Biology subjects

Zimmermann Rollin, I.

Publications and source records attributed to Zimmermann Rollin, I..

3 recordsLinked to original sources

bioRxiv2026

Noninvasive Focal Gene Delivery of Functional Neural Actuators to the Primate Spinal Cord using Focused Ultrasound

Pathologies of the spinal cord -- from degenerative diseases to chronic pain -- represent a substantial global health burden. Although surgical and pharmacological treatments for spinal cord pathologies have advanced considerably, therapies capable of addressing the cellular mechanisms underlying these conditions remain limited. Viral gene therapies present a compelling alternative, allowing for delivery of therapeutic genes that directly target the pathological processes in specific cell-types. Effective viral delivery to the spinal cord, however, remains constrained by a fundamental tradeoff between procedural invasiveness and spatial precision. As such, there remains a need for clinically tractable methods -- that are both noninvasive and focal -- to deliver gene therapeutics across the restrictive vascular boundaries of the blood-spinal cord barrier (BSCB). Here, we demonstrate noninvasive, focal disruption of the BSCB and delivery of systemically administered chemogenetic gene payloads to the cervical and thoracic spinal cord in marmoset nonhuman primates (Callithrix jacchus) using focused ultrasound (FUS). Through systematic testing of ultrasonic pressures and central frequencies, we establish a FUS parameter set optimized for robust, spatially constrained molecular delivery across the marmoset BSCB. Using these optimized parameters, we show that FUS BSCB disruption permitted focal penetrance of systemically administered viral vectors for transduction of both fluorescent transgenes and excitatory chemogenetics within targeted spinal segments. Positron emission tomography (PET) imaging following chemogenetic actuation revealed significantly increased metabolic demand within the targeted region of the spinal cord, demonstrating in vivo evidence of functional transgene expression. Behavioral and histopathological assessments demonstrated preserved neurological function and tissue integrity, supporting the safety of FUS BSCB disruption and viral delivery in nonhuman primates. To facilitate broad application of this platform for noninvasive delivery of receptor-based gene therapeutics in marmosets, we generated an ultra-high-resolution (74 m) multimodal MRI/CT spinal cord template for precise targeting and anatomical localization. We also provide open-access engineering drawings and CAD files for our M-FRAME system (Marmoset Fixation and Reorientation Apparatus for Multimodal Experiments), enabling precise and repeatable spinal targeting without surgical fixation. Together, these results establish FUS-mediated BSCB disruption as a safe and effective approach for noninvasive, focal gene delivery to the primate spinal cord.

neuroscience↗

bioRxiv2025

Noninvasive focal gene transfer of chemogenetic proteins in the primate brain

The development of chemogenetic neuromodulators, including Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have enabled focally specific, long-lasting, and reversible neuromodulation in the primate brain. Although systemically delivered synthetic ligands allow for noninvasive actuation of chemogenetic receptors, direct intraparenchymal injection remains atop the available methods to precisely deliver chemogenetic payloads to a specific target of the brain. The requirement of trephination, however, is accompanied by inherent risks of infection, long recovery times, and often tissue damage with concomitant behavioral complications. When considering therapeutic injections, the requirement of transcranial surgery does not translate well to the clinic, especially when repeated administrations are required. Here, we leverage our recent development of transcranial focused ultrasound (tFUS) for noninvasive and focal delivery of adeno-associated viruses (AAVs) carrying excitatory Gq-DREADDs to frontal cortical targets (areas 6DR and 8aD) in the marmoset brain. Using [18F]-fluorodeoxyglucose (FDG) positron emission tomography, we demonstrate significant increases in glucose metabolism at the site of viral delivery after administering the DREADD-specific agonist deschloroclozapine (DCZ), as compared to vehicle control. Focal neuronal DREADD expression was confirmed by immunohistochemistry at the site of opening. Through comparison of awake resting-state functional connectivity (whole brain connectivity with the sites of delivery) and structural connectivity (directly injected viral neuronal tracing at the sites of delivery) we demonstrate that the increase in glucose metabolism occurs at both mono- and polysynaptically connected brain regions. Taken together, these results demonstrate the ability to focally deliver excitatory chemogenetics without the need for surgery, allowing for activation of long-range frontal cortex circuits of the primate brain.

neuroscience↗

bioRxiv2024

An open-source MRI compatible frame for multimodal presurgical mapping in macaque and capuchin monkeys

HighlightsO_LIWe present a compact MRI-compatible stereotaxic frame for large nonhuman primates. C_LIO_LIThe design is 3D printable, inexpensive, and matches size of an adult human head. C_LIO_LIEnabled real-time, accurate, MRI-guided deep-brain viral vector injection. C_LIO_LIFacilitated multimodal alignment for deep-brain electrophysiology planning. C_LIO_LIAll computer-aided-design files are modularized and publicly available and editable. C_LI BackgroundHigh-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomy mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. New methodWe developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. Comparison with existing methodsWith the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. ResultsWe demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of viral vectors. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. ConclusionsThe computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.

bioengineering↗