Neurobiology Research Unit

Professor Jeff Wickens

 

Abstract

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. Tomomi Shindou, Staff Scientist
• Dr. Mayumi Ochi-Shindou, Staff Scientist
• Dr. Adam Ponzi, Staff Scientist
• Dr. Takashi Nakano, Staff Scientist
• Dr. Sho Aoki, Postdoctoral Scholar
• Dr. Stefano Zucca, Postdoctoral Scholar
• Mr. Andy Liu, Specialist
• Ms. Aya Zucca, Technical Staff
• Mr. Kavinda Liyanagama, Technical Staff
• Mr. Mayank Aggarwal, Graduate Student
• Ms. Sakurako Watanabe, Graduate Student
• Ms. Yukako Suzuki, Research Administrator

2. Collaborations

• Theme: Dopamine signaling and mechanism of pyschostimulant action
  • Type of collaboration: Joint research
  • Researchers:
    • Professor Brian Hyland, University of Otago, New Zealand

• Theme: Neuroplasticity studies using dopamine sensing 
  • Type of collaboration: Research Collaboration
  • Researchers:
    • 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 
  • 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

• Theme: Drug Delivery using Femtosecond Pulses
  • Type of collaboration: Research Collaboration
  • Researchers:
    • Prof. Keshav Dani, Okinawa Institute of Science and Technology, Japan

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 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
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 are currently studying 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.

3.4 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.

3.5 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 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.

4. Publications

4.1 Journals 

Aoki, S., et al. (2013). "Lesion in the lateral cerebellum specifically produces overshooting of the toe trajectory in leading forelimb during obstacle avoidance in the rat." J Neurophysiol 110(7): 1511-1524.

Aquili, L., et al. (2014). "Behavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus accumbens shell during specific time segments." Learn Mem 21(4): 223-231.

Furukawa, E., et al. (2014). "Abnormal striatal BOLD responses to reward anticipation and reward delivery in ADHD." PLoS One 9(2): e89129.

Li, Y. T., et al. (2013). "Integrated wireless fast-scan cyclic voltammetry recording and electrical stimulation for reward-predictive learning in awake, freely moving rats." J Neural Eng 10(4): 046007.

Nakano, T., et al. (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." Front Comput Neurosci 7: 119.

Ponzi, A. and J. R. Wickens (2013). "Optimal balance of the striatal medium spiny neuron network." PLoS Comput Biol 9(4): e1002954.

Ponzi, A. and J. R. Wickens (2013). "The inhibitory network of the striatum at the edge of chaos." BMC Neurosci.  Abstracts from the Twenty Second Annual Computational Neuroscience Meeting: CNS*2013

Ponzi, A. and J. R. Wickens (2013). Input dependent variability in a model of the striatal medium spiny neuron network, Springer Science.

4.2 Books and Other One-Time Publications

Nothing to report

4.3 Oral and Poster Presentations 

Aoki, S., et al. (2013). Effect of pharmacological inactivation of the intermediate cerebellum on overground locomotion in the rat. Japanese Society of Physical Fitness and Sports Medicine. Tokyo, JAPAN.

Aquili, L., et al. (2013). Behavioral flexibility is increased by optogenetic inhibition of nucleus accumbens neurons during specific timeframes. International Symposium - Optogenetics 2013. Keio University, Tokyo, JAPAN.

Nakano, T. and J. R. Wickens (2013). Role of dopamine in corticostriatal synaptic plasticity. Neuro2013. Kyoto, Japan.

Ochi-Shindou, M., et al. (2013). Effects of caged-dopamine photolysis on spike-timing dependent long-term depression in mice striatal neurons. Society For Neuroscience 2013. San Diego, USA.

Ponzi, A. and J. R. Wickens (2013). The inhibitory network of the striatum at the edge of chaos. The Twenty Second Annual Computational Neuroscience Meeting: CNS*2013, Paris, FRANCE. 13-18 July 2013 Paris, France

Ponzi, A. and J. R. Wickens (2013). Optimal balance of the striatal medium spiny neuron network. Neuro2013, Kyoto City, JAPAN.

Ponzi, A. and J. R. Wickens (2013). Order and chaos in the inhibitory network of the striatum. Society For Neuroscience 2013. San Diego, USA.

Ponzi, A. and J. R. Wickens (2013). Order and chaos in the striatal medium spiny neuron network. The Sixth International Neural Microcircuit Conference - Functional Mechanism of Cortical Microcircuit. Okazaki City, Aichi Pref. JAPAN.

Ponzi, A. and J. R. Wickens (2013). The striatum between order and chaos. International Symposium on Prediction and Decision Making 2013  新学術領域研究「予測と意志決定」の研究グループ主催のシンポジウム. Shiran Kaikan, Kyoto University, JAPAN.

Shindou, T., et al. (2013). Electrophysiological properties of ASE neurons of C. elegans. Society For Neuroscience 2013. San Diego, USA.

Wickens, J. R. (2013). Cellular actions of dopamine in the corticostriatal system. Third Symposium on Biology of Decision-Making. Paris, FRANCE.

Wickens, J. R. (2013). Dopaminergic mechanisms in the pathophysiology of attention-deficit hyperactivity disorder. Neurosciences and Mental Health Symposium - "Recent Advances in Neuroscience: Plasticity, Imaging, Regeneration and Addiction". University of Sydney, Sydney, AUSTRALIA.

Wickens, J. R. (2014). A synaptic eligibility trace in the striatum. Gordon Research Conferences - Basal Ganglia Cells and Circuits in Health and Disease. Ventura, CA, USA.

Wickens, J. R. (2014). Use of optical tools in the study of memory & learning mechanisms in the brain. Joint ISSP-OIST Symposium: Lighting Up New Frontiers - From Tokyo to Okinawa, From Materials to Neurons. Okinawa Institute of Science and Technology.

Wickens, J. R., et al. (2013). Methylphenidate specifically rescues deficient anticipatory dopamine release. DOPAMINE 2013. Alghero, ITALY.

 

5. Intellectual Property Rights and Other Specific Achievements

Nothing to report

6. Meetings and Events​

6.1 Seminar

Title: Pharmaceutical R&D for novel anti-Parkinson's disease therapy - Adenosine  A_2A receptor antagonist - 

• Date: June 28, 2014
• Venue: OIST campus seminar room
• Speakers: Akihisa Mori, Ph.D.
• Deputy Director, Strategic Product Portfolio Dpartment, Kyowa Hakko Kirin Co., Ltd. Tokyo, Japan

7. Others

Nothing to report