Neurobiology Research Unit (Jeff Wickens)

FY2017 Annual Report

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 show a role for cholinergic interneurons of the striatum in flexible 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. Sho Aoki, Postdoctoral Scholar (Funded by JSPS)
Dr Andres Carrasco, Staff Scientist
Dr. Atsushi Tamura, Postdoctoral Scholar
Dr Julie Chouinard, Postdoctoral Scholar
Nobuyoshi Kitamura, Engineer
Kiyoto Kurima, Technical Staff
Yumiko Akamine, Technical Staff
Kavinda Liyanagama, Technical Staff
Mayank Aggarwal, PhD Student(JSPS scholarship recipient)
Sakurako Watanabe, PhD Student (JSPS scholarship recipient)
Stefan Pommer, PhD Student
Masakazu Igarashi, PhD Student (JSPS scholarship recipient)
Yoriko Yamamura, PhD Student (JSPS scholarship recipient)
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 Researcher Dr Sho Aoki

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 initiated.

3.4 Modulation of lateral inhibition in the striatal network by serotonin
OIST Researcher: 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. Our ongoing work involves developing tools for experimental manipulation of lateral inhibitory interactions. This work is currently in progress, and has already shown modulation of lateral inhibition by 5HT1B receptors.

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

4. Publications

4.1 Journals

Zucca, S, Zucca, A, Nakano, T, Aoki, S and Wickens , J.R. (2018) Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo. eLife7:e32510, 1-20.

Aoki, S., Liu, A. W., Akamine, Y. , Zucca, A. , Zucca, S. and Wickens, J. R. (2018), Cholinergic interneurons in the rat striatum modulate substitution of habits. Eur J Neurosci, 47: 1194-1205. doi:10.1111/ejn.13820

Ponzi, A. (2017) Sensory stream adaptation in chaotic networks, Scientific Reports. 7: 16844 | DOI:10.1038/s41598-017-16478-z

Aoki S, Liu AW, Zucca A, Zucca S, Wickens JR. (2017) New variations in strategy set-shifting in the rat. Journal of Visualized Experiments (119) e55005, 2017

Nakano, T., Mackay, S.M., Wui, T-E., Dani, K.M., Wickens, J.R. (2016) "Interfacing with Neural Activity via Femtosecond Laser Stimulation of Drug-Encapsulating Liposomal Nanostructures." eNeuro: Volume 3, Issue 6.

4.2 Books and other one-time publications

Aoki, S., Liu, A.W., Zucca, A., Zucca, S., Wickens, J.R. Striatal acetylcholine enables behavioral flexibility. Neurotransmitter 2016; 3: e1086. doi: 10.14800/nt.1086.

4.3 Oral Presentations

Watanabe, Sakurako., Wickens, Jeffery R.(2018). Effects of multiple cortical inputs on the striatal spike timing-dependent plasticity. Gordon Research Seminar Basal Ganglia. Ventura, CA, USA. (2018.03.11)

Wickens, Jeffery R. (2017). Neural mechanisms for reinforcement learning. The International Symposium of Adaptive Circuit Shift 2017. Hitotsubashi Hall, National Center of Sciences. Tokyo, Japan. (2017.12.18)

Aoki, Sho. (2017). How does the striatum access motor cortices. 1st Behavioral Science Cafe 2017. University of Tokyo, Komaba Campus. (2017.12.02)

Aoki, Sho. (2017). A striatal cholinergic mechanism for behavioral flexibility. 1st Behavioral Science Cafe 2017. University of Tokyo, Komaba Campus. (2017.12.02)

Wickens, Jeffery R. (2017). Dopamine, reinforcement, and methylphenidate in attention-deficit hyperactivity disorder: insights from animal neurobiology. Future Medicine 2017. Konkuk University School of Medicine, South Korea. (2017.11.15)

Aoki, Sho. (2017). Anatomical evidence that multiple striatal regions influence motor cortex in the rat. Salk Institute for Biological Studies, Molecular Neurobiology Laboratory. CA, USA. (2017.09.20)

Aoki, Sho. (2017). A striatal cholinergic mechanism for behavioral flexibility. Salk Institute for Biological Studies, Molecular Neurobiology Laboratory. CA, USA. (2017.09.20)

Aoki, Sho. (2017). A striatal cholinergic mechanism for behavioral flexibility. The Scripps Research Institute, Department of Neuroscience. CA, USA. (2017.09.18)

Aoki, Sho. (2017). A striatal cholinergic mechanism for behavioral flexibility. Yale University, School of Medicine, Department of Psychiatry. CT, USA. (2017.09.06)

Wickens, Jeffery R. (2017). Neural mechanisms for reinforcement learning. Developmental Neurobiology Course (DNC). OIST, Seaside House, Onnason, Okinawa. (2017.08.01)

4.4 Poster Presentations

Wickens, Jeffery R., Fuller, Justine A., Burrell, M H., Yee, A., Lipski, J., Hyland, Brian I.(2018). How negative feedback shapes methylphenidate effects on phasic dopamine signalling in the striatum. Gordon Research Conference Basal Ganglia. Ventura, CA, USA. (2018.03.15)

Watanabe, Sakurako., Wickens, Jeffery R.(2018). Effects of multiple cortical inputs on the striatal spike timing-dependent plasticity. Gordon Research Conference Basal Ganglia. Ventura, CA, USA. (2018.03.15)

Aoki, Sho., Igarashi, Masakazu., Coulon, Patrice., Wickens, Jeffery R., Ruigrok, Tom J.H. (2017). Anatomical evidence that multiple striatal regions influence motor cortex in the rat. Procedural Learning Summer School. Amsterdam, The Netherlands. (2017.06.28)

5. Intellectual Property Rights and Other Specific Achievements

Patent filed

6. Meetings and Events

6.1 OIST International Undergraduate Student Collaborative Workshop

Theme: Quantitative Analysis of Behavior & Neurobiology
Date: 22nd July – 7th August 7 2016 Organizers: J. Wickens, D. Van Vacter (Harvard Univ), Mahesh Bandi (OIST).
Visiting/Collaborating Faculty Instructors
Takashi Suzuki, Ph.D. (Professor, Tokyo Institute of Technology)
Karl Johnson, Ph.D. (Professor and Chairman, Department of Neuroscience, Pomona

7. Other

Nothing to report.