Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.
Cortical activity contributes significantly to the high variability of sensory responses of interconnected pyramidal neurons, which has crucial implications for sensory coding. Yet, largely because of technical limitations of in vivo intracellular recordings, the coupling of a pyramidal neuron's synaptic inputs to the local cortical activity has evaded full understanding. Here we obtained excitatory synaptic conductance ( g) measurements from putative pyramidal neurons and local field potential (LFP) recordings from adjacent cortical circuits during visual processing in the turtle whole brain ex vivo preparation. We found a range of g-LFP coupling across neurons. Importantly, for a given neuron, g-LFP coupling increased at stimulus onset and then relaxed toward intermediate values during continued visual stimulation. A model network with clustered connectivity and synaptic depression reproduced both the diversity and the dynamics of g-LFP coupling. In conclusion, these results establish a rich dependence of single-neuron responses on anatomical, synaptic, and emergent network properties. NEW & NOTEWORTHY Cortical neurons are strongly influenced by the networks in which they are embedded. To understand sensory processing, we must identify the nature of this influence and its underlying mechanisms. Here we investigate synaptic inputs to cortical neurons, and the nearby local field potential, during visual processing. We find a range of neuron-to-network coupling across cortical neurons. This coupling is dynamically modulated during visual processing via biophysical and emergent network properties.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.