The big broad question of our lab is how do we perceive and respond to the world through our senses.

Towards this, we are interested in the sensory experience of smell. In our lab, we tackle this system-level question at a cellular level of glia, and at a molecular level of epigenetics.

WHY GLIA?

When we think about the brain, we think about neurons (magenta cells below)

However, if we really look at the brain, neurons are always intertwined with these star-shaped cells (green cells below). These are astrocytes — the primary sub-type of non-neuronal cells, better known as glial cells.

Any and every brain function and every neurological disease have been associated with glial cells. Glia are the underdogs of the nervous system, and in the glial biology field, our primary goal is to put glia on the map of the brain.

WHY EPIGENETICS?

Epigenetics include chemical modifications on histone proteins that package DNA. These modifications can alter the ‘open’-ness or ‘close’-ness of surrounding DNA, influencing activation or silencing of nearby genes. Since installation of these modifications can be influenced by environmental stimuli, epigenetics represent a powerful information processing hub integrating external stimuli into gene regulation. In other words, epigenetic modifications has the capacity to encode information about the environment. In our lab, we are excited to delve into how odor sensory information is epigenetically encoded in glial cells.

Serotonin epigenetics in glia:

In Sardar et al, Science, 2023, I made a fundamental discovery that astrocyte epigenetics is critical for olfaction, presenting the first example of an astrocyte epigenetic pathway impacting behavior. Excitingly, we showed that chemicals like serotonin can enter the astrocyte nucleus, get incorporated into histone proteins, and epigenetically regulate olfaction. This work has uncovered a previously unknown form of gene regulation in astrocytes, representing an exciting new frontier in our understanding of how neuromodulators like serotonin is processed by glial cells — with vast potential for future investigations in our lab.

magenta: histone serotonylation, wherein serotonin is added as a epigenetic chemical modification to histone protein

green: an astrocyte in olfactory bulb - the brain region responsible for processing smell

OUR QUESTIONS:

  1. While role of glial epigenetics has been uncovered in the context of development and diseased states, we know next to nothing on how glial epigenetics influences a healthy functional adult brain circuit in vivo — this is the knowledge gap our lab will aim to advance in the next 5 years.

  2. In the future, we will expand our findings to role of glial epigenetic contribution to circuits connecting olfaction to higher orders of behavior and pathological states.

OUR TOOLS:

All studies will use mouse models and in vivo genetic manipulation in the mouse olfactory bulb:

  1. Molecular neuroscience — epigenomics, transcriptomics, single-cell transcriptomics (genomic sequencing approaches) and proteomics (mass spectrometry)

  2. Cellular neuroscience — glial cell morphology using high resolution microscopy, glial cell calcium signaling using two-photon microscopy, immunohistochemical analyses using confocal microcopy

  3. Systems neuroscience — olfactory behaviors, viral vector delivery into the brain, chemogenetics

Taken together, we use an integrated approach to uncover how genes within cells, and cells withing circuits work together to influence animal behaviors of smell.