The formation and recall of episodic memory requires precise information processing by the entorhinal-hippocampal network. For several decades, the trisynaptic circuit, entorhinal cortex layer II (ECII)→dentate gyrus (DG)→CA3→CA1 and the monosynaptic circuit ECIII→CA1 have been considered the main substrates of the network responsible for learning and memory. Circuits linked to another hippocampal region, CA2, have only recently come to light. Here, by using highly cell type-specific transgenic mouse lines, optogenetics, and patch-clamp recordings, we show that DG cells, long believed not to project to CA2, send functional monosynaptic inputs to CA2 pyramidal cells, through abundant longitudinal projections. CA2 innervates CA1 to complete an alternate trisynaptic circuit but, unlike CA3, projects preferentially to the deep rather than superficial sublayer of CA1. Furthermore, contrary to the current knowledge, ECIII does not project to CA2. These new anatomical results will allow for a deeper understanding of the biology of learning and memory.

Summary Environmental humidity influences the fitness and geographic distribution of all animals [1]. Insects in particular use humidity cues to navigate the environment, and previous work suggests the existence of specific sensory mechanisms to detect favorable humidity ranges [2–5]. Yet, the molecular and cellular basis of humidity sensing (hygrosensation) remains poorly understood. Here, we describe genes and neurons necessary for hygrosensation in the vinegar fly Drosophila melanogaster. We find that members of the Drosophila genus display species-specific humidity preferences related to conditions in their native habitats. Using a simple behavioral assay, we find that the ionotropic receptors IR40a, IR93a and IR25a are all required for humidity preference in D. melanogaster. Yet, while IR40a is selectively required for hygrosensory responses, IR93a and IR25a mediate both humidity and temperature preference. Consistent with this, the expression of IR93a and IR25a includes thermosensory neurons of the arista. In contrast, IR40a is excluded from the arista, but expressed (and required) in specialized neurons innervating pore-less sensilla of the sacculus, a unique invagination of the third antennal segment. Indeed, calcium imaging shows that IR40a neurons directly respond to changes in humidity, and IR40a knockdown or IR93a mutation reduced their responses to stimuli. Taken together, our results suggest that the preference for a specific humidity range depends on specialized sacculus neurons, and that the processing of environmental humidity can happen largely in parallel to that of temperature.

SUMMARY In Drosophila, rapid temperature changes are detected at the periphery by dedicated receptors forming a simple sensory map for hot and cold in the brain1. However, flies show a host of complex innate and learned responses to temperature, indicating that they are able to extract a range of information from this simple input. Here, we define the anatomical and physiological repertoire for temperature representation in the Drosophila brain. First, we use a photolabeling strategy2 to trace the connections that relay peripheral thermosensory information to higher brain centers, and show that they largely converge onto three target regions: the Mushroom Body, Lateral Horn (well-known centers for sensory processing) and the Posterior Lateral Protocerebrum, a region we now define as a major site of thermosensory representation. Then, using in vivo calcium imaging3, we describe the thermosensory projection neurons selectively activated by hot or cold stimuli. Fast-adapting neurons display transient “ON” and “OFF” responses and track rapid temperature shifts remarkably well, while slow-adapting cell responses better reflect the magnitude of simple thermal changes. Unexpectedly, we also find a population of ‘broadly-tuned’ cells that respond to both heating and cooling, and show that they are required for normal behavioral avoidance of both hot and cold in a simple 2-choice temperature preference assay. Taken together, our results uncover a coordinated ensemble of neural responses to temperature in the fly brain, demonstrate that a broadly tuned thermal-line contributes to rapid avoidance behavior, and illustrate how stimulus quality, temporal structure, and intensity can be extracted from a simple glomerular map at a single synaptic station.

Summary The Drosophila antenna contains receptor neurons for mechanical, olfactory, thermal and humidity stimuli. Neurons expressing the ionotropic receptor IR40a have been implicated in the selection of an appropriate humidity range [1, 2], but while previous work indicates that insect hygroreceptors may be made up by a ‘triad’ of neurons (with a dry- a cold- and a humid-air responding cell [3]), IR40a expression included only cold- and dry-air cells. Here, we report the identification of the humid-responding neuron that completes the hygrosensory triad in the Drosophila antenna. This cell type expresses the Ir68a gene, and Ir68a mutation perturbs humidity preference. Next, we follow the projections of Ir68a neurons to the brain, and show that they form a distinct glomerulus in the posterior antennal lobe (PAL). In the PAL, a simple sensory map represents related features of the external environment with adjacent ‘hot’, ‘cold’, ‘dry’, and ‘humid’ glomeruli -an organization that allows for both unique and combinatorial sampling by central relay neurons. Indeed, flies avoided dry heat more robustly than humid heat, and this modulation was abolished by silencing dry-air receptors. Consistently, at least one projection neuron type received direct synaptic input from both temperature and dry air glomeruli. Our results further our understanding of humidity sensing in the Drosophila antenna, uncover a neuronal substrate for early sensory integration of temperature and humidity in the brain, and illustrate the logic of how ethologically relevant combinations of sensory cues can be processed together to produce adaptive behavioral responses

Highlights d The fly antenna contains 3 types of cold-activated sensory neurons d Cold cells converge on ''cold'' domain of the brain thermosensory map d Second-order TPN-IIs relay absolute cold, below D. melanogaster's favorite 25 C d TPN-IIs inhibit DN1a circadian neurons, adapting sleep to cold/dark conditions

Ubiquitin proteasome system (UPS) determines the timing and extent of protein turnover in cells, and it is one of the most strictly controlled cellular mechanisms. Lack of proper control over UPS is attributed to both cancer and to neurodegenerative diseases, yet in different context and direction. Cancerous cells have altered cellular metabolisms, uncontrolled cellular division, and increased proteasome activity. The specialized function prevent neurons from undergoing cellular division but allow them to extend an axon over long distances, establish connections, and to form stable neuronal circuitries. Neurons heavily depend on the proper function of the proteasome and the UPS for their proper function. Reduction of UPS function in vulnerable neurons results in protein aggregation, increased ER stress, and cell death. Identification of compounds that selectively block proteasome function in distinct set of malignancies added momentum to drug discovery efforts, and deubiquitinases (DUBs) gained much attention. This review will focus on ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a DUB that is attributed to both cancer and neurodegeneration. The potential of developing effective treatment strategies for two major health problems by controlling the function of UPS opens up new avenues for innovative approaches and therapeutic interventions.

Ants communicate via large arrays of pheromones and possess expanded, highly complex olfactory systems, with antennal lobes in the brain comprising ~500 glomeruli. This expansion implies that odors could activate hundreds of glomeruli, which would pose challenges for higher order processing. To study this problem, we generated the first transgenic ants, expressing the genetically encoded calcium indicator GCaMP6s in olfactory sensory neurons. Using two-photon imaging, we mapped complete glomerular responses to four ant alarm pheromones. Alarm pheromones robustly activated ≤6 glomeruli, and activity maps for the three pheromones inducing panic-alarm in our study species converged on a single glomerulus. These results demonstrate that, rather than using broadly tuned combinatorial encoding, ants employ precise, narrowly tuned, and stereotyped representation of alarm pheromone cues. The identification of a central sensory hub glomerulus for alarm behavior suggests that a simple neural architecture is sufficient to translate pheromone perception into behavioral outputs.

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