Ethical Considerations in Animal Study Translation

动物研究翻译中的伦理考虑

• 批准号: 10790093
• 负责人: Paul D. Marasco
• 金额: $ 16万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-06 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790093
• 关键词: Address; Amputees; Animal Experimentation; Animal Model; Animals; Attention; Basic Science; Bioethics; Biomedical Research; Brain; Caliber; Characteristics; Clinical; Clinical Research; Code; Conflict of Interest; Consensus; Consent; Consent Forms; Data; Discipline; Disclosure; Disease; Electrophysiology (science); Enrollment; Environment; Esthesia; Ethics; Evaluation; Exhibits; Focal Dystonias; Foundations; Frequencies; Future; Genetic; Goals; Golgi Tendon Organs; Histologic; Human; Immunologics; Individual; Informed Consent; Intervention; Intervention Studies; Kinesthesis; Kinesthetic Illusions; Knowledge; Learning; Link; Liquid substance; Methodology; Modeling; Motor; Movement; Mus; Muscle; Muscle Contraction; Muscle Fibers; Muscle Spindles; Nature; Outcome; Parkinson Disease; Participant; Perception; Peripheral; Peripheral Nervous System Diseases; Phase; Population; Process; Property; Prosthesis; Protocols documentation; Questionnaires; Rattus; Reflex action; Reproducibility; Research; Research Personnel; Risk; Role; Science; Sensory; Sensory Receptors; Skeletal Muscle; Stimulus; Stroke; System; Translating; Translational Research; Translations; Uncertain Risk; Uncertainty; Work; clinical care; design; exposed human population; improved; innovation; motor control; motor deficit; musculoskeletal injury; neural; neural circuit; pre-clinical; pre-clinical research; preclinical study; preservation; prevent; prospective; public trust; receptor; research in practice; response; sensor; sensory stimulus; statistics; stroke model; success; translational study; vibration

Abstract The sense of movement (kinesthesia) provides an interoceptive internal readout of our physical actions in space and is essential for our ability to move fluidly and effectively through our environment. Despite kinesthesia’s importance in motor function and self-reference, our understanding of this sense is plagued by glaring knowledge gaps and inconsistencies. Movement sensations are traditionally believed to be a specialized function of type Ia muscle spindle afferents. Yet, the apparent disconnect between the peripheral coding properties of this receptor and the sensory stimuli known to evoke a sense of movement have raised questions regarding their primary role in kinesthesia. Although proprioceptive interventions provide functional motor improvements for many conditions such as stroke, Parkinson’s disease, focal dystonia, peripheral neuropathies, and musculoskeletal injuries, the lack of a clear scientific foundation for kinesthesia impacts our understanding of sensory-motor deficits and prevents important breakthroughs from translating into clinical successes and targeted intervention strategies. From our recent work we have multiple lines of evidence that suggest there may be sensory muscle receptors, outside of the traditional muscle spindles and Golgi tendon organs that exhibit features consistent with a kinesthetic sensor. First, our peripheral electrophysiological recordings in rat demonstrate a population of fast- conducting rapidly-adapting afferents, that are distinct from muscle spindle and Golgi tendon organ afferents, yet are selectively activated in the frequency bandwidth associated with kinesthetic illusions. Second, our immunological analyses in mouse skeletal muscle reveal a new population of large caliber Calbindin28k+ afferents that do not associate with muscle spindle or Golgi tendon organ receptors but instead terminate in free endings that spread out alongside extrafusal muscle fibers. In a movement-perception study with human neural- machine interface amputees, we found that vibration-induce illusory kinesthetic percepts were linked to muscle contraction not elongation. These results were corroborated in a human stroke model where we amplified kinesthetic perception linked to active muscle contraction which resulted in improved reaching trajectories. With these observations we hypothesize that there are candidate muscle sensory afferents, distinct from type Ia afferents, which selectively respond to muscle fiber contraction. The studies in this proposal will explore the relationships between the response properties and physical characteristics of these candidate kinesthetic receptors and the traditionally defined muscle sensory receptors using genetic, histological, and electrophysiological approaches. Additionally, we will examine this systems functionality with respect to contractile features and its ability to serve as a stimulus for active movement sensing. The discovery and evaluation of the cellular basis of kinesthesia will fundamentally transform our understanding of sensory-motor control and, by extension, will impact design strategies for advanced neural-machine interface prosthetic devices for amputees, as well as other disorders with sensory-motor deficiencies such as stroke.

摘要

项目成果

Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

• DOI: 10.1146/annurev-physiol-040122-081302
• 发表时间: 2023-02-10
• 期刊: Annual review of physiology
• 影响因子: 18.2