Tatiana M. Anderson

A novel excitatory network for the control of breathing

Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer’s disease, Parkinson’s disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice. Glutamatergic–cholinergic neurons form the basis of this network, and GABA (γ-aminobutyric acid)-mediated inhibition establishes the timing and coordination relative to inspiration. We refer to this network as the postinspiratory complex (PiCo). The PiCo has autonomous rhythm-generating properties and is necessary and sufficient for postinspiratory activity in vivo. The PiCo also shows distinct responses to neuromodulators when compared to other excitatory brainstem networks. On the basis of the discovery of the PiCo, we propose that each of the three phases of breathing is generated by a distinct excitatory network: the preBötzinger complex, which has been linked to inspiration; the PiCo, as described here for the neuronal control of postinspiration; and the lateral parafacial region (pFL), which has been associated with active expiration, a respiratory phase that is recruited during high metabolic demand.

Defining modulatory inputs into CNS neuronal subclasses by functional pharmacological profiling

Significance We functionally profiled cells from a locus of the mouse brainstem that contains the neuronal network responsible for generating breathing patterns. By uncovering cell-specific constellations (i.e., distinctive combinations of receptors and ion channels that define each cell type), we identified specific neuronal classes and subclasses within the network. We discovered neuromodulators affecting the activity of specific neuronal subclasses within the functional network. This study provides proof-of-principle that a pharmacological strategy for altering the activity of a specific type of neuron can be developed which has potential as a parallel or complementary approach to genetic strategies for functionally perturbing a specific neuronal cell type in vivo. Additionally, unlike genetic approaches, this pharmacological approach is directly applicable to nonmodel organisms. Previously we defined neuronal subclasses within the mouse peripheral nervous system using an experimental strategy called “constellation pharmacology.” Here we demonstrate the broad applicability of constellation pharmacology by extending it to the CNS and specifically to the ventral respiratory column (VRC) of mouse brainstem, a region containing the neuronal network controlling respiratory rhythm. Analysis of dissociated cells from this locus revealed three major cell classes, each encompassing multiple subclasses. We broadly analyzed the combinations (constellations) of receptors and ion channels expressed within VRC cell classes and subclasses. These were strikingly different from the constellations of receptors and ion channels found in subclasses of peripheral neurons from mouse dorsal root ganglia. Within the VRC cell population, a subset of dissociated neurons responded to substance P, putatively corresponding to inspiratory pre-Bötzinger complex (preBötC) neurons. Using constellation pharmacology, we found that these substance P-responsive neurons also responded to histamine, and about half responded to bradykinin. Electrophysiological studies conducted in brainstem slices confirmed that preBötC neurons responsive to substance P exhibited similar responsiveness to bradykinin and histamine. The results demonstrate the predictive utility of constellation pharmacology for defining modulatory inputs into specific neuronal subclasses within central neuronal networks.

Respiratory rhythm generation: triple oscillator hypothesis

Breathing is vital for survival but also interesting from the perspective of rhythm generation. This rhythmic behavior is generated within the brainstem and is thought to emerge through the interaction between independent oscillatory neuronal networks. In mammals, breathing is composed of three phases – inspiration, post-inspiration, and active expiration – and this article discusses the concept that each phase is generated by anatomically distinct rhythm-generating networks: the preBötzinger complex (preBötC), the post-inspiratory complex (PiCo), and the lateral parafacial nucleus (pF L), respectively. The preBötC was first discovered 25 years ago and was shown to be both necessary and sufficient for the generation of inspiration. More recently, networks have been described that are responsible for post-inspiration and active expiration. Here, we attempt to collate the current knowledge and hypotheses regarding how respiratory rhythms are generated, the role that inhibition plays, and the interactions between the medullary networks. Our considerations may have implications for rhythm generation in general.

The ins and outs of breathing

Distinct populations of neurons within the brainstem are responsible for generating and coordinating the rhythmic patterns of neural activity that underlie breathing.

Sudden Infant Death Syndrome, Sleep, and the Physiology and Pathophysiology of the Respiratory Network

The identification of risk factors associated with sudden infant death syndrome (SIDS) has led to significant advances in the prevention of this tragic outcome. The discovery of the prone sleeping position and smoking as two of the major risk factors (1-5) led to worldwide awareness campaigns, such as, for example, the “Back to Sleep” campaign launched in the United States in 1996, and various smoking cessation campaigns (6, 7). These initiatives resulted in a dramatic reduction in the number of children succumbing to SIDS (5, 8). Unfortunately, SIDS still remains the number-one cause of death in infants under 1 year of age in many countries, despite epidemiological and pathological studies that continue to identify additional risk factors, such as hearing deficiencies, or various genetic alterations associated with SIDS (9-11, 12, 13). To parents and families, as well as some health professionals and researchers, the sheer number of suggested risk factors and gene mutations can also be bewildering.The Triple Risk hypothesis by Dr Hannah Kinney and collaborators (14) can partly resolve this confusion. This hypothesis states that SIDS is caused by an incident in which not just one but three risk factors come together to bring an infant into a situation that leads to the sudden death. Specifically, it was proposed that those factors include [1] a vulnerable infant; [2] a critical period of development in homeostatic control; and [3] an exogenous stressor (14, 15). In other words, in the presence of two risk factors, namely being a vulnerable infant in a critical period of development, a third risk factor (e.g. an exogenous stressor) can become the ultimate cause that triggers an irreversible cascade of events leading to the sudden death.The Triple Risk hypothesis also has important practical implications. The awareness campaigns have shown that it is possible to significantly reduce the risk of an infant being exposed to exogenous stressors. A potentially more challenging task is to identify the infant who is particularly vulnerable, which is clearly one of the major tasks for research. A better understanding of the characteristics of a vulnerable infant would facilitate the development of strategies that target a specific vulnerability. Similarly, it will be important for research to identify and recognize the specific developmental conditions that characterize the critical period for SIDS, especially if they are dysregulated, or to target the important developmental and homeostatic mechanisms to prevent the death. This chapter will describe how different risk factors can contribute to the sudden death, the failure to arouse, the specific conditions associated with sleep, and the neuronal networks controlling cardiorespiratory functions and how they contribute to the events leading to sudden death. In this context we will review the physiology and pathophysiology of important brainstem mechanisms that are critical for survival, but that can sometimes fail. Understanding how these brainstem mechanisms interact with endogenous and exogenous mechanisms can also facilitate understanding of the significance of a variety of risk factors known to contribute to SIDS.