Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

Yang, Yaoheng; Field, Rachael L.; Ye, Dezhuang; Hu, Zhongtao; Xu, Kevin; Xu, Lu; Gong, Yan; Yue, Yimei; Kravitz, Alexxai V.; Bruchas, Michael R.; Cui, Jianmin; Brestoff, Jonathan R.; Chen, Hong

doi:10.1038/s42255-023-00804-z

Cited by 25 publications

(17 citation statements)

References 61 publications

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“…For example, researchers in the Wang group have leveraged an ultrasound-responsive nanomaterial to improve upon the temporal resolution of chemogenetics, opening new opportunities in the field of “sono-chemogenetics.” In a recent publication, the Konofagou group has demonstrated the immunomodulatory effect of focused ultrasound on the blood–brain barrier opening, implying the possibility of focused ultrasound as a treatment for neurological disease . The Chen group has also demonstrated exciting applications of focused ultrasound in the brain through the ultrasound-mediated regulation of hypothermia and hypometabolism for the induction of a torpor-like state in mice . These advancements in neuromodulation technology enabled by force underscore the expanding potential and future growth of force as an ideal modality for brain interfacing.…”

Section: Discussionmentioning

confidence: 99%

Force-Based Neuromodulation

Cooper,

Malinao,

Hong

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Technologies for neuromodulation have rapidly developed in the past decade with a particular emphasis on creating noninvasive tools with high spatial and temporal precision.The existence of such tools is critical in the advancement of our understanding of neural circuitry and its influence on behavior and neurological disease. Existing technologies have employed various modalities, such as light, electrical, and magnetic fields, to interface with neural activity. While each method offers unique advantages, many struggle with modulating activity with high spatiotemporal precision without the need for invasive tools. One modality of interest for neuromodulation has been the use of mechanical force. Mechanical force encapsulates a broad range of techniques, ranging from mechanical waves delivered via focused ultrasound (FUS) to torque applied to the cell membrane. Mechanical force can be delivered to the tissue in two forms. The first form is the delivery of a mechanical force through focused ultrasound. Energy delivery facilitated by FUS has been the foundation for many neuromodulation techniques, owing to its precision and penetration depth. FUS possesses the potential to penetrate deeply (∼centimeters) into tissue while maintaining relatively precise spatial resolution, although there exists a trade-off between the penetration depth and spatial resolution. FUS may work synergistically with ultrasound-responsive nanotransducers or devices to produce a secondary energy, such as light, heat, or an electric field, in the target region. This layered technology, first enabled by noninvasive FUS, overcomes the need for bulky invasive implants and also often improves the spatiotemporal precision of light, heat, electrical fields, or other techniques alone. Conversely, the second form of mechanical force modulation is the generation of mechanical force from other modalities, such as light or magnetic fields, for neuromodulation via mechanosensitive proteins. This approach localizes the mechanical force at the cellular level, enhancing the precision of the original energy delivery. Direct interaction of mechanical force with tissue presents translational potential in its ability to interface with endogenous mechanosensitive proteins without the need for transgenes.In this Account, we categorize force-mediated neuromodulation into two categories: 1) methods where mechanical force is the primary stimulus and 2) methods where mechanical force is generated as a secondary stimulus in response to other modalities. We summarize the general design principles and current progress of each respective approach. We identify the key advantages of the limitations of each technology, particularly noting features in spatiotemporal precision, the need for transgene delivery, and the potential outlook. Finally, we highlight recent technologies that leverage mechanical force for enhanced spatiotemporal precision and advanced applications.

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Section: Discussionmentioning

confidence: 99%

Force-Based Neuromodulation

Cooper,

Malinao,

Hong

2024

Acc. Chem. Res.

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“…In addition, the transcranial ultrasound wave can be focused to concentrate its acoustic energy in the target region, offering unique applications to modifying specific brain circuits with high spatiotemporal regulation. Indeed, a recent study has demonstrated that transcranial focused ultrasound stimulates the hypothalamus preoptic area via TRPM2 channels and causes torpor-like hypothermic and hypometabolic states in rodents (39), promising the feasibility of ultrasound neuromodulation of deep brain circuits in living animals. Furthermore, growing evidence has highlighted the conceptual advance of sonogenetics, and an approach to utilizing genetically encoded ultrasound-responsive mechanosensitive molecules for control of neural activity of genetically defined neuronal population, as a next-generation neuromodulation technology (9,22,40).…”

Section: Discussionmentioning

confidence: 99%

TRPC6 is a mechanosensitive channel essential for ultrasound neuromodulation in mammalian brain

Matsushita,

Yoshida,

Yoshiya

et al. 2024

Preprint

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Ultrasound neuromodulation has become an innovative technology that enables non-invasive intervention in mammalian brain circuits with high spatiotemporal precision. Despite the expanding utility of ultrasound neuromodulation in the neuroscience research field and clinical applications, the molecular and cellular mechanisms by which ultrasound impacts neural activity in the brain are still largely unknown. Here, we report that transient receptor potential canonical 6 (TRPC6), a mechanosensitive non-selective cation channel, is essential for ultrasound neuromodulation of mammalian neuronsin vitroandin vivo. We first demonstrated that ultrasound irradiation elicited rapid and robust Ca2+transients mediated via extracellular Ca2+influx in cultured mouse cortical and hippocampal neurons. Ultrasound-induced neuronal responses were massively diminished by blocking either the generation of action potential or synaptic transmission. Importantly, both pharmacological inhibition and genetic deficiency of TRPC6 almost completely abolished neuronal responses to ultrasound. Furthermore, we found that intracerebroventricular administration of a TRPC6 blocker significantly attenuated the population of neuronal firings in the cerebral cortex evoked by transcranial ultrasound irradiation in mice. Our findings indicate that TRPC6 is an indispensable molecule of ultrasound neuromodulation in the intact mammalian brains, providing fundamental understanding of biophysical molecular mechanisms of ultrasound neuromodulation as well as insight into its future feasibility in neuroscience and translational researches in humans.

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“…Particularly, it is possible that TRPM2 mediates part of its effect via the hypothalamic preoptic area (POA), a temperature sensitive brain region involved in body temperature regulation (51). Preoptic TRPM2 has been shown to mediate autonomic thermoregulatory responses upon warmtemperature stimulation (52)(53)(54). Preoptic temperature pathways may not only drive autonomic thermoregulatory responses, but can also influence temperature preference behaviour (27,51).…”

Section: Discussionmentioning

confidence: 99%

Diverging roles of TRPV1 and TRPM2 in warm-temperature detection

El Hay,

Kamm,

Tlaie

et al. 2023

Preprint

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The accurate perception of innocuous temperatures, particularly those experienced as pleasantly warm, is essential for achieving thermal comfort and maintaining thermoregulatory balance. Warm-sensitive neurons (WSN) innervating the skin play a central role in non-painful warmth detection. The TRP ion channels TRPV1 and TRPM2 have been suggested as sensors of warm temperature in WSNs. However, the precise contribution of these channels to the process of warmth detection is not fully understood.A significant challenge in analysing WSNs lies in their scarcity: fewer than 10 % of sensory neurons in the rodent dorsal root ganglion (DRG) respond to innocuous warm temperatures. In this study, we examined >20,000 cultured mouse DRG neurons using calcium imaging and discovered distinct contributions of TRPV1 and TRPM2 to warm-temperature sensitivity. TRPV1 and TRPM2 affect the abundance of WSNs, with TRPV1 mediating the rapid, dynamic response to warmth.By carefully tracking animal movement in a whole-body thermal preference paradigm, we observe that these cellular differences correlate with nuanced thermal behaviours. Utilizing a driftdiffusion model to quantitatively analyse the decision-making process of animals exposed to different environmental temperatures, we found that: TRPV1 primarily impairs the precision of evidence accumulation, whereas TRPM2 significantly increases the total duration of exposure to uncomfortably warm environments.Our findings provide valuable insights into the distinct molecular responses to warmth stimuli, and underpin the subtle aspects of thermal decision-making when encountering minor temperature variations.

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Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

Cited by 25 publications

References 61 publications

Force-Based Neuromodulation

Force-Based Neuromodulation

TRPC6 is a mechanosensitive channel essential for ultrasound neuromodulation in mammalian brain

Diverging roles of TRPV1 and TRPM2 in warm-temperature detection

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