Breathing Rhythm and Pattern and Their Influence on Emotion

Abstract

Breathing is a vital rhythmic motor behavior with a surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies a complex neural control system, the breathing central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange and coordinate breathing with an array of behaviors. In this review, we focus on selected advances in our understanding of the bCPG. At the core of the bCPG is the preBötzinger complex (preBötC), which drives inspiratory rhythm via an unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue the system with robustness and lability. These dynamics are modulated by inputs from throughout the brain and generate rhythmic, patterned activity that is widely distributed. The connectivity and an emerging literature support a link between breathing, emotion, and cognition that is becoming experimentally tractable. These advances bring great potential for elucidating function and dysfunction in breathing and other mammalian neural circuits.

Keywords: central pattern generators; emotion; motor systems; network dynamics; preBötzinger complex; synchrony.

Figure 1

Structural and functional organization of neural circuits controlling breathing. (a) Myriad physiological and neural functions feed information through a variety of structures into the bCPG to control breathing and respiratory-related behaviors (orange). At the core of the bCPG is the preBötC, which generates inspiratory rhythm and initiates inspiratory patterning and where approximately half of preBötC neurons are Dbx1-derived Glu neurons (light blue), while the other half are Gly/GABAergic (gray). Reciprocal connections between many bCPG structures produce the pattern of breathing and other respiratory-related behaviors. Molecular markers for some bCPG structures and their subpopulations are identified. bCPG activity is transmitted to a variety of muscles and other brainstem and suprapontine circuits to mediate or modulate many behaviors (green). Neuromodulators and peptides as well as a number of diseases (brown) (Supplemental Appendix, Note 1) may modify or alter bCPG function. (b, left) preBötC receives afferent input from brainstem and suprapontine sites (dark red). (Right) SST⁺ (purple), GlyT2⁺ (green), and Cdh9 (via LC, orange) preBötC neurons project throughout the brain to relay breathing information directly (solid lines) or indirectly (dotted lines) to higher-order brain regions with some connected reciprocally. Note that all boundaries and projections are schematic and not intended to represent actual anatomical localization or relationships between neuronal populations, regions, or connections. Abbreviations: Arc, arcuate nucleus; bCPG, breathing central pattern generator; BNST, bed nucleus of the stria terminalis; CCHS, congenital chronic hypoventilation syndrome; Cdh9, cadherin-9; CeA, central amygdala; CL, central medial thalamus; Ctx, cortex; cVRG, caudal ventral respiratory group; Dbx1, developing Brain Homeobox Protein 1; DMH, dorsomedial hypothalamus; Glu, glutamatergic; Gly, glycinergic; GRP, gastrin-releasing peptide; IC, inferior colliculus; KF, Kölliker-Fuse; LC, locus coeruleus; LH, lateral hypothalamus; LPO, lateral preoptic area; MDL, medial dorsal thalamus; MN, motoneuron; MPO, medial preoptic area; NE, norepinephrine; NMB, neuromedin B; NTS, nucleus of the solitary tract; OIRD, opioid-induced respiratory depression; PACAP, pituitary adenylate-cyclase-activating polypeptide; PaF, parafascicular thalamus; PAG, periaqueductal gray; PaH, paraventricular hypothalamus; PBN, parabrachial nucleus; pF_v, parafacial ventral; Phox2b, paired Like Homeobox 2B; preBötC, preBötzinger complex; RN, red nucleus; rVRG, rostral ventral respiratory group; SC, superior colliculus; SIDS, sudden infant death syndrome; SNR, substantia nigra; SST, somatostatin; SUDEP, sudden unexpected death in epilepsy; TRH, thyrotropin-releasing hormone; VIIn, facial nucleus; VRG, ventral respiratory group; XIIn, hypoglossal nucleus/nerve; ZI, zona incerta.

Figure 2

Burstlets point to an emergent rhythmogenic mechanism in preBötzinger complex (preBötC). (a, top) Lowering excitability elicits bilaterally synchronous burstlets (cyan asterisks) and bursts in simultaneous in vitro recordings of hypoglossal (XII) nerve roots (gray) and ipsi- and contralateral preBötC (black) population activity. (Bottom) Small bursts (cyan asterisk) between inspiratory bursts that resemble leak through of burstlets observed in vitro can be observed following injections of excitants in in vivo recordings of airflow and diaphragm electromyograms (EMGs) in anesthetized, vagotomized adult rats. (b) Average burstlet and burst from preBötC and XII population recordings in vitro along with a cell-attached recording of a preBötC neuron, showing representative firing and raster plots during burstlets (cyan) and bursts (teal-aquamarine), where each line of each column represents action potentials of the recorded neuron during instances of burstlets and bursts. (c, top) Superimposed average waveforms of XII bursts and preBötC burstlets and bursts during endogenous rhythm in vitro indicate significant overlap in burstlets (cyan) and the preinspiratory rising phase (teal-aquamarine) of bursts. (Bottom) Sample of XII inspiratory bursts in vitro is shown as a function of number of neurons stimulated by holographic photolysis of caged glutamate. (d,e) The μ-opioid receptor agonist DAMGO depresses the frequency of burstlet-burst rhythms, elicited by lowered excitability (d), and burstlet-only rhythms, elicited by low Cd²⁺ (e), consistent with burstlet theory. Panels a–d adapted from Kam et al. (2013a,b); panel e adapted from Sun et al. (2019).

Figure 3

preBötzinger complex (preBötC) synchronization, gated by background excitation-inhibition (Exc-Inh) balance, drives rhythmicity. (a, b) Connection scheme (legend at bottom left) with firing pattern of rhythmogenic neurons, membrane potential (V_m), and time-frequency decomposition of the V_m trajectory from an output neuron (red) recorded in vitro. (a) When background Exc-Inh balance is tilted toward Inh, rhythmogenic neurons (cyan) spike spontaneously but fail to synchronize, so no collective rhythmicity emerges in the preBötC, as revealed by the power spectra, which exhibit disconnected color patches (increased power) in the low-frequency range of 4–8 Hz. Due to asynchronous inputs, the V_m of output neurons does not cross threshold or generate network output. (b, i) When the background Exc-Inh balance tilts toward Exc, recurrently connected rhythmogenic neurons begin to synchronize, facilitating preBötC burstlet rhythm. Output neurons show a significant increase in low-frequency (4–8 Hz) activity during a burstlet, which reflects emerging synchronization in preBötC resulting in increased synaptic drive onto output neurons. Nascent synchronization at this stage does not cross the tipping point to propagate to (pre)motoneurons (green) to elicit a motor output. (ii) Further shift of background Exc-Inh balance enhances the ability of rhythmogenic neurons to synchronize strongly. Synaptic inputs onto output neurons show a progressive increase in power from low to higher frequencies (4–64 Hz) as the network assembles from preinspiration to the inspiratory burst. When network synchrony crosses the tipping point, the output neuron crosses a threshold (Thr), and an inspiratory burst occurs; activity during the burst propagates to motor output. Here, the burstlet is recognized as preinspiratory activity because it leads inexorably to the inspiratory burst. White contours in the spectrograms in subpanels i and ii enclose regions with significantly increased power as compared to the control in panel a at 95% confidence level. (c) Simultaneous recordings from pairs of output neurons (red traces) illustrate synchronization of their synaptic inputs via their pairwise excitatory postsynaptic potential (EPSP) correlograms (right) as the cycle evolves from interburst interval (➀) to preinspiratory (➁) to inspiratory burst (➂) phases. Spectrograms adapted from Ashhad & Feldman (2020).

Figure 4

Breathing influences cognition and emotion through global entrainments of interacting brain circuits. (a) Forebrain regions involved in cognition/emotion, for example, PFC, amygdala, and hippocampus, can be modulated by breathing signals from a variety of sources. (b) The global breathing rhythm modulates behavior through entrainment of local neuronal dynamics and breathing-locked LFPs across several brain regions on a cycle-by-cycle basis (left) and through plasticity affected by breathing practices (right). Note that all boundaries and projections are schematic and not intended to represent the actual anatomical localization or relationship between neuronal populations, regions, or connections. Abbreviations: BLA, basolateral amygdala; Ctx, cortex; KF/PBN, Kölliker-Fuse/parabrachial nucleus; LFP, local field potential; M1/S1, primary sensorimotor cortex; NAc, nucleus accumbens; OB, olfactory bulb; PFC, prefrontal cortex; Thal, thalamus.