Highlights d SMART-seq and 10x platforms reveal 17 transcriptomic cell types (T-types) in VMHvl d Multiplexed smFISH confirms scRNA-seq and identifies Ttypes with A-P restrictions d Rare female-and male-specific T-types are found among the Esr1 + subclusters d Relatively few VMHvl T-types exhibit behavior-specific activation and connectivity

Neuromodulators play a key role in adjusting animal behavior based on environmental cues and internal needs. Here, we review the regulation of Drosophila feeding behavior to illustrate how neuromodulators achieve behavioral plasticity. Recent studies have made rapid progress in determining molecular and cellular mechanisms that translate the metabolic needs of the fly into changes in neuroendocrine and neuromodulatory states. These neuromodulators in turn promote or inhibit discrete feeding behavioral subprograms. This review highlights the links between physiological needs, neuromodulatory states, and feeding decisions.

Summary Feeding is dynamically regulated by the palatability of the food source and the physiological needs of the animal. How consumption is controlled by external sensory cues and internal metabolic state remains under intense investigation. Here, we identify four GABAergic interneurons in the Drosophila brain that establish a central feeding threshold which is required to inhibit consumption. Inactivation of these cells results in indiscriminate and excessive intake of all compounds, independent of taste quality or nutritional state. Conversely, acute activation of these neurons suppresses consumption of water and nutrients. The output from these neurons is required to gate activity in motor neurons that control meal initiation and consumption. Thus, our study reveals a new layer of inhibitory control in feeding circuits that is required to suppress a latent state of unrestricted and non-selective consumption.

Temporal lobe epilepsy remains amongst the most common and drug refractory of neurological disorders. Gene therapy may provide a realistic therapeutic approach alternative to surgery for intractable focal epilepsies. To test this hypothesis, we applied here a gene therapy approach, using a recombinant adeno-associated viral (rAAV) vector expressing the human neuropeptide Y (NPY) gene, to a progressive and spontaneous seizure model of temporal lobe epilepsy induced by electrical stimulation of the temporal pole of the hippocampus, which replicates many features of the human condition. rAAV-NPY or a control vector lacking the expression cassette (rAAV-Empty) was delivered into the epileptic rat hippocampi at an early progressive stage of the disease. Chronic epileptic rats were video-EEG monitored to establish pre-injection baseline recordings of spontaneous seizures and the effect of rAAV-NPY versus rAAV-Empty vector injection. Both non-injected stimulated controls and rAAV-empty injected rats showed a similar progressive increase of spontaneous seizure frequency consistent with epileptogenesis. The delivery of rAAV-NPY in epileptic rat brain leads to a remarkable decrease in the progression of seizures as compared to both control groups and this effect was correlated with the NPY over-expression in the hippocampus. Moreover, spontaneous seizure frequency was significantly reduced in 40% of treated animals as compared to their pre-injection baseline. Our data show that this gene therapy strategy decreases spontaneous seizures and suppresses their progression in chronic epileptic rats, thus representing a promising new therapeutic strategy.

Fluid intake is an essential innate behavior mainly caused by two distinct types of thirst 1 – 3 . Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolemic thirst in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs (CVOs) in the lamina terminalis (LT) are critical sites for sensing both types of thirst-inducing stimuli 4 – 6 . However, how different thirst modalities are encoded in the brain remains unknown. Here, we employed stimulus to cell-type mapping using single-cell RNA-seq (scRNA-seq) to determine the cellular substrate underlying distinct types of thirst. These studies revealed diverse excitatory and inhibitory neuron types in each CVO structure. Among them, we show that unique combinations of neuron types are activated under osmotic and hypovolemic stresses. These results elucidate the cellular logic underlying 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. Taken together, this study demonstrates that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain.

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Fluid intake is an essential innate behavior mainly caused by two distinct types of thirst [1][2][3] . Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolemic thirst in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs (CVOs) in the lamina terminalis (LT) are critical sites for sensing both types of thirst-inducing stimuli [4][5][6] . However, how different thirst modalities are encoded in the brain remains unknown. Here, we employed stimulus to cell-type mapping using single-cell RNA-seq (scRNA-seq) to determine the cellular substrate underlying distinct types of thirst. These studies revealed diverse excitatory and inhibitory neuron types in each CVO structure. Among them, we show that unique combinations of neuron types are activated under osmotic and hypovolemic stresses. These results elucidate the cellular logic underlying distinct thirst modalities. Furthermore, optogenetic gain-of-function in thirst-modalityspecific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Taken together, this study demonstrates that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain.In the mammalian brain, fluid imbalance is detected by LT CVOs, the sensory organs of the brain that lack the normal blood-brain barrier 7 . The subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT) are the forebrain CVOs that sense internal fluid status and regulate drinking behavior through their downstream brain sites. The majority of excitatory neurons in these CVOs are activated under dehydration, and acute stimulation of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: