Bidirectional modulation of negative emotional states by parallel genetically-distinct basolateral amygdala pathways to ventral striatum subregions.

Distinct basolateral amygdala (BLA) cell populations influence emotional responses in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors (drd1 and drd2 respectively). The role of drd1+ or drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the drd1+ and drd2+ BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through three separate behavioral assays, we found that the drd1+ and drd2+ parallel pathways bidirectionally influence both learned and unlearned emotional states when they are activated or suppressed, and do so depending upon where they synapse in the ventral striatum - with unique contributions of drd1+ and drd2+ circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner.

A single chemosensory GPCR is required for a concentration-dependent behavioral switching in C. elegans.

Animals detect and discriminate countless environmental chemicals for their well-being and survival. Although a single chemical can trigger opposing behavioral responses depending on its concentration, the mechanisms underlying such a concentration-dependent switching remain poorly understood. Here, we show that C. elegans exhibits either attraction or avoidance of the bacteria-derived volatile chemical dimethyl trisulfide (DMTS) depending on its concentration. This behavioral switching is mediated by two different types of chemosensory neurons, both of which express the DMTS-sensitive seven-transmembrane G protein-coupled receptor (GPCR) SRI-14. These two sensory neurons share downstream interneurons that process and translate DMTS signals via distinct glutamate receptors to generate the appropriate behavioral outcome. Thus, our results present one mechanism by which an animal connects two distinct types of chemosensory neurons detecting a common ligand to alternate downstream circuitry, thus efficiently switching between specific behavioral programs based on ligand concentration.

Machine learning-based clustering and classification of mouse behaviors via respiratory patterns.

Breathing is dynamically modulated by metabolic needs as well as by emotional states. Even though rodents are invaluable models for investigating the neural control of respiration, current literature lacks systematic characterization of breathing dynamics across a broad spectrum of rodent behaviors. Here we uncover a wide diversity in breathing patterns across spontaneous, attractive odor-, stress-, and fear-induced behaviors in mice. Direct recordings of intranasal pressure afford more detailed respiratory information than more traditional whole-body plethysmography. K-means clustering groups 11 well-defined behavioral states into four clusters with distinct key respiratory features. Furthermore, we implement RUSBoost (random undersampling boost) classification, a supervised machine learning model, and find that breathing patterns can separate these behaviors with an accuracy of 80%. Taken together, our findings highlight the tight relationship between breathing and behavior and the potential use of breathing patterns to aid in distinguishing similar behaviors and inform about their internal states.

Olfactory receptor 10J5 responding to α-cedrene regulates hepatic steatosis via the cAMP-PKA pathway.

Ectopic expression and functions of odorant receptors (ORs) in the human body have aroused much interest in the past decade. Mouse olfactory receptor 23 (MOR23, olfr16) and its human orthologue, OR10J5, have been found to be functionally expressed in several non-olfactory systems. Here, using MOR23- and OR10J5-expressing Hana3A cells, we identified α-cedrene, a natural compound that protects against hepatic steatosis in mice fed the high-fat diet, as a novel agonist of these receptors. In human hepatocytes, an RNA interference-mediated knockdown of OR10J5 increased intracellular lipid accumulation, along with upregulation of lipogenic genes and downregulation of genes related to fatty acid oxidation. α-Cedrene stimulation resulted in a significant reduction in lipid contents of human hepatocytes and reprogramming of metabolic signatures, which are mediated by OR10J5, as demonstrated by receptor knockdown experiments using RNA interference. Taken together, our findings show a crucial role of OR10J5 in the regulation of lipid accumulation in human hepatocytes.

Odorant Receptors Containing Conserved Amino Acid Sequences in Transmembrane Domain 7 Display Distinct Expression Patterns in Mammalian Tissues.

Mammalian genomes are well established, and highly conserved regions within odorant receptors that are unique from other G-protein coupled receptors have been identified. Numerous functional studies have focused on specific conserved amino acids motifs; however, not all conserved motifs have been sufficiently characterized. Here, we identified a highly conserved 18 amino acid sequence motif within transmembrane domain seven (CAS-TM7) which was identified by aligning odorant receptor sequences. Next, we investigated the expression pattern and distribution of this conserved amino acid motif among a broad range of odorant receptors. To examine the localization of odorant receptor proteins, we used a sequence-specific peptide antibody against CAS-TM7 which is specific to odorant receptors across species. The specificity of this peptide antibody in recognizing odorant receptors has been confirmed in a heterologous in vitro system and a rat-based in vivo system. The CAS-TM7 odorant receptors localized with distinct patterns at each region of the olfactory epithelium; septum, endoturbinate and ectoturbinate. To our great interests, we found that the CAS-TM7 odorant receptors are primarily localized to the dorsal region of the olfactory bulb, coinciding with olfactory epithelium-based patterns. Also, these odorant receptors were ectopically expressed in the various non-olfactory tissues in an evolutionary constrained manner between human and rats. This study has characterized the expression patterns of odorant receptors containing particular amino acid motif in transmembrane domain 7, and which led to an intriguing possibility that the conserved motif of odorant receptors can play critical roles in other physiological functions as well as olfaction.