PROJECTS
Genetic basis of behavior:
​Identifying causal loci for deep sleep defects in hyper-aggression
High resolution detection of chemicals inside the brain
Baseline
Treatment 1
Treatment 2
Sleep defects
Altered genetic pathways
Hyper-aggression
How do genes regulate behavior? Individual phenotypes rarely manifest by themselves, and are often tied to other behavior axes. Deep sleep is heavily disrupted in selected lines of hyper aggressive flies - the Bullies. With genomes that have drastically less variability compared to wild-type flies, these Bully lines are ideal for genetic sleuthing. An identified list of altered genetic loci in them forwards a unique opportunity to understand how genetic variation leads to sleep differences.
An understanding of how genes regulate behavior bridges molecular genetics, neurobiology, and ethology. It enables us to ask how specific genes and their interactions shape neural circuits, modulate neurotransmitter systems, and influence behavioral outcomes across development and environments. It also provides a foundation for investigating behavioral flexibility and susceptibility to its dysfunction.
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One of the manifestations of behavior dysfunctions in Drosophila occurs in the form of hyper-aggression. A series of highly structured patterns of actions gets altered and leads to hyper-aggression. Here, flies start showing aggression early in their life and don't form dominance relationships, which comes at a cost of mating success. I have previously shown that hyper-aggression has a strong genetic basis and aspects of it is regulated by single genes. Not surprisingly, Deep-sleep in these Bully flies is severely affected.
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I have shown that roughly 100 differentially expressed genes and about 50 gene mutations are associated with hyper-aggression and deep sleep defects. The mutated genes can be traced to a tight network of biological functions that comprise of three important transcriptional factors, among others. Future work will be directed at systematic down or up regulation of these genes, and screening of mutants to identify primary genetic loci that cause deep sleep defects in behavioral abnormalities like hyper-aggression.
Neurophysiological basis of behavior:
Identifying Molecular and neural correlates of deep sleep
Fruit fly brain
High resolution detection of chemicals inside the brain
Important neural circuit that regulate deep sleep consolidation
Baseline
Treatment 1
Treatment 2
Complex neural networks and neurophysiological processes govern sleep. All the 139,255 neurons in the fly brain has been mapped, giving us unique access to ask how the brain orchestrates such regulation. New unbiased techniques in metabolite detection are going to uncover what chemicals are flooding the brain during sleep and wakefulness. Drosophila give us the ability to put the puzzle pieces of neurons and neurochemicals together and elucidate mechanisms of sleep control.
Deep sleep plays a critical role in brain function, memory consolidation, emotional regulation, and physical health. It is during this stage that the brain undergoes synaptic pruning, cellular repair, and detoxification processes essential for cognitive performance and well-being. Disruptions in deep sleep are linked to neurodegenerative diseases and as mood disorders. An understanding of neural circuits, neurotransmitters, and molecular mechanisms is imperative to understand how sleep is regulated, and potential development of targeted treatments for sleep disorders and related health conditions, ultimately enhancing both brain and body health.
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I recently showed that sleep homeostasis, the important mechanism that keeps biological systems functioning properly, pays particular attention to long and consolidated bouts of deep sleep. This deep sleep state is necessary and sufficient to engage the sleep homeostatic machinery in flies after periods of sleeplessness. What are the molecular signatures of a sleep deprived brain? Using an unbiased metabolomics approach I am starting to identify potent metabolites that show elevated abundance after sleep loss. I am using high resolution mass spec methods like MALDI-TOF to identify molecules that track sleep pressure in the brain. My initial results suggest conserved neurotransmitters might have a role to play.
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I have also shown that a previously characterized sleep regulating center in the Drosophila brain, the Dorsal Fan-Shaped Body (dFB), is particularly attuned to deep sleep, and when ablated, keeps an animal from consolidating their deep sleep. Using connectomic analysis I am characterizing putative neural pathways that integrate sleep information and relays them to behavioral choice centers. Using the intersectional genetic tools available in the Drosophila model system, I will investigate the role of this and other neural axis in modulating behaviors under states of sleep deprivation.
Internal states and behavioral modulation:
Deep sleep deprivation and its effects on social behavior
Selective Sleep Deprivation
Behavioral decision making
Waking up on the wrong side of the bed is a feeling we are all too familiar with. Yet, exactly how different sleep states affect our mood and subsequent decision making is not well understood. Selective deprivation of different sleep states and assessment of how that alters decision making in flies might provide an inroad. Utilizing the genetic and circuit level understanding in sleep and aggression will provide necessary mechanical support in solving this challenging puzzle.
We live in constant states of sleep-deprivation and often find ourselves waking up on the wrong side of the bed. However, we are still trying to find out the exact behavioral axes along which sleeplessness manifests. The effects of sleep loss are so profound that the World Health Organization has declared it a “Global Epidemic of Sleeplessness”. The urgency for a better understanding of sleep and its effects on health and well-being is also more important than ever as the last pandemic doubled clinical insomnia cases, resulting in a significant increase in anxiety disorders and psychological distress in the population.
My work suggests losing deep sleep can cause drastic effects on behavior and physiology. Selectively depriving of such sleep states in Drosophila has remained a challenge. My novel experimental approach overcomes this obstacle through automated , real-time, and closed-loop behavioral designs that also controls for non-specific effects of sleep depriving stimuli. ​This approach will play a crucial role by generating paired flies with differential sleep pressure for behavior screening and identify changes that are cause by sleep loss, without confounding factor of handling or non-specific stress, greatly increasing my signal to noise ratio. Carried out over their lifetime, and under acute and chronic sleep deprivation, I will also explore how aging affects sleep-dependent behavioral decision making. ​​​​