Welcome to the Ramaswami Lab

 

A major focus in Neuroscience is to decipher molecular cellular and circuit mechanisms that enable neural operations. We predominantly study: (1) how brains learn to recognize and ignore familiar patterns of stimulation; and (2) how local regulation of synaptic mRNA translation occurs and contributes to long-term learning of familiar stimuli.

Two recent insights, which we believe to be of fundamental importance, drive our research.

First, our work on olfactory habituation suggests a "negative-image model for habituation (Ramaswami in prep.)" that theoretically explains habituation in most neural systems and species. The model makes testable proposals for the underlying synaptic mechanisms as well as for how these are induced, gated and regulated by experience and behavioral states of an organism.

Second, we have proposed that altered neuronal mRNP-aggregation mechanisms cause defects in synaptic mechanisms of long-term memory, as well as, unexpectedly, various age-associated neurodegenerative conditions (Ramaswami et al., 2013, Sudhakaran, Hillebrand et al. submitted, McCann 2011). Our findings and those of our collaborators lead to well-developed molecular models for mRNP regulation, which are testable with assays we have developed to assess mRNPs in vivo, as well as their involvement in synaptic memory processes and neurodegenerative disease.

While focused on in vivo studies in Drosophila melanogaster, the scope of our work is extended by deep collaborations with many top Drosophila, neural-circuit, RNA and clinical-research laboratories in the world. Particularly long-standing interactions are with K. VijayRaghavan and K.S. Krishnan in the NCBS Bangalore, and Roy Parker in the HHMI and University of Colorado, Boulder.

There are rich opportunities for young scientists considering working in these areas.

 

Project 1. How do animals ignore familiar stimuli? The negative-image model for habituation.

Habituation is conceptually simple: an animal′s response to an experience reduces if the experience is repeated multiple times. It remains mysterious, in that its mechanisms remain unknown.

Based on studies of olfactory habituation in the fly (Pushkar 2012, Sudhakaran 2012, McCann 2011, Das 2011, Larkin 2010), we have proposed a general mechanism for habituation termed "the negative-image model (Ramaswami in prep.)" We suggest that, frequent or sustained unreinforced exposure to a stimulus creates a neural "negative image" that filters/ dampens the net neuronal response to familiar stimulus. We suggest that such negative images are created through synapse-specific potentiation of highly connected local-circuit interneurons that mediate recurrent (feedback) inhibition driven by a stimulus-evoked excitation.

In a few years, we hope to have determined whether this constitutes a general cellular and neural network mechanism for behavioral habituation. . In addition, we will have discovered how habituation is achieved in terms of molecular and synaptic mechanisms that drive changes in a beautifully accessible neural circuit that underlies olfactory behavior. Further, we expect to have learned, at the level of molecules and individual cells, how mechanisms of olfactory habituation are regulated by attentional, motivational and painful stimuli. Finally, through recently initiated collaborations, we will have new information on how and whether defects in habituation arise and contribute to autism and other forms of neuropsychiatric disease.

The experiments on synaptic signaling and circuit mechanisms of habituation are part of a closely coordinated project with the National Centre for Biological Sciences (NCBS) in Bangalore, initiated with the late Veronica Rodrigues and continued with K.VijayRaghavan. This work may be further advanced by a nascent collaboration with Aravi Samuel and Marta Zlatic′s groups (in Harvard and Janelia Farm).

 

Project 2. How is mRNA translation regulated in neurons? How do these mechanisms contribute to memory and neurodegenerative disease?

The regulation of mRNA is hugely important field in all fields of biology. In neurons, mRNA translation is controlled by miRNAs, RNA binding proteins, multiple associated factors and, importantly, by synaptic signaling. RNA regulation is required for functions ranging from long-term memory to neuronal development and survival. Key insights to which we have contributed significantly are: a) neuronal mRNAs are frequently packaged into mRNP aggregates (particles) from which they may be released for translation (Hillebrand 2010, Cziko 2009,Kwak 2008, Hillebrand 2007,Barbee 2006); b) these mRNP aggregates are functionally related to intracellular aggregates associated with neurodegenerative disease (McCann 2011, Ramaswami et al. 2013); and c) that the identical RNA regulatory mechanisms may participate in long-term memory formation, mRNP aggregate/ inclusion body formation and neurodegenerative disease (Sudhakaran, Hillebrand submitted).

We expect, over the next few years, to have provided new insight into the mechanisms that regulate synaptic mRNAs during memory formation in vivo, as well as to have comprehensively tested the idea that the dysregulation of physiological mechanisms of mRNP aggregate formation revealed by our studies, is a major causal factor in neurodegenerative disease.

We are guided in these experiments by observations, findings and models on mRNA regulatory mechanisms in yeast from the lab of Roy Parker (HHMI and the University of Colorado, Boulder). The project is greatly enabled by Drosophila genomic resources (TFF) being built in the NCBS (in collaboration with MPI Dresden and Munich), new technologies being designed by Pablo Labrador (Trinity) and Markus Affolter (Zurich), as well as nascent collaborations with clinician scientists.

 

Research and "training" opportunities in the lab.

There are several interesting, multidisciplinary (and potentially translationally relevant) projects available to progress the questions outlined above. We hope that innovative and energetic young scientists will join the lab to define and drive the experiments and so advance our thinking.

In addition to learning and doing excellent research, for postdocs and Ph.D students the lab is a place in which to define their interests and long-term goals as well as to proactively map suitable career paths. We try to accommodate diverse interests and aptitudes by maintaining a vigorous, open intellectual environment in which young scientists have the opportunity to pursue independent, creative and multidisciplinary science. More independent and demanding projects are possible with the participation of a wide range of outstanding collaborators and friends. Unique career and funding opportunities exist for young scientists who would like to establish strong links with the NCBS, Bangalore and/or independent research programmes in India.

If you are interested either in the questions that we are currently working on or in developing ideas that might direct your future in science and technology, please feel free to contact us for formal or informal conversations.