Central Control Circuit for Context-Dependent Micturition.

Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior.

Central Network Dynamics Regulating Visceral and Humoral Functions.

The brain processes information from the periphery and regulates visceral and immune activity to maintain internal homeostasis, optimally respond to a dynamic external environment, and integrate these functions with ongoing behavior. In addition to its relevance for survival, this integration underlies pathology as evidenced by diseases exhibiting comorbid visceral and psychiatric symptoms. Advances in neuroanatomical mapping, genetically specific neuronal manipulation, and neural network recording are overcoming the challenges of dissecting complex circuits that underlie this integration and deciphering their function. Here we focus on reciprocal communication between the brain and urological, gastrointestinal, and immune systems. These studies are revealing how autonomic activity becomes integrated into behavior as part of a social strategy, how the brain regulates innate immunity in response to stress, and how drugs impact emotion and gastrointestinal function. These examples highlight the power of the functional organization of circuits at the interface of the brain and periphery.

Promiscuous binding of extracellular peptides to cell surface class I MHC protein.

Algorithms derived from measurements of short-peptide (8-10 mers) binding to class I MHC proteins suggest that the binding groove of a class I MHC protein, such as K(b), can bind well over 1 million different peptides with significant affinity (<500 nM), a level of ligand-binding promiscuity approaching the level of heat shock protein binding of unfolded proteins. MHC proteins can, nevertheless, discriminate between similar peptides and bind many of them with high (nanomolar) affinity. Some insights into this high-promiscuity/high-affinity behavior and its impact on immunodominant peptides in T-cell responses to some infections and vaccination are suggested by results obtained here from testing a model developed to predict the number of cell surface peptide-MHC complexes that form on cells exposed to extracellular (exogenous) peptides.