Saliva in the mouth is a biofluid produced mainly by three pairs of major salivary glands--the submandibular, parotid and sublingual glands--along with secretions from many minor submucosal salivary glands. Salivary gland secretion is a nerve-mediated reflex and the volume of saliva secreted is dependent on the intensity and type of taste and on chemosensory, masticatory or tactile stimulation. Long periods of low (resting or unstimulated) flow are broken by short periods of high flow, which is stimulated by taste and mastication. The nerve-mediated salivary reflex is modulated by nerve signals from other centers in the central nervous system, which is most obvious as hyposalivation at times of anxiety. An example of other neurohormonal influences on the salivary reflex is the circadian rhythm, which affects salivary flow and ionic composition. Cholinergic parasympathetic and adrenergic sympathetic autonomic nerves evoke salivary secretion, signaling through muscarinic M3 and adrenoceptors on salivary acinar cells and leading to secretion of fluid and salivary proteins. Saliva gland acinar cells are chloride and sodium secreting, and the isotonic fluid produced is rendered hypotonic by salivary gland duct cells as it flows to the mouth. The major proteins present in saliva are secreted by salivary glands, creating viscoelasticity and enabling the coating of oral surfaces with saliva. Salivary films are essential for maintaining oral health and regulating the oral microbiome. Saliva in the mouth contains a range of validated and potential disease biomarkers derived from epithelial cells, neutrophils, the microbiome, gingival crevicular fluid and serum. For example, cortisol levels are used in the assessment of stress, matrix metalloproteinases-8 and -9 appear to be promising markers of caries and periodontal disease, and a panel of mRNA and proteins has been proposed as a marker of oral squamous cell carcinoma. Understanding the mechanisms by which components enter saliva is an important aspect of validating their use as biomarkers of health and disease.

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The physiology of salivary secretion

Cell turnover in neuromasts of zebrafish larvae.

Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus and nucleus tractus solitarius (NTS) of the brainstem play important roles in suppressing food intake and maintaining energy homeostasis. Previous tract-tracing studies have revealed the axonal connection patterns of these two brain areas, but the intermingling of POMC neurons with other neuron types has made it challenging to precisely identify the inputs and outputs of POMC neurons. In this study, we used the modified rabies virus to map the brain areas that provide direct inputs to the POMC neurons in the ARC and NTS as well as the inputs to the ARC AgRP neurons for comparison. ARC POMC neurons receive inputs from dozens of discrete structures throughout the forebrain and brainstem. The brain areas containing the presynaptic partners of ARC POMC neurons largely overlap with those of ARC AgRP neurons, although POMC neurons receive relatively broader, denser inputs. Furthermore, POMC neurons in the NTS receive direct inputs predominantly from the brainstem and show very different innervation patterns for POMC neurons in the ARC. By selectively expressing fluorescent markers in the ARC and NTS POMC neurons, we found that almost all of their major presynaptic partners are innervated by POMC neurons in the two areas, suggesting that there are strong reciprocal projections among the major POMC neural pathways. By comprehensively chartering the whole-brain connections of the central melanocortin system in a cell-type-specific manner, this study lays the foundation for dissecting the roles and underlying circuit mechanisms of specific neural pathways in regulating energy homeostasis.

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Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons

Maintenance of a film of saliva on oral surfaces is dependent upon nerve-mediated, reflex salivary gland secretion. Afferent signalling arises from taste, olfaction and mastication and is modified by signalling from other centres in the central nervous system before efferent signals are delivered to salivary glands in autonomic nerves. Salivary fluid secretion is largely dependent upon cholinergic signalling from parasympathetic nerves whilst the protein content of saliva is additionally dependent upon signalling by neuropeptides and, in the major (parotid, submandibular and sublingual) salivary glands, by sympathetic nerves and the release of noradrenaline. There have been significant recent advances in our understanding of the membrane transport proteins involved in intracellular calcium signalling in salivary acinar cells in response to nerve stimulation and of the ion transport proteins responsible for acinar cell secretion of saliva. Salivary glands retain an ability to regenerate following extreme atrophy, and autonomic nerves have an important role in both gland development and maintenance of long-term normal function. Continued advances in the understanding of the nerve-mediated regulation of salivary glands should help in the development of strategies for preventing chronic oral dryness resulting from drugs or atrophic disease associated with inflammation and irradiation.

Salivary secretion: mechanism and neural regulation.

The article discusses advances in osmoregulation and excretion with emphasis on how multicellular animals in different osmotic environments regulate their milieu interieur. Mechanisms of energy transformations in animal osmoregulation are dealt with in biophysical terms with respect to water and ion exchange across biological membranes and coupling of ion and water fluxes across epithelia. The discussion of functions is based on a comparative approach analyzing mechanisms that have evolved in different taxonomic groups at biochemical, cellular and tissue levels and their integration in maintaining whole body water and ion homeostasis. The focus is on recent studies of adaptations and newly discovered mechanisms of acclimatization during transitions of animals between different osmotic environments. Special attention is paid to hypotheses about the diversity of cellular organization of osmoregulatory and excretory organs such as glomerular kidneys, antennal glands, Malpighian tubules and insect gut, gills, integument and intestine, with accounts on experimental approaches and methods applied in the studies. It is demonstrated how knowledge in these areas of comparative physiology has expanded considerably during the last two decades, bridging seminal classical works with studies based on new approaches at all levels of anatomical and functional organization. A number of as yet partially unanswered questions are emphasized, some of which are about how water and solute exchange mechanisms at lower levels are integrated for regulating whole body extracellular water volume and ion homeostasis of animals in their natural habitats. © 2014 American Physiological Society.

Osmoregulation and excretion

The structure of the nephron in the ranid frog, Rana cancrivora, was studied by light and electron microscopy. This frog is the only amphibian species to live in mangrove swamps of very high salinity. The nephron consists of the following parts: renal corpuscle, ciliated neck segment, proximal tubule, ciliated intermediate segment, distal tubule, connecting tubule, and collecting duct. The distal tubule is located in the ventromedial region of the kidney, and the other tubules are situated in the dorsolateral region. Renal corpuscles are found between the two regions. Some renal corpuscles have a wide Bowman's space because of the small glomerulus within them. The proximal tubules are composed of columnar cells with a dense luminal brush border of long microvilli and numerous apical vesicles and vacuoles. The initial part of the distal tubule consists of heavily interdigitated cells, characterized by a very regular palisade arrangement of mitochondria. In the terminal part of the distal tubule, shorter mitochondria of the infolding cells are situated irregularly around the nucleus. The connecting tubule consists of principal cells and canaliculus cells. The collecting duct consists of columnar or cuboidal cells; cytoplasmic organelles are relatively sparse. The canaliculus cells are intercalated between principal cells from the terminal distal tubule to the proximal part of the collecting duct. Our findings indicate that the kidney of R. cancrivora is structurally similar to kidneys of other amphibians. These findings are discussed with regard to probable correlations between ultrastructure and function in R. cancrivora.

Structure of the kidney in the crab‐eating frog, Rana cancrivora

Reflex responses of single salivatory neurons to stimulation of trigeminal sensory branches in the cat.

Changes in cortically induced rhythmic jaw movements after lesioning of the red nucleus in rats

Analyses des differents stades embryonnaires et larvaires de R cancrivora issues d'une eclosion induite par injection d'homogenats de glandes pituitaires Comparaison des resultats a ceux obtenus chez R pipiens

Toshiki Murakami

Papers

Structure of the kidney in the crab‐eating frog, Rana cancrivora

Reflex responses of single salivatory neurons to stimulation of trigeminal sensory branches in the cat.

Changes in cortically induced rhythmic jaw movements after lesioning of the red nucleus in rats

Notes on the development of the crab-eating frog, Rana cancrivora : Developmental Biology

Responses of inferior salivatory neurons to stimulation of trigeminal sensory branches.