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.

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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.

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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.

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Optogenetics is a control technology that allows the fast, selective excitation or inhibition of specific neurons with light by expressing light-sensitive proteins (opsins) in particular cell types, enabling causal control of neuronal activity in behaving animals. We have developed a closed-loop, real-time, on-demand system to utilize optogenetics to provide effective seizure control in experimental models of temporal lobe epilepsy (TLE) (Krook-Magnuson et al., 2013) in a spatial, temporal, cell-type and direction of modulation-(excitation or inhibition) selective manner. Importantly, closed-loop optogenetic intervention (COI) was capable not only of curtailing electrographic seizures, but also of significantly decreasing the number of behavioral seizures. COI has proven to be a powerful new tool to understand epileptic circuits, and our lab has used it to directly test the role of the cerebellum as a distant site for seizure control in TLE (Krook-Magnuson et al., 2014) and the role of mossy cells in epilepsy (Bui et al., 2018). One of the most attractive features of COI is that the intervention is highly selective, occurring only when needed (at the time of seizures) and where it is needed, causing selective disruption of seizures while only minimally interfering with ongoing computations necessary for normal brain function. We have recently shown that prolonged application of COI can ameliorate cognitive deficits in TLE (Kim et al., 2019), providing evidence that this technology can improve both seizure burden and the associated comorbidities of epilepsy. Continuing work in the Soltesz lab is focused on utilizing COI as well as incorporating recently developed molecular tools to use with the system to identify and understand epileptic circuits both within and outside of the hippocampus. Ultimately our work aims to provide critical insight into potential targets and avenues for intervention in the treatment of epilepsy.

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To monitor the activity of specific cells during unrestricted behavior, we use open-source head-mounted miniscopes developed at UCLA (miniscope.org) to measure calcium activity. The main advantage of this approach over head-fixed 2-photon imaging is the ability to perform a broader range of behavioral tasks including artificial intelligence-based behavioral analysis. Combining these cell type-specific recordings with unbiased sub-second behavioral analysis using AI facilitates the characterization of the cellular underpinnings of behavior at a resolution not possible with conventional approaches.

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We’re using 2-photon microscopy to record neuronal activity with single-cell resolution in the hippocampus of awake, behaving mice. Taking advantage of cell type-specific viral targeting of various biosensors, our goal is to better understand how distinct populations of excitatory and inhibitory neurons are recruited during network oscillations in the healthy brain, and during pathological activity such as seizures in the epileptic brain.

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