Mechanisms underlying behavior and neurogenetic models of human brain disorders

Summary Graphic 

Lab direction descriptive schematics (5)

An outline of our approach for studying the role of specific genes associated with neural disorders, but that do not yet have appropriate animal models. This approach was applied to the study of the function of c2orf69 5, and CCSER1 10,11 genes. Manuscripts on nicotinic acetylcholine receptor subunits (Chrna3, Chrna5, Chrnb4), and oxytocin receptor (Oxtr) implicated in multiple disorders are in preparation or in peer review.

Neurogenetic models of human brain disorders

Our lab studies neural mechanisms underlying natural behavior motivated by rewards and risks. Our research focuses on applying the insights gained from such studies to model phenotypes associated with human brain disorders which include substance dependence, depression,  anxiety disorders, neurodegeneration, and dementia. Towards this end, a substantial portion of the work in our lab in the past few years has revolved around developing the appropriate methodology to perform quantitative behavioral studies and analyses using the zebrafish in the laboratory. This research has been particularly valuable in highlighting the benefit of taking individual variability into account when designing experiments to study the normal repertoire of behavior 1–3. This has also improved the power of behavioral studies to examine processes in a malfunctioning brain 4. With collaborating labs in Singapore, we applied the knowledge generated in my lab to model disorders and address a range of questions of biomedical interest 5–9. The next phase of my lab’s efforts is focused on clinical applications such as studying the neurogenetics of addiction and anxiety disorders (summary figure). The foundational steps demonstrating this future research trajectory are available in the form of a publication and preprints 10–12

  1. Mathuru, A. S. Conspecific injury raises an alarm in medaka. Sci. Rep. 6, 36615 (2016).
  2. Haghani, S., Karia, M., Cheng, R.-K. & Mathuru, A. S. An Automated Assay System to Study Novel Tank Induced Anxiety. Front. Behav. Neurosci. 13, 180 (2019).
  3. Stamps, M. T., Go, S. & Mathuru, A. S. Computational geometric tools for quantitative comparison of locomotory behavior. Scientific Reports vol. 9 (2019).
  4. Jesuthasan, S., Krishnan, S., Cheng, R.-K. & Mathuru, A. Neural correlates of state transitions elicited by a chemosensory danger cue. Prog. Neuropsychopharmacol. Biol. Psychiatry 110110 (2020).
  5. Wong, H. H. et al. Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen storage-associated mitochondriopathy. Am. J. Hum. Genet. (2021) doi:10.1016/j.ajhg.2021.05.003.
  6. Hengel, H. et al. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat. Commun. 11, 595 (2020).
  7. Lim, C. H. et al. Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration. Elife 9, (2020).
  8. Koh, A. et al. A Neurexin2aa deficiency results in axon pathfinding defects and increased anxiety in zebrafish. Hum. Mol. Genet. 29, 3765–3780 (2021).
  9. Tay, S. H. et al. A novel zebrafish model for intermediate type spinal muscular atrophy demonstrates importance of Smn for maintenance of mature motor neurons. Hum. Mol. Genet. (2021)
  10. AshaRani, P. V. et al. Whole-Exome Sequencing to Identify Potential Genetic Risk in Substance Use Disorders: A Pilot Feasibility Study. J. Clin. Med. 10, (2021).
  11. Nathan, F. M. et al. Contingent-behavior assay to study the neurogenetics of addiction shows zebrafish preference for alcohol is biphasic. bioRxiv
  12. Mathuru, A. S. et al. Familiarity with companions aids recovery from fear in zebrafish. 

Circuits underlying reward and substance dependence

Rewarding and aversive experiences, or the anticipation of either are tightly coupled to motivation. Gaining a circuit level understanding of brain structures that modulate reward perception has become a topic of increasing interest as the same circuits are expected to operate in more complex cognitive functions linked to attention deficit and depression in humans (Underwood, 2013). However, our knowledge of neural circuits and the molecular processes that animals use to evaluate the quality of an experience are still limited.

The habenula complex, which receives inputs from several forebrain regions and sends output to key midbrain reward centres (Figure 1) is considered an important node where such decisions are influenced (Prolux et al., 2014). Interest in this region has exploded as recent animal studies have implicated it in reward processing, addiction to drugs of abuse, anxiety and depression-like behaviour (Hikosaka, 2010; Fowler et al. 2011; Lee et al., 2010; Lammel et al., 2012), with similar functionality predicted in humans (Lawson et al., 2014).

 The medial habenula in mammals (known as the dorsal habenula in zebrafish) has also been implicated in development of drug dependence. In particular, these epithalamic nuclei and their downstream neural target the interpeduncular nucleus of gudden have been implicated in several aspects of nicotine addiction including withdrawal effects. They also express specific subtypes of nicotinic acetylcholine receptors that have been flagged by human genetic studies as genes whose  variants are associated with nicotine dependence. We are interested in using the nicotine in zebrafish as a window to understand reward processing by habenula in general and development of nicotine dependence in particular. 

We are exploring this issue from many different angles – a) creating behavioral assays to mimic different aspects of human nicotine dependence, b) using the zebrafish system to evaluate smoking deterrence, c) functional (behavioral and physiological) analysis of genes implicated in addiction by human studies to gain a mechanistic insight, etc.

Alarm Responses

Plants and animals use a multitude of ways to detect danger in the environment to avoid harm and predation. In many organisms, special alarm calls or chemical cues signal the presence of such dangers. In the late 1930s the Nobel prize winning ethologist Karl von Frisch reported a phenomenon of alarm behavior in European minnows when a member of their shoal is injured. He coined the term “Schreckstoff” or scary substance to describe the cues that are released and elicit fear in others.

Zebrafish also produce and respond to Schreckstoff released passively from injured conspecifics. The robustness of the phenomenon allows for detailed analysis of the semiochemicals and the organization of neural processes that mediate fear in a vertebrate.

  • AS Mathuru, Conspecific injury raises an alarm in medaka. Scientific Reports 6, Article number: 36615, 2017 DOI:doi:10.1038/srep36615
  • AS Mathuru et. al., Chondroitin Fragments Are Odorants that trigger fear behavior in fish. Current Biology, 2012 DOI:
  • AS Mathuru and S Jesuthasan, Alarm Response in Zebrafish: Innate Fear in a Vertebrate Genetic Model. Journal of Neurogenetics, 2008 DOI: 10.1080/01677060802298475

Comparative studies of neural architecture that mediate species typical expression of fear.

We are interested in understanding how behavior emerges from the action or the organization of circuits. An alternate approach we are interested in using is to compare the neuronal organization and behavior of distant species. Medaka and zebrafish are distantly related freshwater fish species. The two fish have very different evolutionary and life histories as they are separated by approximately 100 million years, making them ideal candidates for comparative analysis of behavior and circuitry.

The objective will be to identify heterogeneity and similarities in the expression of the behavior between the two species. Causes for species-specific differences can then be explored at the level of molecules, genes, anatomy and physiology by extending the study to other species.

  • AS Mathuru, Conspecific injury raises an alarm in medaka. Scientific Reports 6, Article number: 36615, 2017 DOI:doi:10.1038/srep36615

Social Cognition and Behavior

Exported Image_2015-12-16 06-58-59.png
Rendering of a small shoal in a lab aquarium

Zebrafish are freshwater fish that live in small shoals in the wild.

We have found that social partners are highly effective in alleviating fear in fish. We are now  interested in understanding the neural mechanisms underlying this social buffering in fish. More broadly we are also interesting in understanding social cognitive abilities of zebrafish, the brain regions involved, and the molecular players participating in these behaviors.

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