Xiaoxi Zhuang, Ph.D.

APPOINTMENTS

  • Professor, Department of Neurobiology, Committee on Neurobiology, Committee on Molecular Metabolism and Nutrition

EDUCATION

Ph.D., Columbia University, 1996

CONTACT INFORMATION

The University of Chicago
Jules Knapp Center Room 214 (MC 0926)
947 South 58th Street
Chicago, Illinois 60637

xzhuang@bsd.uchicago.edu

Phone: (773) 834-9063

Website (Department of Neurobiology)

RESEARCH SUMMARY

We investigate the molecular machinery for information processing that underlies reward learning, motivation, economic decision making and motor control. Our main approaches include mouse genetics, fly genetics, electrophysiology, computational models and animal learning paradigms.

1. The role of dopamine in reward and reward-dependent behavioral modification

Animal behaviors can be largely modified by reward/punishment histories. Understanding the neurobiological basis of reward learning, motivation and response selection is a critical step in understanding many mental disorders such as addiction and depression as well as the behavioral aspects of obesity, and in developing novel therapies. We are focusing on the role of tonic versus phasic dopamine, the corresponding postsynaptic signaling pathways and corticostriatal plasticity in the above processes.

Our earlier findings indicate the role of distinct dopamine signaling in reinforcement learning and exploration-exploitation choice bias. As an extension of the above research, how do reward learning and economic decision making ultimately affect fitness? In a natural environment, these behaviors are critical for maximizing rewards/gains and minimizing risks/losses and for survival. We are investigating these more complex behaviors (e.g foraging) in a semi-natural environment and how genetic variations may affect fitness in this context.  We take advantage of microeconomic analysis of feeding behavior, combining mouse genetics and fly genetics. Fly genetics allows us to search for genes that confer energy conservation traits while mouse genetics allows us to examine the neurobiological basis rigorously and provides the relevance to human conditions.

2. The role of dopamine in motor learning and motor performance

In parallel to studies on the role of mesolimbic dopamine in reward learning and response selection, another focus of the lab is on the role of nigrostriatal dopamine, the corresponding postsynaptic signaling pathways and corticostriatal plasticity in motor learning and motor performance, in particular, in the context of Parkinson’s disease symptoms and therapies.

In the nigrostriatal pathway, dopamine modulates the intrinsic excitability of striatal neurons. However, it also modulates corticostriatal plasticity, potentially producing cumulative and long-lasting changes in motor performance. Our findings indicate that loss of dopamine leads to both direct motor performance impairments as well as D2 receptor-dependent and task-dependent “learned” motor inhibition that gradually and cumulatively deteriorates motor performance. We hypothesize that such “learned” motor inhibition is accompanied by increased LTP in the indirect pathway corticostriatal synapses. We are using a number of approaches to reduce such LTP as a novel therapeutic strategy for Parkinson’s disease.

3. The biochemical basis of dopamine neuron degeneration in Parkinson's disease

Parkinson's disease is caused by progressive loss of dopamine neurons. Its biochemical basis is poorly understood. Our earlier studies using transgenic mice indicate that dopamine itself can cause oxidative stress. We hypothesize that under normal conditions, dopamine neurons are able to handle such cellular stress. However, in aged animals or in animals with genetic defects, dopamine neurons may die when protective mechanisms are impaired (e.g. defects in protein folding and/or protein degradation pathways). We have recently developed a novel positive feedback gene amplification system to overexpress genes specifically in dopamine neurons. Such an approach has allowed us to mimic human genetic mutations with dominant inheritance and develop Parkinson’s disease models with severe mitochondria pathology and progressive dopamine neuron degeneration. We are using these models to test the above hypotheses.

View Research Papers on PubMed