Title: Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus
Abstract Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3–12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion. more »« less
Hippocampal network activity at theta frequencies (5-10Hz) is important for behavior. However, it remains unclear how behaviorally-relevant network theta rhythms arise and interact with cellular dynamics to dictate spike timing. We performed membrane voltage (Vm) imaging of individual CA1 pyramidal cells and parvalbumin interneurons with simultaneous local field potential (LFP) recordings in mice during locomotion. We found that Vm theta rhythms organize spike timing in both cell types regardless of behavioral conditions, but the Vm of parvalbumin interneurons is better synchronized with LFP. The temporal relationships between spikes and LFP theta reliably reflect the Vm-LFP relationships in parvalbumin cells, but not in pyramidal cells. Thus, cellular theta rhythms broadly organize spike timing in CA1 neurons, and parvalbumin interneurons are critical in coordinating network theta rhythms.
One-Sentence Summary
Cellular membrane voltage of parvalbumin interneurons organizes spiking and network dynamics in the hippocampus.
Rhythmic neural network activity has been broadly linked to behavior. However, it is unclear how membrane potentials of individual neurons track behavioral rhythms, even though many neurons exhibit pace-making properties in isolated brain circuits. To examine whether single-cell voltage rhythmicity is coupled to behavioral rhythms, we focused on delta-frequencies (1–4 Hz) that are known to occur at both the neural network and behavioral levels. We performed membrane voltage imaging of individual striatal neurons simultaneously with network-level local field potential recordings in mice during voluntary movement. We report sustained delta oscillations in the membrane potentials of many striatal neurons, particularly cholinergic interneurons, which organize spikes and network oscillations at beta-frequencies (20–40 Hz) associated with locomotion. Furthermore, the delta-frequency patterned cellular dynamics are coupled to animals’ stepping cycles. Thus, delta-rhythmic cellular dynamics in cholinergic interneurons, known for their autonomous pace-making capabilities, play an important role in regulating network rhythmicity and movement patterning.
Ultrasound has been used to manipulate cells in both humans and animal models. While intramembrane cavitation and lipid clustering have been suggested as likely mechanisms, they lack experimental evidence. Here, high‐speed digital holographic microscopy (kiloHertz order) is used to visualize the cellular membrane dynamics. It is shown that neuronal and fibroblast membranes deflect about 150 nm upon ultrasound stimulation. Next, a biomechanical model that predicts changes in membrane voltage after ultrasound exposure is developed. Finally, the model predictions are validated using whole‐cell patch clamp electrophysiology on primary neurons. Collectively, it is shown that ultrasound stimulation directly defects the neuronal membrane leading to a change in membrane voltage and subsequent depolarization. The model is consistent with existing data and provides a mechanism for both ultrasound‐evoked neurostimulation and sonogenetic control.
Rho, Young-Ah; Sherfey, Jason; Vijayan, Sujith(
, The Journal of Neuroscience)
REM sleep is important for the processing of emotional memories, including fear memories. Rhythmic interactions, especially in the theta band, between the medial prefrontal cortex (mPFC) and limbic structures are thought to play an important role, but the ways in which memory processing occurs at a mechanistic and circuits level are largely unknown. To investigate how rhythmic interactions lead to fear extinction during REM sleep, we used a biophysically based model that included the infralimbic cortex (IL), a part of the mPFC with a critical role in suppressing fear memories. Theta frequency (4–12 Hz) inputs to a given cell assembly in IL, representing an emotional memory, resulted in the strengthening of connections from the IL to the amygdala and the weakening of connections from the amygdala to the IL, resulting in the suppression of the activity of fear expression cells for the associated memory. Lower frequency (4 Hz) theta inputs effected these changes over a wider range of input strengths. In contrast, inputs at other frequencies were ineffective at causing these synaptic changes and did not suppress fear memories. Under post-traumatic stress disorder (PTSD) REM sleep conditions, rhythmic activity dissipated, and 4 Hz theta inputs to IL were ineffective, but higher-frequency (10 Hz) theta inputs to IL induced changes similar to those seen with 4 Hz inputs under normal REM sleep conditions, resulting in the suppression of fear expression cells. These results suggest why PTSD patients may repeatedly experience the same emotionally charged dreams and suggest potential neuromodulatory therapies for the amelioration of PTSD symptoms. SIGNIFICANCE STATEMENT Rhythmic interactions in the theta band between the mPFC and limbic structures are thought to play an important role in processing emotional memories, including fear memories, during REM sleep. The infralimbic cortex (IL) in the mPFC is thought to play a critical role in suppressing fear memories. We show that theta inputs to the IL, unlike other frequency inputs, are effective in producing synaptic changes that suppress the activity of fear expression cells associated with a given memory. Under PTSD REM sleep conditions, lower-frequency (4 Hz) theta inputs to the IL do not suppress the activity of fear expression cells associated with the given memory but, surprisingly, 10 Hz inputs do. These results suggest potential neuromodulatory therapies for PTSD.
The hippocampus contains rich oscillatory activity, with continuous ebbs and flows of rhythmic currents that constrain its ability to integrate inputs. During associative learning, the hippocampus must integrate inputs from a range of sources carrying information about events and the contexts in which they occur. Under these circumstances, temporal coordination of activity between sender and receiver is likely essential for successful communication. Previously, it has been shown that the coordination of rhythmic activity between the lateral entorhinal cortex (LEC) and the CA1 region of the hippocampus is tightly correlated with the onset of learning in an associative learning task. We aimed to examine whether rhythmic inputs from the LEC in specific frequency ranges were sufficient to enhance the temporal coordination of activity in downstream CA1. In urethane‐anesthetized rats, we applied extracellular low‐intensity alternating current stimulation across the length of the LEC. Using this method, we aimed to phase‐bias ongoing neuronal activity in LEC at a range of different frequencies (from 1.25 to 55 Hz). Rhythmic stimulation of LEC at both 35 and 50 Hz increased the proportion of CA1 neurons significantly entrained to the phase of the applied stimulation current. A subset of stimulation frequencies modified CA1 spiking relationships to the phase of local ongoing CA1 oscillations, with each stimulation frequency exerting a unique influence upon downstream CA1, often in frequency ranges outside the target stimulation frequency. These results suggest there are optimal frequencies for LEC–CA1 communication, and that different profiles of LEC rhythms likely have distinct outcomes upon CA1 processing.
Lowet, Eric, Kondabolu, Krishnakanth, Zhou, Samuel, Mount, Rebecca A., Wang, Yangyang, Ravasio, Cara R., and Han, Xue. Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus. Retrieved from https://par.nsf.gov/biblio/10385703. Nature Communications 13.1 Web. doi:10.1038/s41467-022-35314-1.
Lowet, Eric, Kondabolu, Krishnakanth, Zhou, Samuel, Mount, Rebecca A., Wang, Yangyang, Ravasio, Cara R., and Han, Xue.
"Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus". Nature Communications 13 (1). Country unknown/Code not available. https://doi.org/10.1038/s41467-022-35314-1.https://par.nsf.gov/biblio/10385703.
@article{osti_10385703,
place = {Country unknown/Code not available},
title = {Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus},
url = {https://par.nsf.gov/biblio/10385703},
DOI = {10.1038/s41467-022-35314-1},
abstractNote = {Abstract Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3–12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.},
journal = {Nature Communications},
volume = {13},
number = {1},
author = {Lowet, Eric and Kondabolu, Krishnakanth and Zhou, Samuel and Mount, Rebecca A. and Wang, Yangyang and Ravasio, Cara R. and Han, Xue},
}
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