Social Stimuli Induce Activation of Oxytocin Neurons Within the Paraventricular Nucleus of the Hypothalamus to Promote Social Behavior in Male Mice

Resendez, Shanna L.; Namboodiri, Vijay Mohan K.; Otis, James M.; Eckman, Louisa E.H.; Rodríguez-Romaguera, Jose; Ung, Randall L.; Basiri, Marcus L.; Kosyk, Oksana; Rossi, Mark A.; Dichter, Gabriel S.; Stuber, Garret D.

doi:10.1523/jneurosci.1515-18.2020

Cited by 111 publications

(94 citation statements)

References 78 publications

(102 reference statements)

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“…We do note some important distinctions between our findings and the canonical view of OXT function as suggested by mammalian studies, the most significant of which is that the larval zebrafish OXT neurons show widespread activation by social isolation, rather than by cues indicating the presence of conspecifics 2,39 . We propose three possible reasons for these apparent differences: first , representations within both the mammalian and zebrafish OXT population are diverse and thus the observed activity patterns in zebrafish may reflect those of specific subpopulations of mammalian OXT cells (indeed, some zebrafish OXT neurons are activated by conspecific cues, and some mammalian OXT cells are inhibited by conspecific cues 39 ); second , OXT response properties may have changed over the course of evolution, as more sophisticated social functions were derived. Third , there is a possibility that OXT neuron response properties might reverse over the course of development, since adult and kin odor generate opposite activity signatures; however, since the enhancement of preoptic area activation appears to persist at least till juvenile stages (Tunbak et al, preprint online 27 ), when social preference behaviours have developed, any such reversal would have to happen closer to adulthood.…”

Section: Discussioncontrasting

confidence: 58%

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

Wee

Song²,

Nikitchenko

et al. 2020

Preprint

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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...

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Section: Discussioncontrasting

confidence: 58%

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

Wee

Song²,

Nikitchenko

et al. 2020

Preprint

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show abstract

“…Even subtle, largely stress-free social stimuli, such as social investigation of an unknown conspecific, result in elevated electrical activity of OXT neurons [98,99] and a measurable increase in OXT concentrations in the extracellular fluid, for example, within the lateral septum of male mice [66] and rats [65]. Specialized OXT pathways described above consisting of only a few neuronal connections are activated by social interactions and seem to be essential for overcoming social fear [33] and, consequently, for promoting naturally occurring social preference behavior or social memory [65,100].…”

Section: Stimuli Triggering Intracerebral Oxt Releasementioning

confidence: 99%

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

2020

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The neuropeptide oxytocin has attracted great attention of the general public, basic neuroscience researchers, psychologists, and psychiatrists due to its profound pro-social, anxiolytic, and "anti-stress" behavioral and physiological effects, and its potential application for treatment of mental diseases associated with altered socio-emotional competence. During the last decade, substantial progress has been achieved in understanding the complex neurobiology of the oxytocin system, including oxytocinergic pathways, local release patterns, and oxytocin receptor distribution in the brain, as well as intraneuronal oxytocin receptor signaling. However, the picture of oxytocin actions remains far from being complete, and the central question remains: "How does a single neuropeptide exert such pleotropic actions?" Although this phenomenon, typical for many of about 100 identified neuropeptides, may emerge from the anatomical divergence of oxytocin neurons, their multiple central projections, distinct oxytocin-sensitive cell types in different brain regions, and multiple intraneuronal signaling pathways determining the specific cellular response, further basic studies are required. In conjunction, numerous reports on positive effects of intranasal application of oxytocin on human brain networks controlling socio-emotional behavior in health and disease require harmonic tandems of basic researchers and clinicians. During the COVID-19 crisis in 2020, oxytocin research seems central as question of social isolation-induced inactivation of the oxytocin system, and buffering effects of either activation of the endogenous system or intranasal application of synthetic oxytocin need to be thoroughly investigated.

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“…OXTR is widely expressed in human tissues, with particularly high levels being located in limbic brain regions ( Kudwa et al, 2014 ). In conjunction with OXT, OXTR has been reported to regulate diverse social behaviors ( Maejima et al, 2018 ; Gulliver et al, 2019 ; Resendez et al, 2020 ; Soltys et al, 2020 ) and play a role in ASD etiology ( Jacob et al, 2007 ; LoParo and Waldman, 2015 ; Uzefovsky et al, 2019 ), although there has been some controversy with these conclusions ( Tansey et al, 2010 ). Epigenetic modification of OXTR has been widely reported to be associated with ASD development ( Jack et al, 2012 ; Maud et al, 2018 ; Krol et al, 2019 ; Tops et al, 2019 ), although the detailed mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring

Liang

Jiang

et al. 2021

Front. Neurosci.

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Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our in vitro study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor β (ERβ) from the OXTR promoter. Furthermore, our in vivo mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERβ completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.

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Social Stimuli Induce Activation of Oxytocin Neurons Within the Paraventricular Nucleus of the Hypothalamus to Promote Social Behavior in Male Mice

Cited by 111 publications

References 78 publications

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

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

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring

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