Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations dynamically coupled with hippocampal rhythms across brain states.

The granular retrosplenial cortex (gRSC) exhibits high-frequency oscillations (HFOs; ∼150 Hz), which can be driven by a hippocampus-subiculum pathway. How the cellular-synaptic and laminar organization of gRSC facilitates HFOs is unknown. Here, we probe gRSC HFO generation and coupling with hippocampal rhythms using focal optogenetics and silicon-probe recordings in behaving mice. ChR2-mediated excitation of CaMKII-expressing cells in L2/3 or L5 induces HFOs, but spontaneous HFOs are found only in L2/3, where HFO power is highest. HFOs couple to CA1 sharp wave-ripples (SPW-Rs) during rest and the descending phase of theta. gRSC HFO current sources and sinks are the same for events during both SPW-Rs and theta oscillations. Independent component analysis shows that high gamma (50-100 Hz) in CA1 stratum lacunosum moleculare is comodulated with HFO power. HFOs may thus facilitate interregional communication of a multisynaptic loop between the gRSC, hippocampus, and medial entorhinal cortex during distinct brain and behavioral states.

T-DOpE probes reveal sensitivity of hippocampal oscillations to cannabinoids in behaving mice.

Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. We developed a thermal tapering process enabling fabrication of low-cost, flexible probes combining ultrafine features: dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly. We demonstrate T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes achieve in single neuron-scale devices (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. The device tip can be miniaturized (as small as 50 µm) to minimize tissue damage while the ~20 times larger backend allows for industrial-scale connectorization. T-DOpE probes implanted in mouse hippocampus revealed canonical neuronal activity at the level of local field potentials (LFP) and neural spiking. Taking advantage of the triple-functionality of these probes, we monitored LFP while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity (optogenetics). Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPW-Rs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit.

Submillimeter Multifunctional Ferromagnetic Fiber Robots for Navigation, Sensing, and Modulation.

Small-scale robots capable of remote active steering and navigation offer great potential for biomedical applications. However, the current design and manufacturing procedure impede their miniaturization and integration of various diagnostic and therapeutic functionalities. Herein, submillimeter fiber robots that can integrate navigation, sensing, and modulation functions are presented. These fiber robots are fabricated through a scalable thermal drawing process at a speed of 4 meters per minute, which enables the integration of ferromagnetic, electrical, optical, and microfluidic composite with an overall diameter of as small as 250 µm and a length of as long as 150 m. The fiber tip deflection angle can reach up to 54o under a uniform magnetic field of 45 mT. These fiber robots can navigate through complex and constrained environments, such as artificial vessels and brain phantoms. Moreover, Langendorff mouse hearts model, glioblastoma micro platforms, and in vivo mouse models are utilized to demonstrate the capabilities of sensing electrophysiology signals and performing a localized treatment. Additionally, it is demonstrated that the fiber robots can serve as endoscopes with embedded waveguides. These fiber robots provide a versatile platform for targeted multimodal detection and treatment at hard-to-reach locations in a minimally invasive and remotely controllable manner.

Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations coupled with hippocampal theta and gamma in online states or sharp-wave ripples in offline states.

Neuronal oscillations support information transfer by temporally aligning the activity of anatomically distributed 'writer' and 'reader' cell assemblies. High-frequency oscillations (HFOs) such as hippocampal CA1 sharp-wave ripples (SWRs; 100-250 Hz) are sufficiently fast to initiate synaptic plasticity between assemblies and are required for memory consolidation. HFOs are observed in parietal and midline cortices including granular retrosplenial cortex (gRSC). In 'offline' brain states (e.g. quiet wakefulness) gRSC HFOs co-occur with CA1 SWRs, while in 'online' states (e.g. ambulation) HFOs persist with the emergence of theta oscillations. The mechanisms of gRSC HFO oscillations, specifically whether the gRSC can intrinsically generate HFOs, and which layers support HFOs across states, remain unclear. We addressed these issues in behaving mice using optogenetic excitation in individual layers of the gRSC and high density silicon-probe recordings across gRSC layers and hippocampus CA1. Optogenetically induced HFOs (iHFOs) could be elicited by depolarizing excitatory neurons with 100 ms half-sine wave pulses in layer 2/3 (L2/3) or layer 5 (L5) though L5 iHFOs were of lower power than in L2/3. Critically, spontaneous HFOs were only observed in L2/3 and never in L5. Intra-laminar monosynaptic connectivity between excitatory and inhibitory neurons was similar across layers, suggesting other factors restrict HFOs to L2/3. To compare HFOs in online versus offline states we analyzed, separately, HFOs that did or did not co-occur with CA1 SWRs. Using current-source density analysis we found uniform synaptic inputs to L2/3 during all gRSC HFOs, suggesting layer-specific inputs may dictate the localization of HFOs to L2/3. HFOs occurring without SWRs were aligned with the descending phase of both gRSC and CA1 theta oscillations and were coherent with CA1 high frequency gamma oscillations (50-80 Hz). These results demonstrate that gRSC can internally generate HFOs without rhythmic inputs and that HFOs occur exclusively in L2/3, coupled to distinct hippocampal oscillations in online versus offline states.

Tapered Drug delivery, Optical stimulation, and Electrophysiology (T-DOpE) probes reveal the importance of cannabinoid signaling in hippocampal CA1 oscillations in behaving mice.

Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. Here we developed a thermal tapering process (TTP) which enables the fabrication of novel, low-cost, flexible probes that combine ultrafine features of dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly of the probes. We demonstrate that our T-DOpE ( T apered D rug delivery, Op tical stimulation, and E lectrophysiology) probe achieves in a single neuron-scale device (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. With a tapered geometry, the device tip can be minimized (as small as 50 µm) to ensure minimal tissue damage while the backend is ~20 times larger allowing for direct integration with industrial-scale connectorization. Acute and chronic implantation of the probes in mouse hippocampus CA1 revealed canonical neuronal activity at the level of local field potentials and spiking. Taking advantage of the triple-functionality of the T-DOpE probe, we monitored local field potentials with simultaneous manipulation of endogenous type 1 cannabinoid receptors (CB1R; via microfluidic agonist delivery) and CA1 pyramidal cell membrane potential (optogenetic activation). Electro-pharmacological experiments revealed that focal infusion of CB1R agonist CP-55,940 in dorsal CA1 downregulated theta and sharp wave-ripple oscillations. Furthermore, using the full electro-pharmacological-optical feature set of the T-DOpE probe we found that CB1R activation reduces sharp wave-ripples (SPW-Rs) by impairing the innate SPW-R-generating ability of the CA1 circuit.

Multifunctional ferromagnetic fiber robots for navigation, sensing, and treatment in minimally invasive surgery.

Small-scale robots capable of remote active steering and navigation offer great potential for biomedical applications. However, the current design and manufacturing procedure impede their miniaturization and integration of various diagnostic and therapeutic functionalities. Here, we present a robotic fiber platform for integrating navigation, sensing, and therapeutic functions at a submillimeter scale. These fiber robots consist of ferromagnetic, electrical, optical, and microfluidic components, fabricated with a thermal drawing process. Under magnetic actuation, they can navigate through complex and constrained environments, such as artificial vessels and brain phantoms. Moreover, we utilize Langendorff mouse hearts model, glioblastoma microplatforms, and in vivo mouse models to demonstrate the capabilities of sensing electrophysiology signals and performing localized treatment. Additionally, we demonstrate that the fiber robots can serve as endoscopes with embedded waveguides. These fiber robots provide a versatile platform for targeted multimodal detection and treatment at hard-to-reach locations in a minimally invasive and remotely controllable manner.