants for parkinson’s
disease research
--Model PINK1-linked Parkinson's disease using PINK1 null
mice
Principal Investigator: Xiaoxi Zhuang, Ph.D.
Agency: American Parkinson Disease Association
Type: Research Grant
--Genetic manipulation of phasic dopaminergic activity
Postdoctoral applicant: Jeff Beeler; Mentor: Xiaoxi Zhuang
Agency: NIH
Type: NRSA Individual Fellowship
Laboratory personnel:
Mazen Kheirbek, Graduate Student
mazen@uchicago.edu
Linan Chen, Postdoctoral fellow
lichen@delphi.bsd.uchicago.edu
Jeff Beeler, Postdoctoral fellow
jabeeler@uchicago.edu
Hyun Ah Yoon, Undergraduate Student
hyunah@uchicago.edu
Thomas Bullock, Undergraduate Student
tjbster@gmail.com |
