FY2012 Annual Report
Neurobiology Research Unit
Professor Jeff Wickens
The goal of the Neurobiology Research Unit is to understand the cellular mechanisms and neural circuitry underlying learning and adaptive behavior in the mammalian brain. This collaborative, interdisciplinary program of research is focused on the striatum of the basal ganglia and the neuromodulators, dopamine and acetylcholine, which play a central role in the mechanisms of reinforcement learning. Our main achievements have been: to characterize synaptic plasticity in the striatum and its modulation by dopamine; to measure dopamine signaling during learning and its role in the therapeutic mechanisms of methylphenidate; and, to elucidate the dynamics of neural assemblies in the striatum and their significance for behavior. These findings are of broad, general significance for the neuroscience of learning and motivation, and of fundamental importance for clinical understanding of major neuropsychiatric disorders. Our research has the forward goal of developing better treatments for attention-deficit hyperactivity disorder and Parkinson’s disease, which are debilitating neurological disorders of great importance to children and adults.
- Dr. Tomomi Shindou, Researcher
- Dr. Mayumi Ochi-Shindou , Researcher
- Dr. Adam Ponzi, Researcher
- Dr. Takashi Nakano, Researcher
- Dr. Sho Aoki, Researcher
- Mr. Andy Liu, Senior Technician
- Mr. Kavinda Liyanagama, Programmer Technician
- Mr. Hiroaki Hamada, Research Intern
- Mr. Kurt Ruegg, Research Intern (Summer), Harvard University Undergraduate Student
- Ms. Yukako Suzuki, Research Administrator
- Theme: Dopamine signaling and mechanism of pyschostimulant action
- Type of collaboration: Joint research
- Dr Brian Hyland, University of Otago, New Zealand
- Theme: Neuroplasticity studies using dopamine sensing
- Type of collaboration: Research Collaboration
- Professor Jia-Jin J. Chen, Department of Biomedical Engineering, National Cheng kung University, Taiwan
- Mr Yu-Ting Li, Department of Biomedical Engineering, National Cheng kung University, Taiwan
- Theme: Functional imaging of altered reward sensitivity and its relation to human behavior
- Type of collaboration: Research Collaboration
- Professor Gail Tripp, Okinawa Institute of Science and Technology, Japan
- Dr. Emi Furukawa, Okinawa Institute of Science and Technology, Japan
- Dr Jorge Moll, Neuropsychology Center, Cognitive and Behavioral Neuroscience Unit, D’Or Institute for Research and Education, Brazil
- Dr Paulo Mattos, Neuropsychology Center, Cognitive and Behavioral Neuroscience Unit, D’Or Institute for Research and Education, Brazil
- Theme: Drug Delivery using Femtosecond Pulses
- Type of collaboration: Research Collaboration
- Prof. Keshav Dani, OIST
3. Activities and Findings
Research activity has focused on: synaptic plasticity in the corticostriatal pathway; the nature of dopamine signaling during learning; and, the dynamics of neural assemblies in the striatum and their significance for behavior. We have also initiated collaborative studies with other researchers at OIST. These include work on a nanoparticle based drug delivery system for translating our basic science insights into new treatment approaches; and human imaging studies to test theories of altered reward processing in attention-deficit hyperactivity disorder. We use a powerful and unique combination of approaches extending from cellular to behavioral levels of biological organization, including 2-photon microscopy, electrophysiology, fast-scan cyclic voltammetry, behavior, optogenetics and computational modeling, taking advantage of the opportunities for cross-disciplinary research at OIST.
3.1 Synaptic plasticity in the corticostriatal pathway
OIST Researchers Dr Tomomi Shindou and Dr Mayumi Ochi-Shindou
Dopamine release occurs in the brain in response to unexpected rewards and stimuli predicting rewards. Dopamine-dependent plasticity is a potential cellular mechanism underlying reinforcement learning in the striatum. We aim to determine by what rules and mechanisms the dopamine signal is translated into changes in synaptic efficacy?
We previously showed that corticostriatal synapses exhibit dopamine dependent plasticity according to a “three factor rule” for synaptic modification. In particular, a conjunction of presynaptic cortical input and postsynaptic striatal output results in long-term potentiation (LTP) when associated with dopamine inputs, but long-term depression (LTD) in the absence of dopamine. Thus, dopamine may facilitate selection of particular pathways among the matrix of corticostriatal input-output possibilities. However, the nature of this interaction requires further study.
The spiny projection neurons of the striatum differentially express dopamine D1 and D2 receptors. Since D1 and D2 receptor activation causes opposing biochemical responses, different rules for synaptic plasticity may apply to each category. In order to definitively identify D1 and D2 neurons we are using BAC transgenic mice that selectively express green fluorescent protein (GFP) in either D1 or D2 cells.
Using these transgenic mice we tested the hypothesis that dopamine differentially regulates synaptic plasticity in dopamine D1 versus dopamine D2 receptor expressing subtypes of striatal neuron. We found tLTD in dopamine D1a receptor-expressing neurons but not in dopamine D2 cells. Our ongoing work is investigating the biophysical basis for these differences.
3.2 The nature and timing of the dopamine signal in the striatum during learning
Collaboration with Professor Brian Hyland, University of Otago, New Zealand.
One of our main aims is to understand the actions of the dopamine signal in the striatum. Several lines of evidence indicate that phasic firing of dopamine neurons plays a crucial role in reinforcement learning. Because of the low rate of dopamine cell firing activity, changes indicating learning cannot be detected in unit recordings without averaging many trials. To obtain trial-by-trial measures of dopamine responses we developed expertise in fast-scan cyclic voltammetry (FSCV). We wrote in-house software for data acquisition and analysis by principal components regression, designed new head-mounted amplifiers, and developed new methods for fabricating carbon-fiber electrodes with higher sensitivity, lower noise and smaller size. With these methods we are able to measure dopamine concentration in freely moving rats with nanomolar sensitivity and sub second resolution. We are now investigating dopamine signaling in awake rats during learning of simple stimulus-reward associations.
3.3 Activity dynamics of the striatal network
OIST Researcher: Dr Adam Ponzi
The principal neurons of the striatum are projection neurons with local inhibitory collaterals. We have suggested that they form a lateral inhibition type of neural network with sparse excitatory input from the cerebral cortex. Using computational models we simulated realistic networks and investigated the effect of lateral inhibition on network dynamics. We have previously shown that sparse lateral inhibition, which is the reality in the striatum, plays an important role in dynamics, and is optimal for spontaneous generation of assemblies that fire in sequence in response to unstructured input. Our ongoing work is investigating the effects of more structured inputs. Sparse lateral inhibition in the striatum may be relevant to neural activity sequences encoding behavior.
3.4 Drug Delivery Using Femtosecond Pulses
OIST collaborator Professor Keshav Dani; OIST researcher Dr Takashi Nakano
Recently developments in materials and nanotechnology have allowed for the development of biocompatible materials that can be introduced into the body and externally controlled via physical, chemical or biological stimulus. The high power of femtosecond pulses in particular allows for specific control of biomaterials by using their nonlinear optical properties. In collaboration with the Dani Unit at OIST has been developing a novel technique for controlling biocompatible drug delivery systems using femtosecond pulses. This nanoparticle based drug delivery system provide a way to translate our basic science insights into dopamine modulation of plasticity into new treatment approaches.
3.5 Reward prediction in attention deficit hyperactivity disorder (ADHD)
Collaborators: Prof. Gail Tripp (Human Developmental Neurobiology Unit, OIST) and members of D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
We have continued a successful collaboration with Professor Tripp (OIST) and colleagues in Brazil (IDOR) in a human study using functional magnetic resonance imaging (fMRI) to measure brain activation in response to classically conditioned cues predicting reward. We found increased activation in the caudate, nucleus accumbens and ventral putamen during reward anticipation in controls but not in ADHD. In contrast, increased activation was observed during reward delivery in ADHD but not in controls (Furukawa et al., submitted). These findings support our hypothesis that impaired transfer of phasic dopamine release from reward to cues predicting reward may underlie altered reinforcement sensitivity in ADHD.
- Oorschot, D.E., Lin, N., Cooper, B.H., Reynolds, J.N.J., Sun, H., and Wickens, J.R. (2013) Synaptic connectivity between rat striatal spiny projection neurons in vivo: Unexpected multiple somatic innervation in the context of overall sparse proximal connectivity. Basal Ganglia 3 (2013) 93–108.
- Ponzi, A., and Wickens, J.R., The inhibitory network of the striatum at the edge of chaos. BMC Neurosci. 2013; 14(Suppl 1): O19 doi: 10.1186/1471-2202-14-S1-O19
- Ponzi, A., and Wickens, J.R. (2013) Optimal balance of the striatal medium spiny neuron network. PLoS Computational Biology doi: 10.1371/journal.pcbi.1002954. Epub 2013 Apr 11.
- Tripp, G., and Wickens, J.R. (2012) Reinforcement, dopamine and animal models in drug development for ADHD. Neurotherapeutics, 9: 622-634.
- Aggarwal, M., Hyland, B.I., and Wickens, J.R. (2012) Neural control of dopamine neurotransmission: implications for reinforcement learning. Eur J Neurosci 35(7): 1115-1123.
- Ponzi, A., and Wickens, J.R. (2012) Input dependent cell assembly dynamics in a model of the striatal medium spiny neuron network. Frontiers in Systems Neuroscience 6: 1-14.
- Nakano, T., Yoshimoto, J. and Doya, K. (2013) A model-based prediction of the calcium responses in the striatal synaptic spines depending on the timing of cortical and dopaminergic inputs and post-synaptic spikes. Frontiers in Computational Neuroscience 7:119. doi: 10.3389/fncom.2013.00119.
4.2 Books and other one-time publications
- Ponzi, A., and Wickens, J.R. (2012) Input dependent variability in a model of the striatal medium spiny neuron network. Proceedings of The 3rd International Conference on Cognitive Neurodynamics (ICCN), Advances in Cognitive Neurodynamics (III), Yamaguchi, Y. (Ed) Springer, 600p. [ISBN 978-94-007-4791-3]
4.3 Oral Presentations
- Ponzi, A. The inhibitory network of the striatum at the edge of chaos. CNS 2013, Paris, France. (July 2013)
- Ponzi, A. Optimal Balance of the Striatal Medium Spiny Neuron Network. The 36th Annual Meeting of the Japan Neuroscience Society, Kyoto, Japan. (June 2013)
- Wickens, J.R. 2013 Dopaminergic mechanisms in the pathophysiology of ADHD. Plenary Lecture, Recent Advances in Neuroscience: Plasticity, Imaging, Regeneration and Addiction, University of Sydney, 12-13 September 2013
- Wickens, J.R. Basal ganglia: structure and computations, Okinawa Computational Neuroscience Course, Okinawa, July 4th, 2013.
- Wickens, J.R., Cellular actions of dopamine in the corticostriatal system. Third Symposium on the Biology of Decision Making, Paris, 29 May 2013.
- Wickens, J.R., Li, Y-T, Huang, Y-L, Chen, J-J, and Hyland, B.I. Methylphenidate specifically rescues deficient anticipatory dopamine release in an ADHD model. Congress DOPAMINE 2013, May 24-28, 2013, Alghero, Sardinia (Italy)
- Wickens, J.R., The basal ganglia, dopamine and acetylcholine: substrates of reinforcement and learning. 11th Systems Neurobiology Spring School 2013 (SNSS2013) on Neural Coding and Plasticity, Shijonawate City, Japan,10-12th March, 2013
- Wickens, J.R. Cellular physiology of the basal ganglia neurons, Invited Lecture, 11th Triennial meeting of the International Basal Ganglia Society Eilat, Israel , March 3-7, 2013
- Wickens, J.R. A cellular mechanism for reinforcement learning: dopamine-dependent plasticity in the corticostriatal pathway. Plenary lecture, 2012 Korean Society for Brain and Neural Science annual meeting (ISN-Wiley-Blackwell-JNC-International Lecturer). Seoul National University, Seoul, September 25, 2012.
- Tripp, G., Wickens, J.R., Furukawa, E. Dopamine, Reinforcement and ADHD. D’Or Institute for Research and Education. Rio de Janeiro, Brazil, August 10, 2012.
- Wickens, J.R. Basal ganglia circuitry. RIKEN BSI Summer Program, July 5, 2012.
- Wickens, J.R. Synaptic Plasticity and Learning. RIKEN BSI Summer Program, July 6, 2012.
- Wickens, J.R. Methylphenidate-mediated rescue of deficient dopamine reward prediction in an ADHD model. SHIONOGI & OIST Collaborative Seminar, Shionogi R&D Center, Toyonaka-city, Osaka, April 26, 2012.
4.4 Poster Presentations
- Wickens, J.R., Li, Y-T, Huang, Y-L, Chen, J-J, and Hyland, B.I. Methylphenidate (Ritalin) rescues deficient dopamine reward prediction in an ADHD animal model. 11th Triennial meeting of the International Basal Ganglia Society Eilat, Israel , March 3-7, 2013
- Nakano,T. andWickens, J. (2013) Role of dopamine in corticostriatal synaptic plasticity. Neuro2013, Kyoto, Japan. 20-23 June 2013
- Nakano, T., Otsuka, M., Yoshimoto, J. and Doya, K. (2012) A spiking neural network model of memory-based reinforcement learning. Neuroinfomatics 2012, Munich, Germany. 10-12 Sep 2012
- Ponzi, A. and Wickens, J.R. 2012. Optimality in the striatal medium spiny enuron network. In Society for Neuroscience 2012, New Orleans, U.S.A.
- Ponzi, A. and Wickens, J.R. 2012. Optimal balance of the striatal medium spiny neuron network. In The 35th Annual Meeting of the Japan Neuroscience Soceity, Neuroscience 2012, Nagoya City, Japan.
- Ponzi, A. and Wickens, J.R. 2012. Signal and noise in a model of the striatal medium spiny neuron network. In 8th FENS, Forum of Neuroscience, Barcelona, Spain.
- Ponzi, A. and Wickens, 2012. J. Optimal dynamical characteristics of the striatal medium spiny neuron network, Dynamics of memory: What's the evidence? Barcelona, Spain (July 2012)
- Ochi-Shindou, M., Shindou, T., and Wickens, J.R. 2012. State-dependent expression of spike-timing dependent plasticity in D2 receptor-positive spiny neurons in the neostriatum of adult mice. In 8th FENS, Forum of Neuroscience, Barcelona, Spain.
- Fuller, J., Hyland, B.I., and Wickens, J.R. 2012. Evidence that D2 autoreceptor inhibition modulates the action of methylphenidate. In The International Basal Ganglia Society 2013 (IBAGS), Eilat, Israel. [Winner of Student Poster Prize]
- Mayumi Ochi-Shindou, Tomomi Shindou, and Jeffery R Wickens. State-dependent expression of spike-timing dependent plasticity in D2 receptor-positive spiny neurons in the neostriatum of adult mice. In 8th FENS, Forum of Neuroscience, Barcelona, Spain.
- Shindou, T., Ochi-Shindou, M., Wickens, J.R. 2012 Dendritic spine calcium signals associated with spike-timing-dependent synaptic plasticity in the striatum. In 8th FENS, Forum of Neuroscience, Barcelona, Spain.
- Wickens, J.R., Li, Y-T, Huang, Y-L, Chen, J-J, and Hyland, B.I. Methylphenidate-mediated rescue of deficient dopamine reward prediction in an ADHD model. Shionogi & Co., Osaka, 26 April, 2012
5. Intellectual Property Rights and Other Specific Achievements
Nothing to report
6. Meetings and Events
- Date: January 31, 2013
- Venue: OIST, Campus Lab-1
- Speaker: Mr. Sho Aoki, Department of Life Sciences, Graduate School of Arts and Sciences, the University of Tokyo
- Title: Role of lateral cerebellum in control of limb movements during visually guided locomotion in the rat.
- Date: February 13, 2013
- Venue: OIST, Campus Lab-1
- Speaker: Mr. Stafano Zucca, Graduate Student, Interdisciplinary Institute for Neuroscience, University of Bordeaux
- Title: Analysis of synaptic plasticity in CA3 pyramidal cells in vivo using optogenetics tools.