SPOTLIGHT:

hosting a Frontiers special topic on dopamine and behavioral flexibility

an article about our recent study comparing reinforcing effects of sugar and artificial sweeteners

an article about our 2010 Annals in Neurology paper proposing the aberrant learning hypothesis
Jeff A. Beeler [CV]

Research Associate Professor
DEPARTMENT OF NEUROBIOLOGY

The University of Chicago
924 E. 57th St., R222
Chicago, IL 60637
Email: jabeeler [at] uchicago.edu

My non-academic blog about video game design: synaptogaming.com



Research Interests


I am interested in behavioral flexibility and motivation with a focus on dopamine mechanisms in the basal ganglia. I use mouse genetic, viral and pharmacological tools to dissect the neural substrates mediating behavior, placing an emphasis on behavioral paradigms that allow for the examination of behavioral complexity. I have recently begun doing research with human subjects in parallel with animal studies. Through collaboration, I incorporate computational modeling and electrophysiological into my investigations. I currently am developing two extended hypotheses.

(1) Aberrant learning: Parkinson's disease (PD) is a movement disorder arising from the progressive degeneration of dopamine cells. A cardinal feature of PD is bradykinesia, where movement becomes slow and difficult to initiate. Dopamine replacement therapy with L-DOPA improves this symptom, sometimes dramatically. The immediate improvement with administration of L-DOPA shows that the loss of dopamine directly impairs motor performance, an effect believed to arise from dopamine's direct actions on activity in the striatum. However, dopamine also regulates plasticity at corticostriatal synapses. Although evidence suggests that the loss of dopamine induces abnormal plasticity, the role this may play in the symptoms and progression of PD is unknown. In an on-going series of studies, I am pursuing the hypothesis that the loss of dopamine not only directly impairs performance but also inverts normal plasticity [PDF]. This inversion essentially turns learning against the person. While normal learning is designed to improve performance by optimizing processing through the basal ganglia, under conditions of aberrant learning the exact opposite happens: learning degrades performance through anti-optimization. What is critical is that this aberrant learning becomes 'hard-coded' into synapses. In essence, in PD people to 'learn' not to move. The hope is that this work will provide insight into the progression of PD symptoms and offer new avenues for the development of therapeutics.

(2) Dopamine regulation of thrift: Implicated in motivation and reward, the midbrain dopamine system and its projections to the striatum are often seen as a key mechanism underlying compulsive behavior, such as addiction and, more recently, obesity. Based on a series of mouse homecage studies over the last three years, I propose that primary function of dopamine is to adapt energy expenditure to prevailing energy environment in which the organism finds itself. In this view [PDF], dopamine is not maximizing reward or driving reward behavior but, instead, is regulating the degree to which an animal needs to be thrifty in its pursuit of reward and goals. This provides a different window onto dopamine function. Instead of thinking of it as 'pushing' reward and driving compulsive behaviors, this view suggests that dopamine can actually facilitate exploration and new learning-- a sort of energetic generosity. Conversely, diminished dopamine induces energy conservation and increases the degree to which prior reward experience determines behavioral choice.


People


I work with Xiaoxi Zhuang, an associate professor in Neurobiology. Aside from hosting my work, Xiaoxi's lab has a number of interesting projects and investigations [lab website]. Linan Chen has been developing mouse models for understanding dopamine cell degeneration in Parkinson's disease. More recently, Wanhao Chi has established genetic screening and behavioral studies using Drosophila.

I am currently working with Jessica Koranda, a graduate student that is investigating the role of nicotinic signaling in aberrant learning and behavioral flexibility. With assistance from Mitch Roitman at UIC, Jessica has set up voltammetry in our lab and is about to publish her first paper looking at the role of beta2 nicotinic receptors in modulating dopamine in an in-vivo preparation. Shana Augustin, also a graduate student, has been using electrophysiology to further develop work initially started in the lab by a talented (then) graduate student Mazen Kheirbek, now at Columbia. Shana has completed a thorough, systematic parametric study of corticostriatal plasticity in the indirect pathway and is currently writing up her results. Rudy Faust has been developing viral-mediated genetic tools that will contribute to numerous projects in the lab while his own work focuses on the role of D2 in behavioral inhibition.

Finally, I am fortunate to have many collaborators, including Nathaniel Daw at NYU, Michael Frank at Brown, Mitch Roitman and Jamie McCutcheon at UIC, Dan McGehee and John McDaid here at the University of Chicago, and Paul Reber and Cindy Zadikoff at Northwestern University. I enjoy collaborating and hope the list will continue to grow.


Selected Publications


  • Beeler, J.A., McDaid, J, Frank, MJ, Alexander, E., Turkson, S., Bernandez, M.S., McGehee, D.S. and Zhuang, X. (2012). A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson's disease. Cell Reports, v2(6), p 1747. DOI: 10.1016/j.celrep.2012.11.014. [PDF]

  • Beeler, J.A. (2012). Thorndike 2.0: Dopamine and the regulation of thrift. Invited Focused Review, Frontiers in Behavioral Neuroscience.DOI: 10.3389/fnins.2012.00116 [PDF]

  • Beeler, J.A., Frazier, C.R.M., Zhuang, X. (2012). Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources. Frontiers in Integrative Neuroscience, v. 6:49. DOI: 10.3389/fnint.2012.00049 [PDF]

  • Beeler, J.A., McCutcheon, J.E., Cao, Z.F.H., Murakami, M., Roitman, M.F., Zhuang, X. (2012). Taste uncoupled from nutrition fails to sustain reinforcing properties of food. European Journal of Neuroscience, epub ahead of print. DOI: 10.1111/j.1460-9568.2012.08167.x [PDF]

  • Beeler, J.A., Frazier, C.R.M., Zhuang, X. (2012). Dopaminergic enhancement of local food seeking is under global homeostatic control. European Journal of Neuroscience, v 1423, pp.146-159. [PDF]

  • McCutcheon, J.E., *Beeler, J.A., Roitman, M.F. (2012). Sucrose-predictive cues evoke greater phasic dopamine release than saccharin-predictive cues. Synapse, 66(4), pp. 346-351. [PDF]

  • Beeler, J.A. (2011). Preservation of function in Parkinson's disease: what's learning got to do with it? Brain Research, v 35(1), pp 96-113. [PDF]

  • Beeler, J.A., Daw, N., Frazier, C.R.M., Zhuang, X. (2010). Tonic dopamine modulates exploitation of reward learning Frontiers in Behavioral Neuroscience, 4(170). [PDF]

  • Beeler, J.A., Cao, Z.F.H., Khierbek, M.A, Ding, Y., Koranda, J, Kang, U., Zhuang, X. (2010) Dopamine-dependent motor learning: insight into l-dopa's long-duration response. Annals of Neurology, 67(5), p. 639-47. [PDF]

  • Kheirbek, M.A., Beeler, J.A., Chi, W. and Zhuang, X. (2010) A molecular dissociation between cued and contextual learning. Learning and Memory, 17(3), 148-154. [PDF]

  • Beeler, J.A., Cao, Z.F., Kheirbek, M.A., & Zhuang, X. (2009). Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway. Neuropsychopharmacology, 34(5), p. 1149. [PDF]

  • Kheirbek, M.A., Britt, J.P., Beeler, J.A., Ishikawa, Y., McGehee, D.S., Zhuang, X. (2009) Adenylyl cyclase type 5 is critical for corticostriatal plasticity and striatum-dependent learning. Journal of Neuroscience, 29(39), p. 12115-24. [PDF]

  • Kheirbek M.A., Beeler J.A., Ishikawa Y. & Zhuang X. (2008) A cyclic AMP pathway underlying reward prediction in associative learning. Journal of Neuroscience, 28(44), p. 11401. [PDF]

*co- first author