Biology subjects

Berglund, K.

Publications and source records attributed to Berglund, K..

8 recordsLinked to original sources

bioRxiv2026

Kilohertz electrical stimulation drives widespread neuronal activation and temporal interference imposes focal rhythmic modulation

Temporal interference (TI) stimulation has attracted attention as a non-invasive approach that can target deep brain structures through interacting kilohertz-frequency electric fields. Its basic premise is that TI stimulation evokes neuronal responses through low-frequency amplitude modulation (AM), while the underlying kilohertz-frequency stimulation is ineffective to induce activity, the latter of which has not been tested rigorously at the cellular level. Here, we combined two-photon imaging in mouse models with immunohistochemistry and computational modeling to characterize spatiotemporal patterns of neuronal responses during TI stimulation. We found that kilohertz-frequency stimulation was sufficient to evoke activity without AM. In contrast, AM organized neuronal activity into rhythmic responses at AM frequency, with the strongest entrainment near the center of interference. Thus, kilohertz-frequency stimulation can drive widespread neuronal activation, upon which TI imposes focal rhythmic modulation. Our results provide a framework for refining TI stimulation and highlight the potential of kilohertz-frequency stimulation for brain stimulation.

neuroscience↗

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

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

Seizure event detection using intravital two-photon calcium imaging data

SignificanceGenetic cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging. AimTo demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging - including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population-level activity and that of individual cells. ApproachWe developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awake in vivo two-photon calcium imaging during pentylenetetrazol induced seizures in mice. ResultsWe demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves. ConclusionsOur algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.

neuroscience↗

bioRxiv2022

Chronic activation of dopaminergic neurons via bioluminescence-optogenetics provides neuroprotection in a rodent model of Parkinson's disease

Previous studies in human patients and rodent models of Parkinsons disease (PD) have established neuroprotection of dopaminergic (DA) neurons in substantia nigra pars compacta (SNC) by physical exercise, but the precise origin of this neuroprotective effect has yet to be elucidated. In this study, we tested a hypothesis that enhanced activity of DA neurons in SNC results in neuroprotection using the unilateral 6-hydroxydopamine (6-OHDA) injection model in mice. To increase activity of DA neurons chronically and specifically, we injected an adeno-associated viral vector carrying a step-function luminopsin (SFL) - a fusion protein of light-emitting Gaussia luciferase and light-sensing step-function channelrhodopsin 2 - into SNC ipsilateral to 6-OHDA using the pan-neuronal human synapsin I promoter or the Cre-lox system in transgenic mice expressing the recombinase under control of the tyrosine hydroxylase (TH) promoter. Upon application of SFL substrate, coelenterazine (CTZ), the luciferase moiety of luminopsin emits bioluminescence which in turn activate the opsin moiety. Daily injection of CTZ for 4 weeks ameliorated a stereotypical behavior, namely ipsiversive rotations, induced by unilateral 6-OHDA. In addition, postmortem immunohistochemistry against TH revealed less severe neurodegeneration of DA neurons compared to vehicle-injected control animals. Furthermore, when mice were pretreated with ANA-12, a selective antagonist for tropomyosin receptor kinase B (TrkB), the behavioral improvement and neuroprotective effect were diminished. These results suggest that increased neuronal activity of DA neurons provides neuroprotection against 6-OHDA injury and alleviates its symptoms through the brain-derived neurotrophic factor-TrkB pathway.

neuroscience↗

bioRxiv2021

Kinetic Monitoring Of Neuronal Stress Response To Proteostasis Dysfunction

Proteostasis dysfunction and activation of the unfolded protein response (UPR) are characteristic of all major neurodegenerative diseases. Nevertheless, although the UPR and proteostasis dysfunction has been studied in great detail in model organisms like yeast and mammalian cell lines, it has not yet been examined in neurons. In this study, we applied a viral vector-mediated expression of a reporter protein based on a UPR transcription factor, ATF4, and time-lapse fluorescent microscopy to elucidate how mouse primary neurons respond to pharmacological and genetic perturbations to neuronal proteostasis. In in vitro models of endoplasmic reticulum (ER) stress and proteasome inhibition, we used the ATF4 reporter to reveal the time course of the neuronal stress response relative to neurite degeneration and asynchronous cell death. We showed how potential neurodegenerative disease co-factors, ER stress and mutant -synuclein overexpression, impacted neuronal stress response and overall cellular health. This work therefore introduces a viral vector-based reporter that yields a quantifiable readout suitable for non-cell destructive kinetic monitoring of proteostasis dysfunction in neurons by harnessing ATF4 signaling as part of the UPR activation.

cell biology↗