Circuit modules linking internal states and social behaviour in flies and mice

Journal name:
Nature Reviews Neuroscience
Volume:
17,
Pages:
692–704
Year published:
DOI:
doi:10.1038/nrn.2016.125
Published online

Abstract

Goal-directed social behaviours such as mating and fighting are associated with scalable and persistent internal states of emotion, motivation, arousal or drive. How those internal states are encoded and coupled to behavioural decision making and action selection is not clear. Recent studies in Drosophila melanogaster and mice have identified circuit nodes that have causal roles in the control of innate social behaviours. Remarkably, in both species, these relatively small groups of neurons can influence both aggression and mating, and also play a part in the encoding of internal states that promote these social behaviours. These similarities may be superficial and coincidental, or may reflect conserved or analogous neural circuit modules for the control of social behaviours in flies and mice.

At a glance

Figures

  1. P1 and VMHvl neurons control multiple social behaviours.
    Figure 1: P1 and VMHvl neurons control multiple social behaviours.

    a,b | Simplified schematics illustrating extreme alternative views of the possible relationship between aggression and mating circuits. Spheres indicate circuit nodes containing multiple neurons. Signals (for example, pheromones) from male and female conspecifics may activate parallel pathways to release aggression and mating, respectively (part a), or these pathways may converge on a common node that controls both of these social behaviours (part b). In part a, reciprocal inhibition between pathways is omitted for clarity. c | Schematic illustrating a Drosophila melanogaster brain showing the location of the P1 cluster and major projections. d | Coronal section of a mouse brain indicating the location of the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl). e,f | Behavioural phenotypes promoted by optogenetic stimulation of P1 neurons in male flies (part e) or VMHvl oestrogen receptor 1-positive neurons in male mice (part f). Part c is adapted from Ref. 30, Nature Publishing Group. Fly images in part e adapted from drawings courtesy of H. Chiu, California Institute of Technology, USA.

  2. Effects of P1 neuron activation on social behaviour in flies.
    Figure 2: Effects of P1 neuron activation on social behaviour in flies.

    a–c | Effects of activating different populations of P1 neurons either thermogenetically77 using dTrpA1 (parts a,b) or optogenetically using ReaChR75, 80 or CsChrimson81 (part c). Green spheres indicate the subset of P1 neurons that are genetically labelled in each case; purple spheres indicate unlabelled P1 neurons. 'P1a split Gal4' (parts a,c) indicates a subset of 8–10 P1 neurons63 (green shading) that are labelled by a genetic intersection between lines 71G01 (Refs 69,74) and 15A01, which were recovered in the original screen74. 'P1 Gal4 ∩ fru–FLP' (part b) indicates a subset of ~3–5 P1 neurons that are identified by the intersection of 71G01-Gal4 and fru–FLP62, 63. Behavioural readouts (wing extension and lunging) are denoted using arrows: thick arrows indicate an increase in behaviour in pairs of male flies following P1 subset activation; the thin arrow indicates a weaker behavioural phenotype. '–' indicates that there was no observed change in behaviour. Simulated behavioural rasters (red and blue vertical tick marks) are also shown. d,e | Two speculative circuit models to explain the inverse control of courtship and aggression by optogenetic activation of P1a neurons. In the rebound (indirect) model, the influence of P1a neurons on aggression circuits is indirect and inhibitory (part d). During the light-ON phase, P1a neurons activate a wing-extension circuit63 (indicated by 'w'), trigger a persistent internal state (π state) and suppress aggression-promoting neurons (indicated by 'a') through a putative inhibitory interneuron (indicated by 'i'). After light offset (light OFF), and in the presence of a conspecific male, aggression circuits, which are no longer suppressed by the putative inhibitory interneuron, show rebound activity, which persists (dashed arrow) and suppresses wing extension74. In the priming (direct) model, the influence of P1a neurons on aggression circuits is direct and excitatory (part e). During photostimulation (light ON), P1a neurons activate wing-extension and prime aggression circuits ('a'; grey shading), but overt aggressive behaviour is inhibited by downstream courtship circuitry, locomotor arrest or an influence of light74. After light offset (light OFF), the primed aggression circuit activates its downstream targets and the wing-extension circuit is suppressed. In both models, persistent aggression is driven by the internal state. Thin and thick arrows indicate effects requiring low- and high-frequency photostimulation, respectively. f–h | Three possible models to explain the relationship of optogenetically induced social behavioural phenotypes to the cellular composition of the P1a population. In the first model (part f), common P1a neurons promote both courtship and aggression; the dashed arrow indicates that the effect on aggression may be indirect (as in part d) or direct (as in part e). In the second model (part g), separate subpopulations of FruM-positive (FruM+) cells within the P1a population (as in part a) may separately promote courtship (P1c) and fighting (P1f). In the third model (part h), FruM+DsxM+ P1 cells (P1) exclusively promote courtship and inhibit aggression, and aggression is promoted by FruMDsxM+ cells (pC1)22. DsxM, male-specific Doublesex.

  3. P1a neurons promote a persistent internal state of social arousal or motivation.
    Figure 3: P1a neurons promote a persistent internal state of social arousal or motivation.

    a | Transient optogenetic activation66, 75 (middle panel; light ON) or thermogenetic activation82 (not illustrated) of P1 neurons in solitary male flies triggers persistent wing extension. b,c | Schematics illustrating an experiment to reveal the persistent internal state promoting aggression in Drosophila melanogaster74. Circles represent arenas containing two genetically identical male flies that are separated by a removable partition (red vertical lines). Following 30 s of optogenetic stimulation (left panels; pale red shading), the flies are allowed to recover for 10 min; after this, the partition is removed (right panels) to allow the flies to interact for 5 min. Fighting between flies in which P1a neurons were transiently activated is observed following partition removal (part b; right panel), whereas control flies do not fight (part c; right panel). Before partition removal, solitary flies exhibit persistent wing extension for 2–3 min (not illustrated), as in part a. UAS, upstream activating sequence. Fly images in parts b and c adapted from drawings courtesy of H. Chiu, California Institute of Technology, USA.

  4. VMHvl neurons promote aggressive motivation or arousal.
    Figure 4: VMHvl neurons promote aggressive motivation or arousal.

    a | Electrophysiological recordings from the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl) in awake, behaving male mice98 sniffing an intruder male reveal that the average spiking rate during sniffing predicts the likelihood and duration of ensuing attack110. b | Mice in an operant conditioning chamber can be trained to nose poke for access to a subordinate male that they can attack and defeat112, 113. Optogenetic stimulation of non-genetically targeted neurons in the VMHvl reduces the latency to initiate nose-poke behaviour from 200–600 s to less than 100 s. Pharmacogenetic inhibition of the VMHvl reduced nose poking (not shown). Together, these data imply a role for the VMHvl in promoting aggression-seeking behaviour114.

  5. P1 and VMHvl neurons receive ascending inputs from multiple chemosensory systems.
    Figure 5: P1 and VMHvl neurons receive ascending inputs from multiple chemosensory systems.

    a | Schematic illustrating inputs onto P1 neurons from the olfactory system and gustatory system, which detect volatile and non-volatile pheromones, respectively (see also Refs 26,30). b | Schematic illustrating inputs onto the mouse ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl) from the main and accessory olfactory systems. Only a subset of connections is illustrated. Data from Ref. 125. In parts a and b, black arrows indicate excitatory connections, flat-headed arrows indicate inhibitory connections, dashed arrows indicate probable indirect connections, and beige boxes and grey lines illustrate hypothetical connections (of unknown sign) based on extrapolations from known connections26, 65, 66. c | P1a and VMHvl oestrogen receptor 1-positive (ESR1+) neurons may promote multiple functions. These neurons may accumulate (integrate) information about multiple sensory cues (s1–s3) at different times over the course of a social encounter (early stages right arrow late stages) and transform this information into an internal state, classification of conspecific sex and/or behavioural decision. These functions may be exerted via the outputs of these structures in parallel (model 1), in series (model 2) or in some combination of the two (not illustrated). d | In flies, anatomically defined putative inputs onto and outputs from P1 neurons (dashed lines) express the male sex-determination transcription factor FruM, which is encoded by the male-specific form of fruitless60, 62 (left panel). Analogously, in mice, anatomically defined inputs onto and outputs from the VMHvl express ESR1 (Ref. 135), which is required for masculinization of social-behaviour circuits148 (right panel). Electrophysiological confirmation of direct synaptic connectivity between FruM-positive (FruM+) neurons has been demonstrated in only a few cases (for examples, see Refs 66,149,150) and has not yet been shown for ESR1-positive (ESR1+) neurons in this circuit. AHN, anterior hypothalamic nucleus; AOB, accessory olfactory bulb; CoA, cortical amygdala; dPAG, dorsal periaqueductal grey; BNST, bed nucleus of the stria terminalis; BNSTpr, principal division of the BNST; DC1 and LC1, FruM+ interneurons; GRNs, gustatory receptor neurons; MeA, medial amygdala; MeAp, posterior MeA; MOB, main olfactory bulb; MOE, main olfactory epithelium; MPO, medial preoptic nucleus; Or67d, Odorant receptor 67d; ORNs, olfactory receptor neurons; pIP10, pIP10 descending neurons; PMv, ventral pre-mammillary nucleus; PNs, projection neurons; Ppk23, Pickpocket 23; PPN1, pheromone projection neuron class 1; SC, spinal cord; VNC, ventral nerve cord; VNO, vomeronasal organ; vPN1, ventrolateral protocerebrum projection neuron 1.

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  1. Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA.

    • David J. Anderson

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  • David J. Anderson

    David J. Anderson received his A.B. from Harvard College, Cambridge, Massachusetts, USA, his Ph.D. in cell biology from the Rockefeller University, New York, USA, (where his adviser was Günter Blobel) and did postdoctoral research in molecular biology at Columbia University, New York, USA, with Richard Axel. In 1986, he joined the California Institute of Technology faculty (in the Division of Biology) and, in 1989, became a Howard Hughes Medical Institute Investigator. In 2007, he was elected to the US National Academy of Sciences. For the first 20 years of his career, he investigated the cellular and molecular control of neural crest lineage diversification. At the beginning of the millennium, he switched fields to study neural circuits mediating emotional behaviours.

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