FY2015 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.

1. Staff

  • Dr. Adam Ponzi, Staff Scientist
  • Dr. Takashi Nakano, Staff Scientist
  • Dr. Sho Aoki, Postdoctoral Scholar
  • Dr. Stefano Zucca, Postdoctoral Scholar
  • Andew Liu, Specialist
  • Aya Zucca, Technical Staff
  • Kavinda Liyanagama, Technical Staff
  • Mayank Aggarwal, PhD Student
  • Sakurako Watanabe, PhD Student
  • Stefan Pommer, PhD Student
  • Masakazu Igarashi, PhD Student
  • Yoriko Yamamura, PhD Student
  • Yukako Suzuki, Research Unit Administrator

2. Collaborations

  • Drug Delivery using Femtosecond Pulses
    • Type of collaboration: Research Collaboration
    • Researchers:
      • Prof. Keshav Dani, Okinawa Institute of Science and Technology, Japan
      • Prof. Eng Tan, Department of Chemistry, University of Otago, New Zealand
  • Dopamine signaling and mechanism of pyschostimulant action
    • Type of collaboration: Joint research
    • Researchers:
      • Professor Brian Hyland, University of Otago, New Zealand
  • Functional imaging of altered reward sensitivity and its relation to human behavior
    • Type of collaboration: Research Collaboration 
    • Researchers:
      • 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

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: PhD Student Sakuraku Watanabe

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.

Our current projects examine the importance of timing of afferent synaptic activity on synaptic plasticity.

3.2 Role of cholinergic interneurons in the striatum
OIST Researchers Dr Sho Aoki, Ms. Aya Zucca and Mr. Andrew Liu

Striatal cholinergic interneurons play an important but incompletely understood role in movement and learning functions of the striatal network. Striatal cholinergic interneurons fire tonically in different activity patterns: regular, irregular and bursts. Behavioral studies show that salient cues and rewards, important in reinforcement learning, cause a pause in firing of presumed cholinergic interneurons. Often these pauses are associated with a following burst. Using an optogenetic approach we are studying how the burst depends on the trajectory of the membrane potential during the pause. We have successfully expressed halorhodopsin selectively in cholinergic interneurons to reliably pause the cholinergic neurons with light. By changing the shape of the LED power command, we were able to, on average, significantly decrease the rebound firing but not in every trial. If we are able to prevent extra spikes after the pause, we hope to separately identify the role of the pause from the burst at the postsynaptic cell level or in certain behaviors. We have also undertaken behavioural studies that aim to elucidate the role of cholinergic interneurons using rats with immunotoxin-induced specific lesions of the cholinergic interneurons in different striatal regions.

3.3 The nature and timing of the dopamine signal in the striatum during learning
OIST Researchers: Mr Kavinda Liyanagama; PhD Student Mayank Aggarwal, Yoriko Yamamura; Collaboration with Professor Brian Hyland, University of Otago, New Zealand

Using fast-scan cyclic voltammetry we are investigating dopamine signaling in awake rats during learning of simple stimulus-reward associations. We have completed studies of how the dopamine signal is modified by drugs that change dopamine reuptake by the dopamine transporter, or regulation of dopamine release by dopamine D2 receptors. Studies of the role and mechanisms of phasic dopamine release during behavior have been initated.

3.4 Role of lateral inhibition in the striatal network
OIST Researcher: Dr Adam Ponzi; PhD Student Stefan Pommer

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 involves developing tools for experimental manipulation of lateral inhibitory interactions.

3.5 Drug Delivery Using Femtosecond Pulses
OIST collaborator: Professor Keshav Dani   OIST Researcher: Dr Takashi Nakano

In collaboration with the Dani Unit at OIST we have been developing a novel technique for controlling biocompatible drug delivery systems using femtosecond pulses. The high power of femtosecond pulses allows for specific control of biomaterials by using their nonlinear optical properties. This nanoparticle based drug delivery system provides a way to translate our basic science insights concerning dopamine modulation of plasticity into new treatment approaches.  This work has so far led to a patent application and a publication.

3.6 Reward prediction in attention deficit hyperactivity disorder (ADHD)
OIST Researcher: Mr Kavinda Liyanagama; OIST collaborator: Professor Gail Tripp (Human Developmental Neurobiology Unit) 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. 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. We completed design work and extensive pilot testing for a second fMRI study to evaluate the effects of methylphenidate on reward sensitivity in adults with ADHD.

3.7 Neural mechanisms of motor control
OIST researcher: PhD Student Masakazu Igarashi

We have initiated studies to investigate the neural basis for bimanual coordination in rodents, using movement analysis combined with electrophysiological recording.

4. Publications

4.1 Journals

Aoki, S., Liu, A.W., Zucca, A., Zucca, S., Wickens, J.R. (2015). "Role of striatal cholinergic interneurons in set-shifting in the rat." J Neurosci 35(25): 9424-9431.

Nakano, T., Otsuka, M., Yoshimoto, J., Doya, K. (2015). "A spiking neural network model of model-free reinforcement learning with high-dimensional sensory input and perceptual ambiguity." PLoS One 10(3): e0115620.

Nagai, T., Nakamuta, S., Kuroda, K., Nakauchi, S., Nishioka, T., Takano, T., Zhang, X-J., Tsuboi, D., Funahashi, Y., Nakano, T., Yoshimoto, J., Kobayashi, K., Uchigashima, M., Watanabe, M., Miura, M., Nishi, Al, Kobayashi, K., Yamada, K., Amano, M., Kibuchi, K. (2016). "Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo." Neuron 89(3): 550-565.

Perk, C. G., Wickens, J., Hyland, B.J. (2015). "Differing properties of putative fast-spiking interneurons in the striatum of two rat strains." Neuroscience 294: 215-226.

4.2 Books and other one-time publications

Plenz, D. and J. R. Wickens (2015). Handbook of Basal Ganglia Structure and Function, a Decade of Progress. Amsterdam [In Press], Elsevier/Academic Press.

4.3 Oral Presentations

Nakano, T., Dani, K.M., Wickens, J.R. (2015). Manipulation of neural function using laser-stimulated liposome. Medical Optics & Spectroscopy 2015. Tokyo, Japan.

Nakano, T. (2015). A new way to manipulate the brain. OIST, Okinawa, Japan.

Ponzi, A., Wickens, J.R. (2015). Expectation in Recurrent Networks. Neuroscience 2015 The 38th Annual Meeting of the Japan Neuroscience Society, Kobe Convention Center, Kobe City, Japan.

Ponzi, A., Wickens, J.R. (2015). How chaotic dynamics works in the striatum and for temporal expectation. Howard Hughes Medical Institute. Host : Nelson Spruston. Janelia Research Campus, Ashburn, VA, USA.

Ponzi, A., Wickens, J.R. (2015). How chaotic dynamics works in the striatum and for temporal expectation. University of College London, United Kingdom.  Host Karl Friston.

Wickens, J.R. (2015). Reinforcement learning at the synaptic level. Neuroscience Symposium, OIST-RIKEN. C32 Ohkouchi Hall, RIKEN Wako City.

Wickens, J.R. (2015). Neural mechanisms for reinforcement learning in the striatum. Osaka University.

Wickens, J.R. (2015). Neural mechanisms for reinforcement learning in the striatum. University of Fukui.

Wickens, J.R. (2016). Bending Brain with Wickens Unit. OIST SCIENCE CHALLENGE 2016. OIST, C210.

4.4 Poster Presentations

Aoki, S., Liu, A.W., Zucca, A., Zucca, S., Wickens, J.R. (2015). Role of striatal cholinergic interneurons in set-shifting in the rat. IBNS 2015 International Behavioral Neuroscience Society. Victoria Conference Centre. Victoria, British Columbia, Canada. Posster Session 2.

Aoki, S., Igarashi, M., Wickens, J.R., Coulon, P., Ruigrok, T. (2015). Ventral striatum as a limbic-motor interface: A new anatomical finding. Japanese Society of Physical Fitness and Sports Medicine. Wakayama City, Wakayama, Japan.

Aoki, S., Liu, A.W., Igarashi, M., Zucca, A., Zucca, S., Wickens, J.R. (2016). A new set-shifting task suited for a within-subject comparison in the rat. Gordon Research Conference, Basal Ganglia. Four Points Sheraton, Ventura, CA.

Nakano, T., Tan, E., Dani, K.M., Wickens, J.R. (2015). Rapid drug delivery using femtosecond laser stimulated liposomes to interface with neural activity. IBRO 2015 International Brain Research Organization. Rio de Janeiro, Brazil. 1147.

Nakano, T., Wickens, J.R., Yoshimoto, J. (2015). Intracellular mechanisms of dopamine modulation of the medium spiny neurons in the striatum through KCNQ channels. Neuroscience 2015. The 38th Annual Meeting of the Japan Neuroscience Society. Kobe Convention Center, Kobe City, Japan: 2P065.

Nakano, T., Dani, K.M., Wickens, J.R. (2015). Manipulation of neural function using laser-stimulated liposome. Medical Optics & Spectroscopy 2015. Tokyo, Japan.

Ponzi, A., Wickens, J.R. (2015). How recurrent networks respond to complex stimulus sequences. SfN 2015 Society for Neuroscience USA. Chicago, USA. Topic: Computation, Modeling, and Simulation: 95.09/BB84.

Ponzi, A., Wickens, J.R. (2015). Recurrent Networks Expect. OCNS 2015 Organization for Computational Neuroscience. Prague, Czech Republic.

Sieveritz, B., et al. (2015). Effects of unconscious priming with brand logos in a real life context based on the underlying motivation of participants. IBRO 2015 International Brain Research Organization. Rio de Janeiro, Brazil. 70: Poster Session I - Cognition and Behavior.

Watanabe, S., Wickens, J.R. (2015). Effects of synaptically activated spikes on plasticity of the mouse cotricostriatal synapse. BNA 2015 Festival of Neuroscience. Edinburgh, UK.: Poster Ref: P1-B-015.

Yamamura, Y., Zucca, A., Wickens, J.R. (2015). Modeling the intrinsic mechanism of irregular firing in striatal cholinergic interneurons. IBRO 2015 International Brain Research Organization. Rio de Janeiro, Brazil, Poster Session II - Excitability, Synaptic Transmission, Network Function. 764.

5. Intellectual Property Rights and Other Specific Achievements

Patent filed

6. Meetings and Events

6.1 OIST Minisymposium: Cholinergic Mechanisms in Adaptive Behaviour

Date: 14-15th April, 2016
Organizers: Jeff Wickens, Aya Zucca, and Stefano Zucca

James Surmeier (Northwestern University, USA)
Andrew Sharott (University of Oxford, UK)
Stephanie Cragg (University of Oxford, UK)
Margaret Rice (New York University, USA)
David Lovinger (NIH-NIAAA, USA)
Bernard Balleine (University of Sydney, Australia)
Angela Langdon (Princeton, USA)
Kazuto Kobayashi (Fukushima Medical University, Japan)
Yasushi Kobayashi (Osaka University, Japan)
Anastasia Christakou (University of Reading, UK)
Genela Morris (University of Haifa, Israel)

6.2 OIST International Undergraduate Student Collaborative Workshop

 Decoding the Brain.
Date: 31st July – 7th August 7 2015
Organizers: J. Wickens, D. Van Vacter (Harvard Univ), T. Hensch (RIKEN BSI)
Participants: (Neuroscience Symposium OIST-RIKEN BSI)

Thomas Clandinin (Stanford University)
Hitoshi Okamoto (RIKEN BSI)Florian Engert (Harvard University)
Jeff Wickens (OIST)
Yukiko Goda (RIKEN BSI)
Shigeo Okabe (The University of Tokyo)Bernd Kuhn (OIST)
Masanori Murayama (RIKEN BSI)
Takao Hensch(Harvard University)

6.3 OIST Seminar: Reward, reinforcement and the neural bases of decision-making.

Date: July 16, 2015
Venue: OIST Campus Lab3Speaker: Prof. Bernard Balleine, University of Sydney, Brain & Mind Research Institute, Australia.

7. Other

Nothing to report.