Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics and dynamics of two separate neuron populations that regulate energy and fluid homeostasis by using cell type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

Midbrain dopamine neurons regulate many important behavioral processes and their dysfunctions are associated with several human neuropsychiatric disorders such as Attention Deficit Hyperactivity Disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of cGMPdependent protein kinase (PKG). GC-C knockout mice exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.

The present study aimed to investigate the effects of sodium butyrate on the intestinal barrier and mast cell activation, as well as inflammatory mediator production, and determine whether mitogen-activated protein kinase signaling pathways are involved in these processes. A total of 72 piglets, weaned at 28 AE 1 d age, were allotted to two dietary treatments (control vs. 450 mg/kg sodium butyrate) for 2 wk. The results showed that supplemental sodium butyrate increased daily gain, improved intestinal morphology, as indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function reflected by increased transepithelial electrical resistance and decreased paracellular flux of dextran (4 kDa). Moreover, sodium butyrate reduced the percentage of degranulated mast cells and its inflammatory mediator content (histamine, tryptase, TNF-a and IL-6) in the jejunum mucosa. Sodium butyrate also decreased the expression of mast cell-specific tryptase, TNF-a and IL-6 mRNA. Sodium butyrate significantly decreased the phosphorylated ratio of JNK whereas not affecting the phosphorylated ratios of ERK and p38. The results indicated that the protective effects of sodium butyrate on intestinal integrity were closely related to inhibition of mast cell activation and inflammatory mediator production, and that the JNK signaling pathway was likely involved in this process.