Biology subjects

Gutekunst, C.-A.

Publications and source records attributed to Gutekunst, C.-A..

6 recordsLinked to original sources

bioRxiv2024

Organellular imaging in vivo reveals a depletion of endoplasmic reticular calcium during post-ictal cortical spreading depolarization

AO_SCPLOWBSTRACTC_SCPLOWDuring cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.

neuroscience↗

bioRxiv2024

Exercise Evokes Retained Motor Performance without Neuroprotection in a Mouse Model of Parkinson's Disease

Exercise has been extensively studied in Parkinsons Disease, with a particular focus on the potential for neuroprotection that has been demonstrated in animal models. While this preclinical work has provided insight into the underlying molecular mechanisms, it has not addressed the neurophysiological changes during exercise. Here, first, we tested for neuroprotective effects of adaptive wheel running exercise in the 6-hydroxydopamine mouse model of Parkinsons disease, assessing for dopaminergic cell preservation. Finding none, despite running performance that equaled the pre-parkinsonian state, we probed the neurophysiology of running exercise as a transient state of high motor function amidst an unameliorated Parkinsonian lesion. Exercise was associated with characteristic, excitatory changes in the dopamine-depleted substantia nigra, which could be suppressed along with running itself by dopamine receptor blockade. Going forward, the functional state evoked by exercise merits further study, as it has parallels in human disease and may represent an optimal physiologic target for neuromodulation.

neuroscience↗

bioRxiv2024

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinsons disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico (p<0.0056, N=1,000) and in vivo (p=0.0036, N=20). This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

neuroscience↗

bioRxiv2024

Adaptive Wheel Exercise for Mouse Models of Parkinson's Disease

Exercise is widely studied as a therapy in mouse models of neurological disease. However, the established techniques for exercise in mice are not ideally suited toward motor deficient disease models, nor do they facilitate active measurement of neurophysiology with tethered assays. To address this, we developed an apparatus and technique for inducing exercise in mice without aversive stimuli, using a motorized wheel with closed-loop acceleration that tracks subject performance. We demonstrated the efficacy of this approach in the 6-hydroxydopamine mouse model of PD, including with single-unit electrophysiology. This approach should allow for exercise to be better studied as a dynamic, physiological intervention in neurological disease models.

bioengineering↗

bioRxiv2024

Improved Temporal and Spatial Focality of Non-invasive Deep-brain Stimulation using Multipolar Single-pulse Temporal Interference with Applications in Epilepsy

Temporal Interference (TI) is an emerging method to non-invasively stimulate deep brain structures. This innovative technique is increasingly recognized for its potential applications in the treatment of various neurological disorders, including epilepsy, depression, and Alzheimers disease. However, several drawbacks to the TI method exist that we aim to improve upon. To begin, the applied electric field in the TI target is not much higher than what non-invasive transcranial alternating current stimulation (TACS) provides in the cortex. Additionally, the TI stimulation onset is dependent on the envelope of the amplitude modulated (AM) signal, where for example 1 Hz and 100 Hz envelopes have significantly different rise times to reach maximum envelope amplitude - unlike square biphasic pulses. This limitation in turn prevents classic TI, from applying bursts of pulses. Finally, the electric field intensity of TI cannot be increased or decreased at the target without dramatically altering the spatial profile of the stimulation focus. In the work presented here, we efficiently address all three of these limitations. First, we performed two-photon calcium imaging to show that individual neurons selectively respond to the TI envelope frequency, providing evidence that TI modulates neural activity with temporal specificity. This marks a significant advancement, representing the first empirical demonstration of neuronal activation at the {Delta}f frequency within the context of TI and in an imaging modality. Subsequently, we compared the AM signals of TI with phase-shift keying (PSK) modulated signals to highlight the superior effectiveness of noninvasive pulses in contrast to the traditional TI method, particularly in inducing epileptic activity (after-discharges) in mice. We also added a multipolar configuration to create a significant increase in the electric field at the target without significantly altering the spatial profile and applied Fourier components to replicate classic biphasic bursts of square pulses - all transcranially, without the use of penetrating electrodes. These innovations aim to enhance the precision and efficacy of TI stimulation, to advance its application in neurological research and therapy. Key Points / HighlightsO_LINon-invasive temporal interference stimulation modulates the activity of individual neurons at the envelope frequency. C_LIO_LIA non-invasive multi-pulse TI stimulation paradigm improves both temporal and spatial focality in the deep target neural tissue when compared to traditional continuous wave (amplitude-modulated) TI stimulation. C_LIO_LIPulse TI paradigms can stimulate deep neural targets with reduced amplitude of the topical high-frequency stimulation, decreasing off-target stimulation when compared to continuous wave TI patterns. As a consequence, pulse TI stimulation reduces the risk of undesired side effects such as high-frequency conduction block in off-target tissues or cortical areas. C_LIO_LIBoth temporal and spatial focality of the TI stimulation pattern positively correlate with the efficacy of the stimulation to induce seizures in the mouse hippocampus. C_LI

neuroscience↗

bioRxiv2023

The Entrainment of the Substantia Nigra During Temporal Lobe Seizures is Dependent on the Seizure Onset Pattern

Temporal lobe (TL) epilepsy is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit and the structures composing the temporal lobe. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Evidence suggests that the network involved in temporal lobe seizure may depend on their onset and offset pattern but studies on the relationship between the patterns and extralimbic activity are limited. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe seizures induced in two nonhuman primates (NHP). The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then analyzed the three first and last seconds of the seizure as well as 3-second segments of recorded in pre-ictal and post-ictal periods and compared the changes based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that seizures with both low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase of HPC/SI coherence was similar for both type of onset, while the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This result suggests that the SN might be involved differently in the termination of the BS seizure pattern. This study constitutes the first demonstration of temporal lobe seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the seizure onset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure.

neuroscience↗