Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C14 and PC14
Preproglucagon neurons project heavily to autonomic control regions of the CNS
S. Trapp1, F. Reimann2, F. M. Gribble2, I. J. Llewellyn-Smith3
1. Department of Surgery and Cancer, Biophysics Section, Imperial College London, London, United Kingdom. 2. Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom. 3. Departments of Medicine and Physiology, Flinders University, Bedford Park, South Australia, Australia.
Receptors for glucagon-like peptide 1 (GLP-1) are found in many brain regions. Central application of GLP-1 or its analogue exendin-4 inhibits food intake and reduces blood glucose levels. Activation of central GLP-1 receptors also increases blood pressure and heart rate. The only endogenous sources of GLP-1 within the CNS are preproglucagon (PPG) neurons. We suggest that these central GLP-1 neurons modulate sympathetic and vagal outflow. As one step in testing this hypothesis, we analysed the projections of YFP-tagged PPG neurons to key CNS sites involved in autonomic control. Coronal sections from transgenic mice expressing YFP under the control of the PPG promoter were revealed with an anti-GFP antibody and avidin-biotin-peroxidase. The distribution of immunoreactive cell bodies and fibres was analysed from the anterior commissure to the spinomedullary junction. YFP-immunoreactivity was intense and axons were clearly visible. YFP-immunoreactive cell bodies were located in the caudal brainstem, primarily within the caudal nucleus tractus solitarius (NTS). Additional somata were observed in the intermediate reticular nucleus, at the ventral border of the hypoglossal nucleus and in the raphe obscurus. The caudal NTS contained a dense network of dendrites, some of which extended into the area postrema (AP). Immunoreactive axons were widespread throughout the NTS, the dorsal vagal nucleus and the reticular nucleus (except for the parvicellular section) but more limited within the hypoglossal nucleus and the pyramids. The AP, rostral ventrolateral medulla, pontine central grey, parabrachial nucleus and locus coeruleus were moderately innervated and some axons extended into the amygdala. In contrast, dorsomedial and paraventricular hypothalamus, periaqueductal grey and the paraventricular nucleus of the thalamus exhibited heavy innervation with YFP-immunoreactive axons. These results demonstrate that PPG neurons innervate primarily brain regions involved in autonomic control. Our data also show that YFP-PPG neurons in the mouse project more widely than GLP-1 immunoreactive neurons in the rat. This finding highlights the greatly increased sensitivity provided by immunohistochemical detection of neurochemically distinct populations of neurons that have been genetically modified to express GFP or a GFP analogue. Hence, central PPG neurons are in a prime position to modulate sympathetic and parasympathetic outflow through input at a variety of central locations.
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