The Mechanisms Underlying Sigh Generation in the PreBötzinger Complex are Dependent on Neuroglial Interactions

Abstract

Rhythm generation is a vital component of life. Rhythmic activity regulates the circadian clock, which controls hormonal cycles, sleep wake states, blood pressure, body temperature, and reaction times. Rhythmogenesis underlies breathing and produces several behaviors -such as eupnea, sighs, and gasps- that are critical to everyday life. Moreover, rhythmic oscillations have emerged throughout the brain that link these coordinated activities together. Gaining a better understanding of rhythm generation and the underlying cell activities that make up these behaviors can help to provide a better understanding of many diseases which originate from the disruption of these cycles. The breathing networks in the medulla are a fantastic model system for studying rhythm generation. These areas maintain their intrinsic rhythm generating properties in vitro for extended periods of time, providing valuable insight into how individual cells and ion channels contribute to producing complex breathing behaviors. The preBötzinger Complex (preBötC) in the ventral-lateral medulla is one of these rhythmogenic circuits. Within this circuit, three behaviors necessary for normal breathing arise- normal breathing ‘eupnea’, sighing, and gasping. This thesis primarily focuses on the generation of the sigh rhythm.Sighing is a critical element of normal breathing that has vital physiological functions. Sighs are deep augmented breaths that are critical for survival as they prevent collapse of the lungs, clinically referred to as atelectasis, by re-inflating collapsed alveoli. Furthermore, during sleep, sighs trigger arousal to hypoxic conditions and are more common during REM sleep and transitions between different sleep states. Indeed, reduced sighing has been reported in infants who have died from sudden infant death syndrome (SIDS). Sighing is also linked to higher-order brain function and emotions such as love, stress, exasperation, and is clinically tied to several anxiety disorders. These ‘augmented breaths’ occur at a rate of ~12 per hour in adults and much more frequently in infants. Sighs often occur as a superimposed burst overlaying the ongoing eupneic burst, giving the sigh its characteristic biphasic shape. Eupnea consists of three primary phases: inspiration, postinspiration, and active expiration, each hypothesized to be generated by an excitatory rhythmogenic microcircuit in the ventral lateral medulla. Evidence suggests that eupneic inspiration, gasping, and sighing are generated by the same breathing circuit, the preBötC. Yet, how the same neural circuit gives rise to two distinct rhythmic activities with separate timing characteristics remains unknown. The primary directive of this thesis is to provide a novel hypothesis for sigh generation.