A gut-to-brain signal of fluid osmolarity controls thirst satiation.

Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested1-12. By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour

The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement

The brain transforms the need for water into the desire to drink, but how this transformation is performed remains unknown. Here we describe the motivational mechanism by which the forebrain thirst circuit drives drinking. We show that thirst-promoting subfornical organ neurons are negatively reinforcing and that this negative-valence signal is transmitted along projections to the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO). We then identify molecularly defined cell types within the OVLT and MnPO that are activated by fluid imbalance and show that stimulation of these neurons is sufficient to drive drinking, cardiovascular responses, and negative reinforcement. Finally, we demonstrate that the thirst signal exits these regions through at least three parallel pathways and show that these projections dissociate the cardiovascular and behavioral responses to fluid imbalance. These findings reveal a distributed thirst circuit that motivates drinking by the common mechanism of drive reduction

Changes in Abundance of Oral Microbiota Associated with Oral Cancer

<div><p>Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of <i>Firmicutes</i> (especially <i>Streptococcus</i>) and <i>Actinobacteria</i> (especially <i>Rothia</i>) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.</p></div

Genetic Identification of Vagal Sensory Neurons That Control Feeding

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding

Discovery Cohort Cancer Patient Characteristics.

1<p>Pathologic tumor stage according to the American Joint Committee on Cancer guidelines (T  =  tumor size, N  =  regional lymph node metastasis, M =  distant metastasis)</p

Conformation Cohort Cancer Patient Characteristics.

1<p>Pathologic tumor stage according to the American Joint Committee on Cancer guidelines (T  =  tumor size, N  =  regional lymph node metastasis, M  =  distant metastasis</p

Change in relative abundance of phyla associated with cancer compared to anatomically matched contralateral clinically normal samples in Study 1.

<p>(a – e) Relative abundance of each of the five more abundant phyla in cancers compared to clinically normal samples from each of five patients. Note, that data are shown on different scales, reflecting the abundance of the phyla. The magnitudes of the changes in abundance are clearly greater than the statistical counting noise, as indicated by the error bar estimates, which are based on the square root of the actual number of reads. (f) Change in relative abundance shown as the difference in abundance of phyla associated with cancers compared to anatomically matched contralateral clinically normal samples. In cancers, decreases in the relative abundance of <i>Firmicutes</i> and <i>Actinobacteria</i> were seen in all patients, while the relative abundance of <i>Fusobacteria</i> was elevated in cancers from all patients.</p

Distinguishing cancer and normal samples.

<p>PCoA based on Weighted UniFrac distance between samples given abundance of 12 OTUs. Axis 1 (PCoA1): 54% of variation explained. Axis 2 (PCoA2): 24% of variation explained. N0 and N+ indicate the nodal status of the cancer patient, N0  =  node negative, N+  =  node positive. Cancer control and pre-cancer control are contralateral clinically normal patient samples. Other identifies samples from healthy normal individuals.</p

Distribution of phyla in normal and cancer samples in Study 1.

<p>The relative distribution of phyla (percent of sequences) is shown for each patient sample with clinically normal samples shown together on top and cancer samples on the bottom.</p

Thirst neurons anticipate the homeostatic consequences of eating and drinking

Thirst motivates animals to drink in order to maintain fluid balance. Traditionally, thirst has been viewed as a homeostatic response to changes in the blood volume or tonicity(1–3). However, most drinking behavior is regulated too rapidly to be controlled by blood composition directly and instead appears to anticipate homeostatic imbalances before they arise(4–11). How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst. We show by monitoring deep-brain calcium dynamics that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking, which they then integrate with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then adjust behavior preemptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in multiple contexts. These findings provide a neural mechanism to explain longstanding behavioral observations, including the prevalence of drinking during meals(10,11), the rapid satiation of thirst(7–9), and the fact that oral cooling is thirst-quenching(12–14)