Brain H+ /CO2 sensing and control by glial cells.

Maintenance of constant brain pH is critically important to support the activity of individual neurons, effective communication within the neuronal circuits, and, thus, efficient processing of information by the brain. This review article focuses on how glial cells detect and respond to changes in brain tissue pH and concentration of CO2 , and then trigger systemic and local adaptive mechanisms that ensure a stable milieu for the operation of brain circuits. We give a detailed account of the cellular and molecular mechanisms underlying sensitivity of glial cells to H+ and CO2 and discuss the role of glial chemosensitivity and signaling in operation of three key mechanisms that work in concert to keep the brain pH constant. We discuss evidence suggesting that astrocytes and marginal glial cells of the brainstem are critically important for central respiratory CO2 chemoreception-a fundamental physiological mechanism that regulates breathing in accord with changes in blood and brain pH and partial pressure of CO2 in order to maintain systemic pH homeostasis. We review evidence suggesting that astrocytes are also responsible for the maintenance of local brain tissue extracellular pH in conditions of variable acid loads associated with changes in the neuronal activity and metabolism, and discuss potential role of these glial cells in mediating the effects of CO2 on cerebral vasculature.

Early development of respiratory motor circuits in larval zebrafish (Danio rerio).

Rhythm-generating circuits in the vertebrate hindbrain form synaptic connections with cranial and spinal motor neurons, to generate coordinated, patterned respiratory behaviors. Zebrafish provide a uniquely tractable model system to investigate the earliest stages in respiratory motor circuit development in vivo. In larval zebrafish, respiratory behaviors are carried out by muscles innervated by cranial motor neurons-including the facial branchiomotor neurons (FBMNs), which innervate muscles that move the jaw, buccal cavity, and operculum. However, it is unclear when FBMNs first receive functional synaptic input from respiratory pattern-generating neurons, and how the functional output of the respiratory motor circuit changes across larval development. In the current study, we used behavior and calcium imaging to determine how early FBMNs receive functional synaptic inputs from respiratory pattern-generating networks in larval zebrafish. Zebrafish exhibited patterned operculum movements by 3 days postfertilization (dpf), though this behavior became more consistent at 4 and 5 dpf. Also by 3dpf, FBMNs fell into two distinct categories ("rhythmic" and "nonrhythmic"), based on patterns of neural activity. These two neuron categories were arranged differently along the dorsoventral axis, demonstrating that FBMNs have already established dorsoventral topography by 3 dpf. Finally, operculum movements were coordinated with pectoral fin movements at 3 dpf, indicating that the operculum behavioral pattern was driven by synaptic input. Taken together, this evidence suggests that FBMNs begin to receive initial synaptic input from a functional respiratory central pattern generator at or prior to 3 dpf. Future studies will use this model to study mechanisms of normal and abnormal respiratory circuit development.

Forebrain control of breathing: Anatomy and potential functions.

The forebrain plays important roles in many critical functions, including the control of breathing. We propose that the forebrain is important for ensuring that breathing matches current and anticipated behavioral, emotional, and physiological needs. This review will summarize anatomical and functional evidence implicating forebrain regions in the control of breathing. These regions include the cerebral cortex, extended amygdala, hippocampus, hypothalamus, and thalamus. We will also point out areas where additional research is needed to better understand the specific roles of forebrain regions in the control of breathing.

Coordinated cadherin functions sculpt respiratory motor circuit connectivity.

Breathing, and the motor circuits that control it, is essential for life. At the core of respiratory circuits are Dbx1-derived interneurons, which generate the rhythm and pattern of breathing, and phrenic motor neurons (MNs), which provide the final motor output that drives diaphragm muscle contractions during inspiration. Despite their critical function, the principles that dictate how respiratory circuits assemble are unknown. Here, we show that coordinated activity of a type I cadherin (N-cadherin) and type II cadherins (Cadherin-6, -9, and -10) is required in both MNs and Dbx1-derived neurons to generate robust respiratory motor output. Both MN- and Dbx1-specific cadherin inactivation in mice during a critical developmental window results in perinatal lethality due to respiratory failure and a striking reduction in phrenic MN bursting activity. This combinatorial cadherin code is required to establish phrenic MN cell body and dendritic topography; surprisingly, however, cell body position appears to be dispensable for the targeting of phrenic MNs by descending respiratory inputs. Our findings demonstrate that type I and II cadherins function cooperatively throughout the respiratory circuit to generate a robust breathing output and reveal novel strategies that drive the assembly of motor circuits.

The neural circuits which control breathing are established in the womb, ready to switch on with the first gulp of air. Defects in the way that this network is assembled can result in conditions such as sudden infant death syndrome. This process, however, remains poorly understood; in particular, it is still unclear exactly how the two main types of nerve cells which form respiratory circuits start to 'talk' to each other. Known as Dbx1-derived interneurons and phrenic motor neurons, these cell populations reside in different parts of the body and perform distinct roles. The interneurons, which are present in the brainstem, act as a pacemaker to set the rhythm of respiration; the motor neurons reside in the spinal cord, connecting the interneurons with the muscles which allow the lungs to fill with air. Vagnozzi et al. aimed to identify how phrenic motor neurons connect to and relay signals from other neurons involved in breathing to the diaphragm muscle. To do so, the team focused on cadherins, a group of proteins which allow cells to attach to one another. Studded through the membrane, these molecules are also often involved in forming connections from one cell to another that allow them to communicate. Newborn mice in which phrenic motor neurons lacked a specific combination of cadherins experienced respiratory failure, showing that these proteins were needed for breathing circuits to develop normally. Electrical activity recorded from these cells showed that phrenic motor neurons lacking cadherins could not receive the signals required to activate the breathing muscles. Microscopy imaging also revealed that the loss of cadherins shifted the position of the phrenic motor neurons within the spinal cord; however, this change did not seem to affect the connections these cells could establish. The ability to breathe is compromised in many incurable human diseases such as muscular dystrophies and amyotrophic lateral sclerosis. It may be possible to alleviate some of these symptoms by integrating phrenic motor neurons created in the laboratory into existing circuits. Studies which aim to decipher how the respiratory network is established, such as the one conducted by Vagnozzi et al., are essential in this effort.