The optical transparency and small brain sizes of larval zebrafish have enabled unprecedented access to single-cell neural dynamics across the whole brain.  With this, we seek to discover novel principles of cellular resolution communication networks that are integral for generating pathological seizure dynamics. Just recently, we have incorporated the chronically epileptic mouse into our analysis. Which is to say, we can now draw insights across evolutionary time, and which will be directly relevant towards translation. Our key advances so far:

• Built biologically constrained single-cell whole brain effective connectivity models optimized from experimentally acquired calcium dynamics as a platform for hypothesis testing.
• With the help of novel clustering algorithms, we discovered a new ‘type’ of neuron – the higher-order hub neuron – which is responsible for destabilizing epileptic networks by facilitating unrestrained excitation downstream.
• Things are surprisingly similar in chronically epileptic mice! This means we have characterized a previously unrecognized organization of epileptic networks that leads us to predict a new target for seizure control.

Moving forward, we will use our lab’s full-scale data-driven models of hippocampal dentate gyrus and CA1 to dig deeper into the underlying circuit mechanisms responsible for the emergence of higher-order hubs in epileptic networks.

Lab Members

Cephalopods, including the cuttlefish, octopus, and squid, possess one of the most advanced nervous systems among invertebrates. With their advanced nervous systems, cephalopods are able to perform sophisticated behaviors such as navigating in open water to search for food. Yet how their nervous systems accomplish spatial navigation remains completely unknown. On the other hand, much work has been done in mammals, especially the rodent, to reveal the part of their nervous systems underlying spatial navigation. In particular, neurons in the hippocampus exhibit spatially-selective activity that is thought to provide an internal estimate of animals’ current location. This brings up an interesting question: do cephalopods, with their lineage diverges from the vertebrates more than 500 million years ago, evolve a similar or distinct strategy in their nervous systems to solve the navigation problem? To address this question, this project aims to record neuronal activity in the octopus brain while the octopus perform a spatial navigation task. This work has the potential to reveal essential neuronal mechanism underlying spatial navigation, irrespective of different animal species.

Lab Members

A major impediment to progress towards reproducible, rigorous preclinical research in epilepsy is that current experimental approaches often require prohibitively time and labor-intensive 24/7 video-EEG monitoring and inherently subjective scoring of seizures by human observers. In collaboration with the Datta lab at Harvard, who showed that complex animal behaviors are structured in stereotyped modules (“syllables”) at sub-second timescales arranged according to specific rules (“grammar”), we are developing a technique employing video imaging with a 3D camera and artificial intelligence (AI)-assisted video analysis to assess epileptic behavior in an automated and unbiased manner.

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We use high-density silicon probes in the hippocampus and related circuits to record from single neurons and monitor the local field potential dynamics with high spatiotemporal resolution. When combined with optogenetics, we can “tag” neurons to achieve cell-type specific recordings as mice navigate a cue-rich treadmill while head-fixed or during restraint-free behavior. Optogenetics also enables us to study how specific cells within and outside of the hippocampus control important LFP dynamics, including theta and sharp-wave ripples. We use a variety of electrode layouts, including Neuropixel probes, to cover a range of research questions.

Lab Members