Overview
We are broadly interested in drugs that may be used for treating depression. We want to know how therapeutic behavioral effects are produced by a drug’s action on synapses and neurons in the brain. Many of our experiments involve optical imaging and electrophysiology in awake mice. By gaining neurobiological insights and engineering new tools, our long-term goal is to discover effective strategies for treating depression. Current projects in the lab focus on ketamine and psychedelics such as psilocybin and 5-MeO-DMT (Kwan et al., Nat Neurosci 2022; Kelmendi et al., Curr Biol 2022). We have made progress in three areas.
Drug action on synapses and dendrites
Depression is associated with a loss of synapses in the prefrontal cortex. There is growing evidence that antidepressants may counteract the deficit by enhancing synaptic plasticity. Our lab was the first to use two-photon microscopy to track in vivo how ketamine induces rapid remodeling of neuronal connections (Phoumthipphavong et al., eNeuro 2016). Recent studies showed that the drug-evoked structural rewiring persists for many weeks after a single dose of psilocybin (Shao et al., Neuron 2021) or 5-MeO-DMT (Jefferson et al., NPP 2023). We are keen to delineate the molecular and cellular mechanisms that underlie the enduring structural plasticity (Savalia et al., Trends Neurosci 2021).
Drug action on neural circuit dynamics
Behavior is generated by neural activity, which is orchestrated by excitatory and inhibitory neurons in the brain. However, we have a limited understanding of how antidepressants alter the firing patterns of various cell types. Our work has revealed how chronic stress, a risk factor for depression, can progressively cause maladaptive neural activity in the frontal cortex (Barthas et al., Biol Psychiatry 2020). We found that ketamine acts on dendrite-targeting GABAergic neurons to elevate synaptic calcium signaling (Ali et al., Nat Commun 2020), which may be precursor to neural plasticity. Currently we are exploring how psilocybin may impact cortical circuits, particularly during translationally relevant behaviors (Woodburn et al., ACS Chem Neurosci, 2024).
Optical methods for drug discovery
A key challenge in drug development lies in the screen of dozens of compounds to identify a lead to advance to clinical trials. For neuropsychiatric disorders, the targets for screening are often unreliable because the biology is unclear. We are creating assays based on whole-brain cellular-resolution imaging via light sheet fluorescence microscopy to quantify drug action in native brain tissues. Using this approach, we found that ketamine and psilocybin evoke plasticity-related gene expression in numerous similar brain regions, but also have distinct signatures (Davoudian et al., ACS Chem Neurosci, 2023). We developed a machine learning pipeline to classify and predict psychedelics and related psychoactive drugs (Aboharb et al., bioRxiv, 2024).
Funding
We are grateful for current and past support from NIMH, NINDS, NIA, Simons Foundation Autism Research Initiative, Brain & Behavior Research Foundation, One Mind, Epilepsy Foundation, Yale Program for Psychedelic Science, Yale CTNA, and Inscopix DECODE Program.
We appreciate fellowship support for trainees from NIMH, NIDA, NSF, Source Research Foundation, Brain & Behavior Research Foundation, Philippe Foundation, Alzheimer’s Association, and Alzheimer’s Drug Discovery Foundation.