Social isolation modulates appetite and defensive behavior via a common oxytocinergic circuit in larval zebrafish

Abstract

24How brains encode social stimuli and transform these representations into advantageous 25 behavioral responses is not well-understood. Here, we show that social isolation activates an 26 oxytocinergic, nociceptive circuit in the larval zebrafish hypothalamus. We further demonstrate 27 that chemical cues released from conspecific animals modulate its activity to regulate defensive 28 behaviors and appetite. Our collective data reveals a model through which social stimuli can be 29 integrated into fundamental neural circuits to mediate adaptive behaviour. 30 31 32 33 34In mammals, signaling in oxytocinergic (OXT) circuits modulates a wide spectrum of socially 36 driven behaviors, ranging from pair bonding and parental care to the responses to stress and 37 pain 1-3 . OXT has also been described as a potent regulator of appetite 4,5 . We reported recently 38 that the larval zebrafish OXT circuit encodes a response to aversive, particularly noxious stimuli 39 and directly drives nocifensive behavior via brainstem premotor targets 6 . Moreover, studies in 40 both zebrafish 6-8 and mammals 9,10 suggest that the OXT-expressing neuronal population is 41 anatomically and functionally diverse, and might also modulate multiple behaviors in zebrafish. 42Here, in a brain-wide screen 11 for neuronal populations whose activity reflects social context, we 43show that larval zebrafish oxytocinergic circuits display diverse responses to conspecific 44 chemosensory stimuli, and are key effectors for social context modulation of nociceptive and 45 appetite-driven behaviors. Our results reveal a simple algorithm by which neuromodulatory 46 neurons can represent social context to exert flexible control over hard-wired behavioral drives. 47 48 RESULTS 49Brain-wide activity mapping of social isolation and its rescue by conspecific chemical cues 50Using pERK based whole-brain activity mapping (MAP-Mapping 11 ), neural activity in brains of 51 briefly (2 hrs) socially-isolated larvae (7 -8 days-post-fertilization; dpf) was compared to 52 animals that had been maintained in the presence of similarly-aged conspecifics. We found that 53 isolated fish showed an enhancement of neural activity in specific regions, including the 54 telencephalon (especially subpallium), hindbrain, locus coeruleus, area postrema, caudal 55 hypothalamus, preoptic area (PO, homolog of the hypothalamic paraventricular nucleus in 56 mammals) and posterior tuberculum (PT) ( Fig. 1a-b , Supplementary Movie 1, Supplementary 57Data 1). Many of these same regions are activated by noxious or aversive stimuli 6,7 ; they may 58 thus represent the signature activity pattern of a negative internal state, which can be similarly 59 triggered by social deprivation. Neurons expressing the peptide oxytocin (OXT) are abundant in 60 the PO and PT 6,12,13 regions, and as we describe below, OXT-positive neuron clusters in both of 61 these areas (OXT PO and OXT PT respectively) display greater activity in socially-isolated fish. To 62 acquire a more precise quantitation of OXT activi...

Precise visuomotor transformations underlying collective behavior in larval zebrafish

“…The social responses observed in group swimming experiments and the responses we probed using the VR assay were based solely on visual input. Previous studies showed that larval zebrafish also use non-visual cues, such as mechanosensory (33, 56) and chemical stimuli (32) for social interactions. In this study we did not test how different sensory modalities operate jointly to support collective behavior.…”

“…In this study we did not test how different sensory modalities operate jointly to support collective behavior. It will be interesting to test how visual information at longer distances is supported by mechanosensory sensation at shorter distances to elicit social responses (33), or how visual social information is related to chemical stimulation that represents conspecifics (32). These combinations can now be tested in future studies.…”

“…The zebrafish model system is uniquely situated to help address this gap of knowledge. First, this fish species exhibits complex social behaviors, even at the larval stage, that are expected to have a strong visual component ( (20,24,26,(29)(30)(31), but see (32,33) for other modalities). Second, previous studies in larval zebrafish have successfully characterized the underlying computations and brain mechanisms of other complex behaviors such as prey capture (34)(35)(36)(37)(38), predator avoidance (39,40), motor learning (41) and decision making (42)(43)(44).…”

Collective behavior emerges from genetically controlled simple behavioral motifs in zebrafish

“…Although fish have many sensory inputs that contribute to group behaviors, zebrafish are highly visual 28,30,35 , suggesting that visual drives likely play a dominant role. Other sensory modalities, such as somatosensation through the lateral line 19,20 and olfaction 13,21 , undoubtedly also can play a role in modulating social interactions, as might currently less decipherable elements such as "internal state" [12][13][14] and "personality" [15][16][17][18] .…”

“…To achieve such synchronized movements in groups, individual members need to assess certain properties of their near neighbors, including their speed, distance, and orientation, and they need to respond rapidly to these features and then execute the appropriate motor commands. The ability to perform such socially relevant sensorimotor transformations, and thereby the ability to form groups, differ between different genetic backgrounds [8][9][10][11] and are modified by hunger [12][13][14] and innate "personalities'' of individual fish 15,16,17,18 . Further, while inputs from several sensory modalities, such as lateral line mechanoreception 19,20 , olfaction 21,22 and vision, all likely play a role in this process, vision is critical to certain attributes, such as the rapidity of turning responses, the necessary integration of distal cues, and the precision of the alignment responses 11,23,24 .…”