Neurones in the dorsal vagal complex may be more tasteful than expected

The dorsal vagal complex (DVC) comprises many intermixed cellular types encompassing a vast array of neurochemical, biophysical and morphological phenotypes scattered throughout the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus (DMV) and the area postrema (AP). These nuclei border the ventral floor of the fourth ventricle and play essential roles in the proper coordination of gastrointestinal and cardiorespiratory functions. Most importantly, the whole AP as well as portions of NTS and DMV are located strategically outside the blood–brain barrier, making them accessible to a multitude of circulating hormones that can alter their responsiveness dramatically. Cerebrospinal fluid contacting neurones (CSF-cNs) are present along the walls of the four cerebral ventricles, the aqueduct and the central canal. These neurones have been observed in, among other areas, the hypothalamus and the spinal cord. The role(s) of these CSF-cNs has been described in relation to the specific functions of the areas in which they reside. For example, in the hypothalamus CSF-cNs appear to have neurochemical similarities with magnocellular neurones, as they express neuronal NOS and oxytocin or arginine-vasopressin, their role may thus be associated with neuroendocrine regulation of the hypothalamohypophyseal axis (Xiao et al. 2005). In the spinal cord, instead, CFS-cNs appear to function as potential neural stem cells which contribute to the glial scar that occurs following minimal spinal cord injury (Marichal et al. 2009; Meletis et al. 2008; Mothe & Tator, 2005). Relatively recent work by Huang et al. (2006) demonstrated that the presence of a polycystic-kidney-disease like ion channel (PKD2L1) implies these cells are candidates as for a mammalian sour taste sensor in the tongue. These authors further showed that PKD2L1 is also expressed in specific neurones surrounding the central canal of the spinal cord, thus suggesting that cells containing PKD2L1 may be components of the cerebrospinal fluid chemosensory system. In an article in this issue of The Journal of Physiology, Orts-Del'Immagine et al (2012) utilized transgenic PKD2L1-EGFP adult mice to successfully identify and investigate CSF-cNs expressing PKD2L1 in the DVC. Since many DVC neurones reside outside the blood–brain barrier and contact the cerebrospinal fluid of the fourth ventricle and the rostral portions of the central canal, it should not come as a surprise that Orts-Del'Immagine et al. report the presence of a subpopulation of cells that resemble the CSF-cNs described in the spinal cord and the hypothalamus. The work of Orts-Del'Immagine et al. documents that medullar CSF-cNs have the characteristic neurochemical phenotype and morphology of spinal CSF-cNs, i.e. a PKD2L1 positive, small, round cell body from which a primary neurite projects toward and ends in the central canal. Their small size, small capacitance and high membrane resistance distinguish the CSF-cNs from the adjacent neurones of the NTS and DMV. Independent from either tonic or phasic firing membrane characteristics, all CSF-cNs receive robust spontaneous synaptic inputs enhanced by hyperosmotic shock. These spontaneous currents are carried by chloride ions flowing through GABAA and glycine receptors, but, in contrast to spinal CSF-cNs and adjacent NTS and DMV neurones, ionotropic glutamatergic or purinergic currents are not observed. A series of voltage clamp experiments describe both the whole cell and the unitary current properties of CSF-cNs, viz cationic non-selective currents flowing through a channel of large conductance; sensitivity to variations in osmolarity; fast current activated and quickly desensitized by acidification followed by a smaller sustained current; delayed rebound activity once the acidification is stopped; sensitivity to the acid sensing ionic channel (ASIC) antagonist psalmotoxin, which reduced the current but did not alter either the average channel open probability or the amplitude; sensitivity to the non-selective antagonist amiloride, which blocked the acid-induced current; and activatation by alkalinization. These characteristics indicate that CSF-cNs express functional ASICs responsible for the fast acid-induced current along with PKD2L1 channels classically inhibited by acidic exposure but activated by increases in pH, as described in oocytes and HEK293 cells by Chen et al. (1999) and Shimizu et al. (2009), among others. The discovery that CSF-cNs cells, potentially acting as chemosensors, are present in the DVC is one that is likely to provide future insights into the mechanisms of action, and the pathophysiology associated with them, of many peptides regulating autonomic functions. The position and the potential chemosensitive function of these CSF-cNs makes them ideal candidates for the detection of gastrointestinal peptides implicated in energy homeostasis. Indeed, the sites of action of many of these peptides are often thought to be of paracrine origin because of their release site close to afferent vagal fibres, which would convey the information centrally. The demonstration that potential chemosensors are present in the DVC and are bathed by cerebrospinal fluid uncovers one more mechanism and site of actions that must be taken into consideration when investigating actions of many gastrointestinal hormones. Furthermore, this type of cellular organization within the DVC should force us all to be extremely cautious in the often simplistic interpretation of manipulations that analyse a single physiological outcome, such as cFos expression or calcium oscillations, in response to systemic administration of peptides. The present article by Orts-Del'Immagine et al. opens up a new line of research in brainstem autonomic circuits. Several questions remain unanswered regarding the role of these CSF-cNs. Where are the synaptic inputs impinging onto these cells coming from? Where do these cells project to? Do these cells respond indiscriminately to ‘any’ type of perturbation in the CSF, such as inflammatory cytokines or low levels of peptides, or are they ‘task-coded’? Do these cells represent a potential group of ‘first responders’ to pathophysiological changes in the CSF, or does their response resemble more a ‘steady state’ communication to brainstem autonomic areas? The answers to these questions will undoubtedly advance the understanding of how homeostatic reflexes are integrated and provide potential avenues for treatment of autonomic pathologies.