The cellular basis of distinct thirst modalities

Fluid intake is an essential innate behaviour that is mainly caused by two distinct types of thirst. Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolaemic thirst, in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs in the lamina terminalis are critical sites for sensing both types of thirst-inducing stimulus. However, how different thirst modalities are encoded in the brain remains unknown. Here we employed stimulus-to-cell-type mapping using single-cell RNA sequencing to identify the cellular substrates that underlie distinct types of thirst. These studies revealed diverse types of excitatory and inhibitory neuron in each circumventricular organ structure. We show that unique combinations of these neuron types are activated under osmotic and hypovolaemic stresses. These results elucidate the cellular logic that underlies distinct thirst modalities. Furthermore, optogenetic gain of function in thirst-modality-specific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Together, these results show that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain

Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior

The ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) contains ∼4,000 neurons that project to multiple targets and control innate social behaviors including aggression and mounting. However, the number of cell types in VMHvl and their relationship to connectivity and behavioral function are unknown. We performed single-cell RNA sequencing using two independent platforms—SMART-seq (∼4,500 neurons) and 10x (∼78,000 neurons)—and investigated correspondence between transcriptomic identity and axonal projections or behavioral activation, respectively. Canonical correlation analysis (CCA) identified 17 transcriptomic types (T-types), including several sexually dimorphic clusters, the majority of which were validated by seqFISH. Immediate early gene analysis identified T-types exhibiting preferential responses to intruder males versus females but only rare examples of behavior-specific activation. Unexpectedly, many VMHvl T-types comprise a mixed population of neurons with different projection target preferences. Overall our analysis revealed that, surprisingly, few VMHvl T-types exhibit a clear correspondence with behavior-specific activation and connectivity

Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior

The ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) contains ∼4,000 neurons that project to multiple targets and control innate social behaviors including aggression and mounting. However, the number of cell types in VMHvl and their relationship to connectivity and behavioral function are unknown. We performed single-cell RNA sequencing using two independent platforms—SMART-seq (∼4,500 neurons) and 10x (∼78,000 neurons)—and investigated correspondence between transcriptomic identity and axonal projections or behavioral activation, respectively. Canonical correlation analysis (CCA) identified 17 transcriptomic types (T-types), including several sexually dimorphic clusters, the majority of which were validated by seqFISH. Immediate early gene analysis identified T-types exhibiting preferential responses to intruder males versus females but only rare examples of behavior-specific activation. Unexpectedly, many VMHvl T-types comprise a mixed population of neurons with different projection target preferences. Overall our analysis revealed that, surprisingly, few VMHvl T-types exhibit a clear correspondence with behavior-specific activation and connectivity

Inhibitory Control in the Drosophila melanogaster Feeding Circuit

Feeding behavior is essential for achieving metabolic homeostasis and is critical for survival. Animals adjust their food intake based on their physiological needs and food availability. How sensing deprivation signals and detection of taste gets converted to feeding behaviors remains poorly understood. Here I use the genetically tractable model organism Drosophila melanogaster to examine the neural mechanisms underlying feeding decisions. The genetic conservation of molecular signaling pathways, the simpler nervous system and the powerful genetic tools make it an excellent system to explore the organization and logic behind brain circuits controlling food intake.This thesis investigates the neuronal mechanisms underlying inhibition in the Drosophila feeding circuit. Here I describe the identification of 4 GABA-ergic interneurons in the Drosophila brain that establish a central feeding threshold which is required for any taste and satiety dependent feeding decisions. I show that these neurons control consumption in an activity dependent manner. Inactivation of these cells results in indiscriminate and excessive ingestion, independent of taste quality or nutritional state. Conversely, acute activation of these neurons significantly reduces consumption of water and nutrients. I show that their output is acutely required to express any feeding preference and that these neurons are not regulated by taste processing pathways or satiety signals. This work reveals a new layer of inhibitory control in insect feeding circuits that is required to suppress a latent state of unrestricted and nonselective consumption. Furthermore I identify the recurrent nerve as a peripheral source of post-ingestive inhibition of nutrient intake in Drosophila and show that the two feeding inhibitory mechanisms are distinct and independent of each other. The work presented here opens the door to analyzing how central and peripheral inhibition regulates feeding behaviors in Drosophila melanogaster

The cellular basis of distinct thirst modalities

Fluid intake is an essential innate behaviour that is mainly caused by two distinct types of thirst. Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolaemic thirst, in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs in the lamina terminalis are critical sites for sensing both types of thirst-inducing stimulus. However, how different thirst modalities are encoded in the brain remains unknown. Here we employed stimulus-to-cell-type mapping using single-cell RNA sequencing to identify the cellular substrates that underlie distinct types of thirst. These studies revealed diverse types of excitatory and inhibitory neuron in each circumventricular organ structure. We show that unique combinations of these neuron types are activated under osmotic and hypovolaemic stresses. These results elucidate the cellular logic that underlies distinct thirst modalities. Furthermore, optogenetic gain of function in thirst-modality-specific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Together, these results show that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain

Severe Chloroquine Retinopathy without Bull’s Eye Maculopathy

Chloroquine has long been used for the treatment of autoimmune diseases, beside its use for treatment and prevention of malaria. We herein report a chloroquine retinopathy case with a history of 250 mg per day chloroquine treatment for SLE for the last 15 years. Besides clinical evaluation, the patient was assessed with different functional (visual field, microperimetry, electroretinography, multifocal electroretinography) and structural (optical coherence tomography, retinal nerve fiber layer thickness analysis) retinal analysis methods. (Turk J Ophthalmol 2014; 44: 403-6