Saturday, November 23, 2024
11/23/2024
Project Summary The integration of brain, breathing and the heart is vital to meet the continuously changing metabolic and behavioral demands of an organism. Consequently, disorders of breathing are rarely limited to breathing disturbances and typically also include disturbances in cardiorespiratory coupling and arousal. Failure to arouse can lead to SIDS, while the ability to gasp and arouse is a reliable predictor for a positive long-term outcome after cardiac arrest. On the other hand, frequent arousals in obstructive sleep apnea result in sleep disturbances. However, understanding, how the neuronal control of breathing is integrated within the wider nervous system to control arousal and autonomic motor outputs has been challenging since this requires a broader understanding of respiratory rhythmogenesis, cardiorespiratory coupling and the ascending and descending control of the arousal network. This grant will use cutting-edge molecular, genomic and systems level approaches to obtain a detailed understanding of the connectomes that integrate the respiratory network with the arousal network. The recently developed Neuropixel approach enabled us to record from thousands of neurons across the CNS which includes the ventral respiratory column (VRC). Recordings obtained in urethane anesthetized freely breathing mice reveal that the activity of expiratory and inspiratory neurons along the entire VRC gives rise to rotational population dynamics which gradually transitions from expiration into inspiration before the respiratory cycle terminates in the inspiration off-switch. Since expiratory activity is largely absent in isolated in vitro preparations, Aim 1 will test the hypothesis that the generation of expiratory activity in vivo requires afferent input from the lungs. We will explore how mechanosensory input controls eupneic breathing by combining lung inflations with optogenetic stimulations of neurons located in the VRC and nucleus tractus solitarius (NTS). Aim 2 will explore the reconfiguration of the respiratory network as it transitions from eupnea into gasping. Due to a loss of expiratory activity, the respiratory network dynamically extends rostrally to generate inspiratory-phased VRC population activity. We hypothesize that this spatial extension recruits the arousal network. Aim 3 studies the gasping-induced activation of the arousal network and the effects of vagal stimulations in alert and behaving animals to test the hypothesis that the arousal network is reciprocally connected with a network that decreases anxiety. Neuropixel recordings from the medial prefrontal cortex (mPFC), the Locus coeruleus (LC), parabrachial complex (PB) and basal forebrain (BF) will be combined with targeted opto- and chemogenetic approaches to gain first insights into the emotional control of breathing.
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