A Microglia Sublineage Protects from Sex-Linked Anxiety Symptoms and Obsessive Compulsion.

Aberrant microglia activity is associated with many neurological and psychiatric disorders, yet our knowledge about the pathological mechanisms is incomplete. Here, we describe a genetically defined microglia sublineage in mice which has the ability to suppress obsessive compulsion and anxiety symptoms. These microglia derive from precursors expressing the transcription factor Hoxb8. Selective ablation of Hoxb8-lineage microglia or the Hoxb8 gene revealed that dysfunction in this cell type causes severe over-grooming and anxiety-like behavior and stress responses. Moreover, we show that the severity of the pathology is set by female sex hormones. Together, our findings reveal that different microglia lineages have distinct functions. In addition, our data suggest a mechanistic link between biological sex and genetics, two major risk factors for developing anxiety and related disorders in humans.

Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain.

Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here, we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases, we provide an extensive resource for further investigation of mouse neuronal cell types.

Sweet and bitter taste in the brain of awake behaving animals.

Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals. In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain. Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map, with each taste quality encoded by distinct cortical fields. Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input.

Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways.

Asthma is a common debilitating inflammatory lung disease affecting over 200 million people worldwide. Here, we investigated neurogenic components involved in asthmatic-like attacks using the ovalbumin-sensitized murine model of the disease, and identified a specific population of neurons that are required for airway hyperreactivity. We show that ablating or genetically silencing these neurons abolished the hyperreactive broncho-constrictions, even in the presence of a fully developed lung inflammatory immune response. These neurons are found in the vagal ganglia and are characterized by the expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel. However, the TRPV1 channel itself is not required for the asthmatic-like hyperreactive airway response. We also demonstrate that optogenetic stimulation of this population of TRP-expressing cells with channelrhodopsin dramatically exacerbates airway hyperreactivity of inflamed airways. Notably, these cells express the sphingosine-1-phosphate receptor 3 (S1PR3), and stimulation with a S1PR3 agonist efficiently induced broncho-constrictions, even in the absence of ovalbumin sensitization and inflammation. Our results show that the airway hyperreactivity phenotype can be physiologically dissociated from the immune component, and provide a platform for devising therapeutic approaches to asthma that target these pathways separately.

The cells and logic for mammalian sour taste detection.

Mammals taste many compounds yet use a sensory palette consisting of only five basic taste modalities: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate). Although this repertoire may seem modest, it provides animals with critical information about the nature and quality of food. Sour taste detection functions as an important sensory input to warn against the ingestion of acidic (for example, spoiled or unripe) food sources. We have used a combination of bioinformatics, genetic and functional studies to identify PKD2L1, a polycystic-kidney-disease-like ion channel, as a candidate mammalian sour taste sensor. In the tongue, PKD2L1 is expressed in a subset of taste receptor cells distinct from those responsible for sweet, bitter and umami taste. To examine the role of PKD2L1-expressing taste cells in vivo, we engineered mice with targeted genetic ablations of selected populations of taste receptor cells. Animals lacking PKD2L1-expressing cells are completely devoid of taste responses to sour stimuli. Notably, responses to all other tastants remained unaffected, proving that the segregation of taste qualities even extends to ionic stimuli. Our results now establish independent cellular substrates for four of the five basic taste modalities, and support a comprehensive labelled-line mode of taste coding at the periphery. Notably, PKD2L1 is also expressed in specific neurons surrounding the central canal of the spinal cord. Here we demonstrate that these PKD2L1-expressing neurons send projections to the central canal, and selectively trigger action potentials in response to decreases in extracellular pH. We propose that these cells correspond to the long-sought components of the cerebrospinal fluid chemosensory system. Taken together, our results suggest a common basis for acid sensing in disparate physiological settings.

Molecular basis of an inherited form of incomplete achromatopsia.

Mutations in the genes encoding the CNGA3 and CNGB3 subunits of the cyclic nucleotide-gated (CNG) channel of cone photoreceptors have been associated with autosomal recessive achromatopsia. Here we analyze the molecular basis of achromatopsia in two siblings with residual cone function. Psychophysical and electroretinographic analyses show that the light sensitivity of the cone system is lowered, and the signal transfer from cones to secondary neurons is perturbed. Both siblings carry two mutant CNGA3 alleles that give rise to channel subunits with different single-amino acid substitutions. Heterologous expression revealed that only one mutant forms functional channels, albeit with grossly altered properties, including changes in Ca2+ blockage and permeation. Surprisingly, coexpression of this mutant subunit with CNGB3 rescues the channel phenotype, except for the Ca2+ interaction. We argue that these alterations are responsible for the perturbations in light sensitivity and synaptic transmission.