Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives
Introduction
Rhythmicity is involved in almost all behaviors and brain functions [1••, 2]. This includes the generation of rhythmic behaviors, communication, encoding, attention, learning and memory [3, 4]. Thus, understanding rhythmogenesis is a core issue in neuroscience. Rhythmogenesis can be studied in microcircuits isolated from invertebrates [5, 6], mammalian [7•, 8•, 9, 10, 11•, 12], and non-mammalian vertebrates [13, 14••, 15•, 16] as well as fully integrated behavioral systems [17••, 18, 19, 20, 21•, 22, 23]. Yet, the quest to unravel the mechanisms underlying rhythmogenesis has been a difficult journey. Concepts developed using intact systems have often conflicted with those obtained from isolated networks. In particular in mammalian studies, some discrepancies have been attributed to developmental differences, since many in vivo studies were conducted in adults, while in vitro experiments have often been limited to neonates [24•], a difficulty that can be overcome by studying non-mammalian model systems [25•].
Mechanisms commonly found in rhythm generating networks include reciprocal inhibition [26•, 27, 28], rhythmic pacemaker properties [11•, 29, 30, 31, 32, 33] and recurrent excitatory network mechanisms [10, 34•, 35, 36•]. However, their roles within a given network vary and are often different than originally hypothesized. We learned that the relative contribution of neuronal mechanisms is not fixed, but dynamically regulated, resulting in state-dependent reconfiguration of neuronal networks [37, 38, 39, 40]. Mechanisms that are essential in one condition can become non-essential contributors in another state even within the same network [41].
This review will discuss the mechanisms underlying rhythm generation in a variety of brain networks with a focus on the respiratory rhythm-generating network. This network has well-defined physiological roles and it is amenable to a rigorous cellular analysis [17••, 42, 43, 44]. Moreover, the respiratory rhythm is integrated with the activity of numerous networks distributed throughout the brainstem and forebrain [45•, 46]. A comparative approach among vertebrates may provide important insights into how multiple rhythmic circuits become functionally intertwined to produce and coordinate ventilatory and non-ventilatory behaviors. By unraveling the complexities of the breathing rhythm, we may also gain insights into rhythmicity involved in other CNS functions ranging from locomotion to memory and emotion.
Section snippets
Rhythm generating networks and the role of synaptic inhibition
Most rhythm generating networks are heterogeneous, consisting of silent, tonic and rhythmically bursting neurons (Figure 1a) [2, 47]. Neurons endowed with these discharge patterns form the building blocks of neuronal networks and are often incorporated into computational models. One of those models, the so-called half-center oscillator (HCO) was one of the first models to mechanistically explain rhythmogenesis [48, 49, 50] and has been particularly influential. In this model, two non-rhythmic
The role of excitatory mechanisms in rhythm generation
The critical role of synaptic excitation within the respiratory network has never been questioned. Two principle rhythmogenic mechanisms have been proposed for excitatory networks in general: (1) Interconnected endogenous bursting, pacemaker neurons: In its extreme, the temporal characteristics of amplitude and period are defined by the intrinsic membrane properties of pacemakers [63, 64]. (2) Excitatory interactions between non-pacemakers: In this configuration temporal and amplitude
The role of glia in the generation of rhythmic activity
Neuron–glia interactions are increasingly being considered important for generating physiological and pathophysiological rhythmicity in the brain [78]. Although glia do not synchronize with each other through mechanisms of glutamatergic synaptic transmission, they are capable of synchronous activity via other mechanisms such as gap junctions [79]. The resulting Ca+2 oscillations or ‘waves’ between interconnected glia have important network functions [80•], and models of astrocyte–neuron
Coupled oscillators in respiratory rhythmogenesis and their evolution
The preBötC likely originated from similar rhythm generating structures present in early vertebrates [15•]. In lamprey, the respiratory rhythm generator is located in the pons, in the so-called para-trigeminal respiratory group (pTRG) (Figure 3a). This differs from the respiratory rhythm-generating network of dogfish, carp and tench that seems to span the length of the brainstem [14••] including medullary regions. Evidence for a localized microcircuit comes from bullfrogs: the gill/buccal
Conflicts of interest statement
The authors do not have any conflict of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Supported by grants from the National Institute of Health (HL090554 and HL126523-01.
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2024, Respiratory Physiology and NeurobiologyEvolution of vertebrate respiratory central rhythm generators
2022, Respiratory Physiology and NeurobiologyCitation Excerpt :Just as passive exhalation is the first event in the lung ventilation cycle in anuran amphibians, active expiration driven by recruitment of axial muscles innervated by spinal nerves becomes the first phase of the respiratory rhythm in reptiles and birds, as well as in some mammals at rest and all mammals under conditions of elevated respiratory drive (Janczewski and Feldman, 2006; Jenkin and Milsom, 2014; Milsom, 2010). While the source of the active expiration that occurs in reptiles and birds remains unknown, in mammals it arises from the lateral parafacial nucleus (pFL), a subpopulation within the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), which is situated rostral to the Bötzinger Complex (BötC) and ventral to the facial (VII) motor nucleus ((Baertsch et al., 2018; Champagnat and Fortin, 1997; Ramirez et al., 2016) (Fig.7). Under resting conditions, active expiration is actively inhibited in many mammals (Flor et al., 2020; Pagliardini et al., 2011) and disinhibition is dependent on excitatory drive from the pons (Abdala et al., 2009a, b; Jenkin et al., 2017; Molkov et al., 2010).
The lamprey respiratory network: Some evolutionary aspects
2021, Respiratory Physiology and NeurobiologyCitation Excerpt :In this context, it seems appropriate to recall that even though the pTRG and the preBötC have similar functional characteristics within the breathing network, they do not appear to be homologous from an embryonic point of view. The pTRG is located in the rostral rhombencephalon/isthmic region corresponding to the rostral pons in mammals and arises from rhombomeres 2–3 (Murakami et al., 2004; Funk, 2017; Milsom, 2018), while the preBötC is located in the medulla and derives from rhombomeres 7–8 (Champagnat and Fortin, 1997; Gray, 2013; Ramirez et al., 2016). In mammals, respiratory neurons are present in the rostral pons at the level of the parabrachial complex and Kölliker-Fuse nuclei.
Neural mechanisms underlying respiratory regulation within the preBötzinger complex of the rabbit
2021, Respiratory Physiology and NeurobiologyExcitatory and inhibitory modulation of parafacial respiratory neurons in the control of active expiration
2021, Respiratory Physiology and NeurobiologyCitation Excerpt :Excitatory drives and synaptic inhibition are essential to control/modulate, as well as generate respiratory rhythm and pattern (Feldman et al., 2013). The proper balance between inhibitory and excitatory synapses contributes to coordination and shaping the respiratory phases (Smith et al., 2013; Ramirez et al., 2016). Disinhibition and activation of pFL region, using different tools, consistently evoked active expiration in adult rats (Pagliardini et al., 2011; Huckstepp et al., 2015, 2016, 2018; Silva et al., 2019; Zoccal et al., 2018; Malheiros-Lima et al., 2020) (Figs. 2–4).
Revisiting the two rhythm generators for respiration in lampreys
2023, Frontiers in Neuroanatomy