Biology subjects

Wolff, S. B. E.

Publications and source records attributed to Wolff, S. B. E..

6 recordsLinked to original sources

bioRxiv2026

Neurobehavioral effects of focused ultrasound-mediated blood-brain barrier opening

Microbubble-enhanced focused ultrasound (MB-FUS) enables noninvasive blood-brain barrier (BBB) opening to improve the delivery of drugs and other therapeutics to the brain, supporting more effective treatment of brain disorders. The benefits of this rapidly advancing and highly versatile technology have been demonstrated in clinical trials, sparking a growing interest in expanding FUS applications that require higher intensity treatments, larger targeted brain volumes and larger therapeutics. However, in-depth safety profiling of such treatments has not been done and is limited in the clinic. Preclinical studies have been restricted in their readouts, focusing on acute imaging and simple behaviors. To address the need for more holistic safety profiling, we present a novel preclinical workflow for determining adverse effects of MB-FUS in rats, both acutely and long-term, by combining MRI, histology, and a custom motor task which provides fine-scaled readouts for complex learned behavior. Using this approach and taking advantage of our previous delineation of the relevant circuitry, we show dose- and target-dependent adverse effects in high dosing regimens. All prescribed acoustic doses opened the BBB; but while low doses had no overt adverse effects, high doses targeting the involved circuitry had severe effects on both behavior and brain tissue integrity. These effects persisted for weeks and recovered over differing time courses, with tissue disruptions and behavioral changes outlasting general performance deficits. Our results reinforce the need for multimodal, highly sensitive, and longitudinal readouts to holistically characterize adverse effects of MB-FUS, allowing for its safe use across a wide range of applications. SignificanceMicrobubble-enhanced focused ultrasound is emerging as a powerful noninvasive approach for delivering drugs, genes, and cell therapies through the blood-brain barrier, sparking broad interest in expanding clinical and preclinical applications. However, its effects on complex neurological function, especially for higher dosing regimens, remain poorly defined. To address this, we have established a novel multimodal preclinical strategy for defining functional safety limits and guiding clinical translation, integrating sensitive behavioral testing with MRI, histology and acoustic emissions analysis. We show dose- and target-dependent impairments in complex learned motor behavior and evidence of possible brain injury, with substantially different recovery time courses. Together, our findings demonstrate the importance of a multimodal, longitudinal approach for comprehensively characterizing treatment-related adverse effects and evaluating safety.

neuroscience↗

bioRxiv2023

Modeling an ultra-rare epilepsy variant in wildtype mice with in utero prime editing

Generating animal models that mirror a patients seizures within clinically-useful timeframes is an important step toward advancing precision medicine for genetic epilepsies. Here we report a somatic cell genome editing approach that rapidly incorporated a patients genomic variant into mice, which developed seizures recapitulating elements of the patients pathology. This approach offers a versatile in vivo platform for clinical, preclinical, and basic research applications, including tailoring pharmacotherapy, assessing variants of uncertain significance, and screening compounds to develop drugs for rare epilepsies. As proof-of-principle, we modeled an epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A using prime editing in utero directly in the developing brain of wild-type mice. This methodology achieved high-fidelity genome editing in vivo sufficient to induce frequent spontaneous seizures without necessitating germline modification or extensive breeding. Leveraging the speed and versatility of this approach, we propose a generalizable workflow to generate bedside-to-bench animal models of individual patients within weeks. This advance holds promise for providing a cost-effective, expedient in vivo testing platform that reduces barriers to access for precision medicine, and accelerates drug development for rare and neglected neurological conditions.

neuroscience↗

bioRxiv2021

Long-term stability of neural activity in the motor system

How an established behavior is retained and stably produced by a nervous system in constant flux remains a mystery. One possible solution is to fix the activity patterns of single neurons in the relevant circuits. Alternatively, activity in single cells could drift over time provided that the population dynamics are constrained to produce stable behavior. To arbitrate between these possibilities, we recorded single unit activity in motor cortex and striatum continuously for several weeks as rats performed stereotyped motor behaviors - both learned and innate. We found long-term stability in single neuron activity patterns across both brain regions. A small amount of drift in neural activity, observed over weeks of recording, could be explained by concomitant changes in task-irrelevant behavioral output. These results suggest that stereotyped behaviors are generated by stable single neuron activity patterns.

neuroscience↗

bioRxiv2020

Encoding of 3D Head Orienting Movements in Primary Visual Cortex

Animals actively sample from the sensory world by generating complex patterns of movement that evolve in three dimensions. At least some of these movements have been shown to influence neural codes in sensory areas. For example, in primary visual cortex (V1), locomotion-related neural activity influences sensory gain, encodes running speed, and predicts the direction of visual flow. As most experiments exploring movement-related modulation of V1 have been performed in head-fixed animals, it remains unclear whether or how the naturalistic movements used to interact with sensory stimuli- like head orienting-influence visual processing. Here we show that 3D head orienting movements modulate V1 neuronal activity in a direction-specific manner that also depends on the presence or absence of light. We identify two largely independent populations of movement-direction-tuned neurons that support this modulation, one of which is direction-tuned in the dark and the other in the light. Finally, we demonstrate that V1 gains access to a motor efference copy related to orientation from secondary motor cortex, which has been shown to control head orienting movements. These results suggest a mechanism through which sensory signals generated by purposeful movement can be distinguished from those arising in the outside world, and reveal a pervasive role of 3D movement in shaping sensory cortical dynamics.

neuroscience↗

bioRxiv2019

The basal ganglia can control learned motor sequences independently of motor cortex

How the basal ganglia contribute to the execution of learned motor skills has been thoroughly investigated. The two dominant models that have emerged posit roles for the basal ganglia in action selection and in the modulation of movement vigor. Here we test these models in rats trained to execute highly stereotyped and idiosyncratic task-specific motor sequences. Recordings and manipulations of neural activity in the striatum were not well explained by either model, and suggested that the basal ganglia, in particular its sensorimotor arm, are crucial for controlling the detailed kinematic structure of the learned behaviors. Importantly, the neural representations in the striatum, and the control functions they subserve, did not depend on the motor cortex. Taken together, these results extend our understanding of basal ganglia function, by suggesting that they can control and modulate lower-level subcortical motor circuits on a moment-by-moment basis to generate stereotyped learned motor sequences.

neuroscience↗

bioRxiv2019

Distinct roles for motor cortical and thalamic inputs to striatum during motor learning and execution

The acquisition and execution of learned motor sequences are mediated by a distributed motor network, spanning cortical and subcortical brain areas. The sensorimotor striatum is an important cog in this network, yet how its two main inputs, from motor cortex and thalamus respectively, contribute to its role in motor learning and execution remains largely unknown. To address this, we trained rats in a task that produces highly stereotyped and idiosyncratic motor sequences. We found that motor cortical input to the sensorimotor striatum is critical for the learning process, but after the behaviors were consolidated, this corticostriatal pathway became dispensable. Functional silencing of striatal-projecting thalamic neurons, however, disrupted the execution of the learned motor sequences, causing rats to revert to behaviors produced early in learning and preventing them from re-learning the task. These results show that the sensorimotor striatum is a conduit through which motor cortical inputs can drive experience-dependent changes in subcortical motor circuits, likely at thalamostriatal synapses.

neuroscience↗