An organism's external environment is dynamic and ever-changing. Survival depends on an animal's ability to engage with its surroundings through adaptive and purpose driven movement. Organisms that rely on such movement are endowed with an internal sensory system, known as proprioception, which enables the precise detection and awareness of the body and its limbs in space. The principal receptors that give rise to this system are known as "proprioceptors", a unique population of peripheral sensory neurons embedded within skeletal muscle and tendons, referred to as muscle spindles and Golgi tendon organs, respectively. Over the years, advancements in cellular, molecular, and electrophysiological techniques have provided fundamental insight into the signaling pathways that regulate proprioceptor development. These same approaches have also facilitated the discovery of the ionic and neuromodulator mechanisms that regulate proprioceptor activity. In more recent years, emerging evidence suggests that proprioceptive feedback may engage in non-cell autonomous regulation of other physiological systems, potentially expanding their role beyond detectors of movement and force. In this review, we will examine the cellular and molecular mechanisms that govern the development and function of muscle spindle afferents. Furthermore, we will highlight their emerging influence on neurological and musculoskeletal disease.
Respiratory dysfunction is increasingly recognized as a clinically relevant yet underexplored feature of neurodegenerative diseases, particularly Parkinson’s disease (PD). Although traditionally defined by motor symptoms resulting from dopaminergic degeneration, PD also affects neural systems involved in autonomic and respiratory control. Clinical and experimental evidence demonstrates that respiratory impairments in PD include alterations in respiratory rhythm generation, chemosensitivity, ventilatory responses to hypoxia and hypercapnia, and sleep-related breathing regulation. Emerging data indicate that these disturbances are not merely secondary consequences of motor dysfunction, but instead reflect selective vulnerability of brainstem respiratory networks. In this review, we discuss current evidence from human studies and experimental models, with emphasis on circuit-level mechanisms underlying respiratory dysfunction in PD. We highlight how oxidative stress, neuroinflammation, and neuromodulatory alterations contribute to degeneration and dysfunction of respiratory-related nuclei. We further examine the complex interactions between chemosensory control, sleep-wake regulation, and respiratory stability, as well as compensatory mechanisms that may partially preserve ventilatory function during disease progression. Finally, we discuss potential treatments for these dysfunctions, as well as major conceptual gaps and controversies in the field, including species-dependent differences, limitations of current experimental models, and challenges in translating mechanistic findings into clinical interventions. We propose that respiratory control networks represent a mechanistically relevant and selectively vulnerable system in PD, with important implications for early diagnosis, biomarker discovery, and the development of targeted therapeutic strategies.
Tropical freshwater fishes evolved under historically stable thermal, oxygen, and chemical regimes that favored physiological specialization within narrow environmental ranges. Rapid climate warming is now compressing these already limited safety margins by simultaneously increasing metabolic demand, reducing oxygen availability, altering ionoregulatory balance, and intensifying exposure to pollutants. Evidence from Amazonian systems shows that physiological limits emerge from interacting constraints rather than single stressors, and that tolerance measured under controlled conditions often overestimates persistence in nature. As safety margins erode, energetic trade-offs propagate from molecular stress and metabolic disruption to impaired growth, reproduction, and population stability, ultimately altering ecosystem function. This integrative perspective reveals that vulnerability is defined not by absolute thermal limits alone, but by how multiple constraints accumulate and scale across levels of biological organization. Understanding these scaling relationships is essential for predicting resilience and for advancing physiology from documenting responses toward anticipating ecological outcomes in a rapidly warming world.
