In the first 18 months of DEEPER, partners focused on developing genetically encoded sensors, optogenetic actuators, and photopharmacological tools for neuromodulation and deep-brain activity recording, enabling real-time tracking of dopamine, norepinephrine, and serotonin. A small library of photoswitchable drugs was initiated for potential light-based treatment of chronic inflammatory pain, while new optogenetic actuators were created for in vivo neurosignaling control. Hardware innovations included tapered fiber optrodes for simultaneous optical and electrical readout, µLED-integrated microelectrodes, and a three-photon laser system improving multimode fiber-based endoscopic imaging with electrophysiology. These technologies supported clinically relevant studies on addiction, chronic pain, Alzheimer’s, and psychiatric disorders using fiber photometry and specialized probes for freely moving animals. Additionally, new methods were developed to investigate developmental miswiring in schizophrenia and autism models, enabling large-scale network analysis in neonatal and juvenile mice.
In the second 18 months of DEEPER, partners advanced molecular tools, implantable probes, and deep-brain imaging systems through collaborations with clinical experts, creating ultrasensitive fluorescent sensors, opsin sequences for synaptic transmission, and photoswitchable compound libraries including red-light activatable drugs. Microfabrication enabled electrode integration on tapered fibers, the development of dual-color silicon probes with micro-LEDs, and flexible substrates combining electrodes and fluidic channels for localized drug delivery and optimal signal recording. Imaging innovations included minimally invasive endoscopes with GRIN lenses, three-photon holographic microscopes, and a two-photon fiber-based micro-endoscope with an extended field of view, complemented by wireless head stages, μLaser arrays, and custom control software (“DeeperScope”). Preliminary system tests validated these technologies, while fiber photometry experiments revealed regional drug responses and dopamine release in freely moving mice. Proof-of-principle studies on Alzheimer’s, schizophrenia, and autism uncovered nonlinear excitatory neuron reorganization during adolescence, opening new paths for understanding neurodevelopmental disorders.
In the final months of DEEPER, the consortium delivered a new class of photonic tools for deep-brain imaging and manipulation, achieving unprecedented penetration depth, resolution, and specific molecular sensors and actuators for neuroscience researches. This platform enabled clinically relevant studies on addiction, chronic pain, Alzheimer’s, and psychiatric disorders, revealing key molecular and cellular dysfunctions. Major achievements include the integration of nonlinear microscopy and innovations in tapered fibers, the transformation of holographic endoscopy for long-term high-resolution studies, the development of ultrasensitive biosensors and pain-control strategies, and the design of dual-color µLED probes and wireless head stages for freely behaving experiments. Additional breakthroughs came from patented µLED implants, identification of critical developmental windows in neonatal and adolescent periods for insights into neurodevelopmental disorders and therapies, and insights into cocaine’s dual action. Complementary advances from different partners introduced cutting-edge optogenetic actuators, photopharmacology, commercialized probe arrays, and depth-selective laser-fiber systems, collectively setting the stage for transformative neuroscience and translational applications.
