2-Photon Imaging and Optogenetics
We image neural activity at cellular resolution across in vivo mouse and ex vivo human preparations. We combine three excitation lasers to image distinct cell populations simultaneously, integrate imaging with electrophysiology and behavior, and perform two-photon optical stimulation for targeted circuit manipulation.
We also image living human cortical tissue to investigate network activity and the effects of molecular perturbations directly in human neurons (Farrell et al., Nature, 2024; Singh, Abbaspoor et al., 2026).
Videos show representative two-photon calcium imaging from human cortical slices expressing scrambled-control shRNA and FMR1-targeting shRNA.
We manipulate genetically defined cell populations with optogenetics to test their causal contributions to circuit dynamics and behavior. We combine optogenetic manipulation with two-photon imaging, high-density electrophysiology, and behavioral measurements to link targeted perturbations to changes in neural activity and function.
We use two-photon optical stimulation to manipulate targeted cells with high spatial precision while monitoring surrounding network activity. We combine optical stimulation with calcium imaging to test how defined cells or ensembles influence local circuit dynamics and distributed network states.
High Density Electrophysiology
We record large neuronal populations across hippocampal, subcortical and cortical circuits with NeuroNexus and Neuropixels probes in both head-fixed and freely moving mice. We operate two dedicated electrophysiology rigs and simultaneously capture single-unit activity, local field potentials during different types of behaviors and brain-behavioral states.
We have used these approaches to study hippocampal dentate spikes, sharp-wave ripples, and distributed brain-state dynamics (Farrell et al., Nature, 2024; Farrell and Soltesz, Science, 2025).
Cell Type-Guided Focused Ultrasound Neuromodulation
Using an ultrasound transducer that is coupled to a fiber optic cannula, we can monitor the activity of genetically defined cell populations at the site of sonication. Importantly, different parameters can have profoundly different effects on the local circuit and can bias the network towards inhibitory or excitatory states. In many cases, fUS parameters can be optimized to have a desired effect on the network to counteract pathophysiology, which we showed was possible for rodent models of temporal lobe epilepsy (see Murphy et al., PNAS 2022). We will move towards studying the neuromodulatory effects of ultrasound in vivo at sub-cellular resolution to better understand which cells, including where (dendrites vs. axons?) and when (rapid onset vs. delayed?), are most affected.
Fiber Photometry
We monitor genetically defined cell populations in deep brain structures during behavior with fiber photometry. We can combine these recordings with circuit manipulations to track how specific neuronal populations respond in real time. We have used cell-type-specific photometry to characterize and optimize the effects of focused ultrasound across neuronal populations and brain regions (Murphy et al., PNAS, 2022; Murphy et al., Neuron, 2024).
Molecular & Transcriptomic Approaches
We combine multiplexed HCR, viral gene manipulation, FACS, RT-qPCR, and single-cell RNA sequencing to connect molecular identity and gene-expression changes with neural circuit function. We use these approaches to identify cell types, validate genetic manipulations, and uncover cell-type-specific molecular mechanisms across experimental models.
We have applied this framework to human cortical tissue, where we combined AAV-mediated FMR1 knockdown with cell sorting and single-cell transcriptomics to identify molecular changes associated with altered neuronal and network function (Singh, Abbaspoor et al., 2026).