ReviewAscending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure
Introduction
Metabolic homeostasis reflects the complex output of endocrine, autonomic, and behavioral control circuits that extend throughout the central nervous system (CNS). Brain regions that control energy intake and expenditure are privy to continuous interoceptive feedback from the body that can modulate appetite, satiety, digestion, and metabolism. Interoceptive signals from the gastrointestinal tract and associated digestive viscera are delivered to the brain primarily by vagal afferents that terminate centrally within the medullary dorsal vagal complex (DVC), comprising the dorsal motor nucleus of the vagus (DMV), nucleus of the solitary tract (NST), and area postrema (AP) (Rinaman, 2003a). In addition to vagal inputs from gastrointestinal and other thoracic and abdominal viscera, DVC neurons receive direct and indirect interoceptive signals from olfactory, glossopharyngeal, trigeminal, facial, and spinal afferent systems. A strong topography is evident in the terminal arborizations of primary visceral afferents, with inputs from the gut terminating within the caudal medial NST (Altschuler et al., 1989, Shapiro and Miselis, 1985). In addition to synaptic inputs, the AP and a significant portion of the caudal medial NST contain fenestrated capillaries, allowing blood-borne factors (e.g., toxins, cytokines, hormones, and osmolytes) to alter local neural activity within the DVC and other brainstem targets (Cunningham et al., 1994).
A major product of integrated DVC neural activity is the modulation of autonomic vagal parasympathetic outflow to the stomach, small intestine, pancreas, and other digestive viscera (Altschuler et al., 1992). In addition, and as summarized in this review, ascending axonal projections from neurons within the caudal medial (i.e., gastrointestinal) NST target virtually every pontine, diencephalic, and telencephalic circuit node that has been implicated in the central control of energy homeostasis (Horst and Streefland, 1994), highlighting gastrointestinal interoception as a potentially critical modulator of neural circuit activity throughout the brain. Ample evidence supports the view that descending projections from hypothalamus to caudal brainstem provide critical control over the initiation and termination of food intake and feeding-related autonomic adjustments (Berthoud, 2002, Berthoud et al., 2006, Coll et al., 2007, Smith, 2000, Smith, 2004, Woods and D'Alessio, 2008, Zheng et al., 2005). Ascending projections from NST to hypothalamus are clearly involved in regulating hormone release from the anterior and posterior pituitary in response to gastrointestinal and other visceral sensory signals (Rinaman, 2007). Conversely, the influence of these ascending projections in regulating food intake is less firmly established (Luckman and Lawrence, 2003, Renner et al., 2010). Appetite and satiety are clearly modulated both by external (i.e., environmental) and internal (i.e., physiological) contexts, and, therefore, are only loosely dependent on past or current visceral sensory feedback signals.
Results from neuroanatomical studies performed primarily in rats have revealed potential pathways by which visceral sensory feedback signals can reach the hypothalamus and limbic forebrain, and thereby potentially affect the ways in which these forebrain regions control food intake. This article begins with an overview of ascending axonal projections from neurons within the caudal visceral NST to higher brain regions in adult rats. For this purpose, projections were identified using a standard anterograde tracer microinjected into the caudal NST, and also by immunocytochemical localization of glucagon-like peptide-1 (GLP-1). GLP-1-positive fibers within the brain arise exclusively from non-noradrenergic (non-NA) neurons within the caudal visceral NST and closely adjacent reticular formation (Larsen et al., 1997, Merchenthaler et al., 1999, Rinaman, 1999b, Vrang et al., 2007), thereby providing a clear view of ascending pathways arising from this small group of phenotypically distinct neurons. Projection pathways identified by these two approaches also are compared to the distribution of CNS neurons that become infected/labeled after inoculating the ventral stomach wall with H129, a neurotropic α-herpesvirus virus that transneuronally infects synaptically-linked chains of neurons in the anterograde direction (Rinaman and Schwartz, 2004).
The focus of this report is the anatomical organization and neurochemical phenotypes of ascending projections from the caudal gastrointestinal region of the NST in rats. Although some discussion of the hypothesized roles of these ascending projections is included where relevant, the reader is referred to several recent comprehensive reviews for more detailed information regarding the involvement of particular diencephalic and limbic forebrain regions in the central neural control of food intake and energy expenditure (Berthoud, 2002, Berthoud, 2008, Broberger, 2005, Woods and D'Alessio, 2008).
Section snippets
Ascending visceral pathways: standard anterograde tracing from the noradrenergic (NA) region of the caudal NST
Since most neural pathways conveying interoceptive signals from body to brain involve a synaptic relay within the NST, a description of the central projections of NST neurons effectively reveals most CNS recipients of viscerosensory information (Bailey et al., 2006, Horst et al., 1989, Horst and Streefland, 1994, Ricardo and Koh, 1978), albeit without identifying the central targets of organ-specific sensory signals. A multitude of anterograde and retrograde tract-tracing studies, performed
Ascending projections from the caudal visceral NST: immunocytochemical localization of GLP-1
GLP-1 is expressed by a relatively small number of neurons located within the caudal visceral NST (Fig. 11) and adjacent dorsal reticular formation (Jin et al., 1988, Larsen et al., 1997, Merchenthaler et al., 1999). GLP-1-positive neurons are not adrenergic, but co-express β inhibin 1, somatostatin, and met-enkephalin (Sawchenko et al., 1990). Their ascending axonal projections largely parallel NA projections from the caudal NST. Indeed, all brain regions that contain GLP-1-positive fibers and
Ascending gastric sensory pathways: viral transneuronal anterograde tracing
Standard anterograde and retrograde tracing techniques are useful tools with which to survey the inputs and outputs of various brain regions. However, light microscopic tracing using PhAL or other standard tracers cannot by itself demonstrate synaptic connections between labeled projection neurons and their targets. Further, PhAL tracing experiments like the one illustrated in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10 cannot discriminate projections that
Conclusion
The CNS is privy to a plethora of peripheral neural and humoral signals that reflect current digestive status and energy availability, energy needs, and energy stores. Body energy homeostasis depends on the organism's ability to integrate and respond adaptively to these signals by modulating current and future energy intake and expenditure. Clearly, descending projections from the hypothalamus and limbic forebrain to the DVC and other caudal brainstem regions are critical in the central control
Acknowledgments
Research supported by the National Institutes of Health (MH59911). The expert technical assistance of Victoria Maldovan Dzmura, Hana Bakalli and Vanessa Cole is gratefully acknowledged.
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