Publications by authors named "Jaclyn Beckinghausen"

Deep brain stimulation (DBS) relieves motor dysfunction in Parkinson's disease, and other movement disorders. Here, we demonstrate the potential benefits of DBS in a model of ataxia by targeting the cerebellum, a major motor center in the brain. We use the Car8 mouse model of hereditary ataxia to test the potential of using cerebellar nuclei DBS plus physical activity to restore movement. While low-frequency cerebellar DBS alone improves Car8 mobility and muscle function, adding skilled exercise to the treatment regimen additionally rescues limb coordination and stepping. Importantly, the gains persist in the absence of further stimulation. Because DBS promotes the most dramatic improvements in mice with early-stage ataxia, we postulated that cerebellar circuit function affects stimulation efficacy. Indeed, genetically eliminating Purkinje cell neurotransmission blocked the ability of DBS to reduce ataxia. These findings may be valuable in devising future DBS strategies.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

Alzheimer's and Parkinson's disease are late onset neurodegenerative diseases that will require therapy over decades to mitigate the effects of disease-driving proteins such tau and α-synuclein (α-Syn). Previously we found that TRIM28 regulates the levels and toxicity of α-Syn and tau (Rousseaux et al., 2016). However, it was not clear how TRIM28 regulates α-Syn and it was not known if its chronic inhibition later in life was safe. Here, we show that TRIM28 may regulate α-Syn and tau levels via SUMOylation, and that genetic suppression of Trim28 in adult mice is compatible with life. We were surprised to see that mice lacking Trim28 in adulthood do not exhibit behavioral or pathological phenotypes, and importantly, adult reduction of TRIM28 results in a decrease of α-Syn and tau levels. These results suggest that deleterious effects from TRIM28 depletion are limited to development and that its inhibition adulthood provides a potential path for modulating α-Syn and tau levels.

The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.

Most of the current closed-loop DBS devices use a single biomarker in their feedback loop which may limit their performance and applications. This paper presents design, fabrication, and validation of a programmable multi-biomarker neural sensor which can be integrated into closed-loop DBS devices. The device is capable of sensing a combination of low-frequency (7-45 Hz), and high-frequency (200-1000 Hz) neural signals. The signals can be amplified with a digitally programmable gain within the range 50-100 dB. The neural signals can be stored into a local memory for processing and validation. The sensing and storage functions are implemented via a combination of analog and digital circuits involving preamplifiers, filters, programmable post-amplifiers, microcontroller, digital potentiometer, and flash memory. The device is fabricated, and its performance is validated through: (i) bench tests using sinusoidal and pre-recorded neural signals, (ii) in-vitro tests using pre-recorded neural signals in saline solution, and (iii) in-vivo tests by recording neural signals from freely-moving laboratory mice. The animals were implanted with a PlasticsOne electrode, and recording was conducted after recovery from the electrode implantation surgery. The experimental results are presented and discussed confirming the successful operation of the device. The size and weight of the device enable tetherless back-mountable use in pre-clinical trials.