National Institute on Drug Abuse - Intramural Research Program
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The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron
Using a large-scale GPCR profiling approach, this study systematically characterized the pharmacology of 41 classical psychedelics. The results show that these compounds engage multiple receptor families beyond 5-HT2A and provide a comprehensive dataset for studying psychedelic mechanisms and developing new therapeutic compounds.
H-bonded organic frameworks as ultrasound-programmable delivery platform. Nature This study introduces ultrasound-programmable hydrogen-bonded organic frameworks that enable precise, non-invasive drug activation deep within brain tissue. By combining theory-guided material design with focused ultrasound, the approach offers rapid, targeted control of neural activity and opens new possibilities for spatiotemporally precise molecular therapies.
AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation. Nat Commun
In this study, Wu et al introduce the muscone-induced transgene system (MUSE), in which an odorant receptor is repurposed to make a ligand-inducible gene expression vector. The authors demonstrate treatment with this construct of mouse models of nonalcoholic fatty liver disease (NAFLD) and OVA-induced allergic asthma, targeting liver and lung tissue, respectively. This approach offers a promising method for ligand-controlled gene expression, with potential applications in addiction and substance use disorder research.
Cocaine chemogenetics blunts drug-seeking by synthetic physiology. Nature
Cocaine-gated chemogenetics enables selective modulation of addiction-related circuits while sparing natural reward.
Long-term labeling and imaging of synaptically connected neuronal networks in vivo using double-deletion-mutant rabies viruses Nat Neurosci
Rabies-virus-based monosynaptic tracing is a common tool used in neuroscience research; however, toxicity of the virus limits the duration of experimental observations. Jin et al. have produced a second generation system for long-term monosynaptic tracing using a double-deletion-mutant rabies virus that reduces this toxicity and allows for viral replication and spread through neuronal subsets.
Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release bioRxiv
This study presents the development and characterization of NOPLight, a genetically encoded fluorescent sensor designed to detect the evoked and endogenous release of the nociceptin/orphanin FQ (N/OFQ) opioid peptide with high spatial and temporal resolution. NOPLight enables real-time monitoring of endogenous N/OFQ release during natural behaviors, chemogenetic stimulation, and pharmacological interventions in vitro, ex vivo, and in vivo.
Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex Mol Psychiatry.
This study introduces a novel multi-channel fluorescence and ultra high-resolution optical coherence Doppler microscope (fl-ODM) that enables simultaneous in vivo imaging of neuronal, astrocytic, and vascular dynamics in the mouse brain. Using this tool, the research uncovers how astrocytes dynamically regulate cocaine-induced changes in cerebral blood flow and neuronal activation in the prefrontal cortex.
Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states. Published in Science.
Understanding how psychedelics exert therapeutic effects without inducing hallucinogenic side effects is a key challenge in neuropsychiatric drug development. Muir et al. combine multiple cutting-edge neuroscience approaches to dissociate the neural mechanisms underlying the anxiolytic-like and hallucinogenic-like effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). They identify a population of DOI-responsive neurons in the medial prefrontal cortex that mediate anxiolytic-like effects without inducing hallucinogenic-like behaviors, paving the way for the development of more targeted psychedelic therapies.
A fast and responsive voltage indicator with enhanced sensitivity for unitary synaptic events Neuron.
The paper introduces ASAP5, a genetically encoded voltage indicator (GEVI) optimized for detecting electrical activity in neurons with improved speed, sensitivity, and signal resolution. The study highlights ASAP5’s in vitro and in vivo utility across species (flies, fish, mice, and human neurons). It bridges the gap between low-throughput electrophysiology and non-invasive imaging, making it a valuable resource for investigating synaptic dysfunction in neurodevelopmental and neurodegenerative diseases.
DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity Nat Methods.
Understanding how specific brain cells drive behavior requires targeted, cell- and circuit-specific neuropharmacology. DART.2 (Drugs Acutely Restricted by Tethering, version 2) offers improved cellular precision for targeting drugs compared to the original DART.1 technology, enabling unprecedented brain-wide drug distribution and bidirectional modulation of neurotransmitter pathways to examine behavior.
