Neural Circuitry and Behavior



Suresh obtained an undergraduate degree in Electrical Engineering from Stanford University, California, in 1990. His interest in biology was spurred by two summers at the Hopkins Marine Station, in Monterey. He then went to Oxford University as a Rhodes Scholar, where he obtained a D. Phil. in Zoology working in the laboratory of Julian Lewis. During this time, he spent two summers at the Marine Biological Laboratory in Woods Hole, learning microscopy and embryology. Suresh began experimenting in neuroscience during a four-year post-doctoral fellowship at the Max Planck Institute for Developmental Biology in Tuebingen, Germany, in the department of Friedrich Bonhoeffer. He joined A*Star in February 2009.


Neural circuitry and behavior

An animal’s survival depends on its ability to react appropriately to environmental stimuli. The responses can be innate, and can also be modified by experience. The goal of the lab is to gain insight into how neural circuits in the vertebrate brain generate an optimal response. To achieve this, we use the zebrafish and a combination of behavioral assays, high-speed brain imaging and manipulation.

The Alarm Response
A starting point for experiments is the alarm response. In the 1930’s Karl von Frisch noticed that injury to a European minnow caused a fright reaction in other members of the fish school. He demonstrated that the skin contained substances, termed Schreckstoff, which act via the olfactory system to trigger a state of fear. The fish change their swimming behavior dramatically - either darting or freezing - in response to this alarm pheromone. 

Subsequent experiments by other scientists established that many freshwater fish species have this response. All the classical hallmarks of fear, including physiological changes such as increase in blood cortisol levels, can be triggered by Schreckstoff.

We have used classical biochemical separation to characterize the alarm substance. We find that the substance is a mixture, and one component is a glycan, chondroitin sulfate. Calcium imaging of the olfactory bulb has enabled identification of regions that are activated following detection of the alarm substance. Current experiments are focused on characterization of the receptor neurons, as well as the higher brain regions involved in the response.

The approach that we are taking to identify the circuits mediating innate fear is to image the entire brain, at single cell resolution, in fish that express genetically encoded calcium indicators. Mathematical analysis is then carried to determine how the networks function.

The habenula
One node in information flow from the forebrain to midbrain is the habenula. This evolutionarily conserved structure is involved in the regulation of dopamine, serotonin, norepinephrine and histamine, and receives extensive input from the basal ganglia. The medial habenula has an important role in reward and addiction, while the lateral habenula is involved in learning, especially with regards to aversive stimuli.

The habenula provides an attractive model to investigate how microcircuits regulate behavior. We are able to image activity in all cells in the habenula, as a larval zebrafish is exposed to aversive or attractive stimuli. Additional, neural activity can be manipulated either optically (for example using KillerRed transgenic lines) or by expression of tetanus toxin. Using a larval fear conditioning assay, we have found that the medial habenula modulates fear responses. Current experiments are directed at understanding the basis of this.

Click here to view the Video of "The scent of danger: A 70-year-old puzzle solved " .


Department: Suresh JESUTHASAN

Name: Ruey Kuang CHENG

Designation: Research Fellow


Name: Joanne Shu Ming CHIA

Designation: Research Fellow



Recent Publications

Chia, J. S. M. et al. 
Bacteria evoke alarm behaviour in zebrafish. 
Nat Commun 10, 3831 (2019).

Jesuthasan, S. 
The thalamo-habenula projection revisited. 
Seminars in Cell & Developmental Biology 78, 116–119 (2018).

Mohamed, G. A. et al. 
Optical inhibition of larval zebrafish behaviour with anion channelrhodopsins. 
BMC Biology 15, 103 (2017).

Cheng, R.-K., Krishnan, S., Lin, Q., Kibat, C. & Jesuthasan, S. 
Characterization of a thalamic nucleus mediating habenula responses to changes in ambient illumination. 
BMC Biology 15, 104 (2017).

Lin, Q. & Jesuthasan, S. 
Masking of a circadian behavior in larval zebrafish involves the thalamo-habenula pathway. 
Sci Rep 7, 4104 (2017).

Lupton, C. et al. 
Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish.

eNeuro 4, ENEURO.0326–16.2017 (2017).

Kibat, C., Krishnan, S., Ramaswamy, M., Baker, B. J. & Jesuthasan, S. 
Imaging voltage in zebrafish as a route to characterizing a vertebrate functional connectome: promises and pitfalls of genetically encoded indicators. 
J. of Neurogenetics 30, 80–88 (2016).

Cheng, R.-K., Krishnan, S. & Jesuthasan, S. 
Activation and inhibition of tph2 serotonergic neurons operate in tandem to influence larval zebrafish preference for light over darkness. 
Sci Rep 6, 20788 (2016).

Krishnan, S. et al. 
The right dorsal habenula limits attraction to an odor in zebrafish. 
Curr Biol 24, 1167–1175 (2014).

Tan, S. J., Kee, M. Z. L., Mathuru, A. S., Burkholder, W. F. & Jesuthasan, S. J. 
A microfluidic device to sort cells based on dynamic response to a stimulus. 
PLos ONE 8, e78261 (2013).

Mathuru, A. S. & Jesuthasan, S. 
The medial habenula as a regulator of anxiety in adult zebrafish. 
Front Neural Circuits 7, 99 (2013).

Mathuru, A. S. et al. 
Chondroitin Fragments Are Odorants that Trigger Fear Behavior in Fish. 
Curr Biol 22, 538–544 (2012).

Lee, A. et al. 
The habenula prevents helpless behavior in larval zebrafish. 
Curr Biol 20, 2211–2216 (2010).

Hendricks, M. & Jesuthasan, S. PHR regulates growth cone pausing at intermediate targets through microtubule disassembly. 
J Neurosci 29, 6593–6598 (2009).



S. Jesuthasan (2012)
Fear, anxiety and control in the zebrafish.
Dev. Neuro, 72, 395 - 403.

R. Cheng, S. Jesuthasan and T. Penney (2011)
Time for Zebrafish.
Frontiers in Integrative Neuroscience, 5, 40.

S. Jesuthasan and A. Mathuru (2008)
The alarm response in zebrafish: innate fear in a vertebrate genetic model.
J. Neurogenetics, 22, 1-18