Disengagement of Somatostatin Neurons From Lateral Septum Circuitry by Oxytocin and Vasopressin Restores Social Fear Extinction and Suppresses Aggression Outbursts in a Prader-Willi Syndrome Model

Dromard, Yann; Borie, Amélie M.; Chakraborty, Prabahan; Muscatelli, Françoise; Guillon, Gilles; Desarménien, Michel G.; Jeanneteau, Freddy

doi:10.1016/j.biopsych.2023.10.016

Cited by 3 publications

(11 citation statements)

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“…Using a mouse model of PWS, the present study examined the activity of OXT neurons as conditioned mice recalled social fear while in the presence of a safe social stimulus. Compared to WT, Magel2 KO mice had similar response during conditioning and equivalent recall of social fear memory 24 h later, in agreement with our recent observations (11). We add that this memory of social fear is persistent and lasts at least up to 7 days after conditioning.…”

Section: Discussionsupporting

confidence: 92%

“…We aimed to track the activity of SON OXT neurons in vivo – that have been previously implicated in social fear (11) - during recall of social fear memory over days while in presence of a socially safe cue. Thus, we stereotaxically targeted the SON in oxytocin-Cre mice crossed with Magel2 KO to inject a Cre-dependent virus expressing GCaMP7s (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Apart from well-documented developmental deficits, PWS patients also show a high comorbidity with autism symptoms (2,3) including decreased social responsiveness in non-threatening contexts (4), increased temper outbursts (5)(6)(7) and social fear (8). Remarkably, most of these clinical symptoms are well-replicated in Magel2 knockout (KO) mice, which report impaired response to social novelty following social habituation (9,10) as well as high social fear that is difficult to extinguish (11).…”

Section: Introductionmentioning

confidence: 99%

“…Remarkably, recruitment of the specific source of OXT and AVP in the brain may be cued to behavioral experience. For instance, OXT neurons in the supraoptic nucleus (SON), but not in the paraventricluar nucleus (PVN), are specifically activated during social fear extinction (11). While we have recently reported that impairment in the SON-lateral septum OXT pathway underlies social fear extinction deficits in Magel2 KO (11), how the SON neurons themselves respond during social fear recall remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, OXT neurons in the supraoptic nucleus (SON), but not in the paraventricluar nucleus (PVN), are specifically activated during social fear extinction (11). While we have recently reported that impairment in the SON-lateral septum OXT pathway underlies social fear extinction deficits in Magel2 KO (11), how the SON neurons themselves respond during social fear recall remains unexplored. Intriguingly, common social assays in rodents test response towards a single social cue at one instant.…”

Section: Introductionmentioning

confidence: 99%

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Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Chakraborty,

Lamat,

André

et al. 2024

Preprint

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Introduction: Exposure to social trauma may alter engagement with both fear-related and unrelated social stimuli long after. Intriguingly, how simultaneous discrimination of social fear and safety is affected in neurodevelopmental conditions like autism remains underexplored. The role of the neuropeptide oxytocin is established in social behaviors, and yet unexplored during such a challenge post-social trauma. Methods: Using Magel2-knockout mice, an animal model of Prader Willi Syndrome (PWS) and autism spectrum disorders, we tested memory of social fear and safety after a modified social fear conditioning task. Additionally, we tracked the activity of oxytocin neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus by fibre photometry, as animals were simultaneously presented with a choice between a fear and safe social cue during recall. Results: Male Magel2 KO mice trained to fear females with electrical footshocks avoided both unfamiliar females and males during recalls, lasting even a week post-conditioning. On the contrary, trained Magel2 WT avoided only females during recalls, lasting days rather than a week postconditioning. Inability to overcome social fear and avoidance of social safety in Magel2 KO mice were associated with reduced engagement of oxytocin neurons in the SON, but not the PVN. Conclusion: In a preclinical model of PWS, we demonstrated region-specific deficit in oxytocin activity associated with behavioral generalization of social fear to social safety. Insights from this study add to our understanding of oxytocin action in the brain at the intersection of social trauma, PWS and related autism spectrum disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Chakraborty,

Lamat,

André

et al. 2024

Preprint

Self Cite

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Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model

Borie,

Dromard,

Chakraborty

et al. 2024

Cell Reports Medicine

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MAGEL2 (patho‐)physiology and Schaaf–Yang syndrome

Schubert,

Schaaf

2024

Develop Med Child Neuro

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Schaaf–Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader–Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss‐of‐function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation.

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Disengagement of Somatostatin Neurons From Lateral Septum Circuitry by Oxytocin and Vasopressin Restores Social Fear Extinction and Suppresses Aggression Outbursts in a Prader-Willi Syndrome Model

Cited by 3 publications

References 61 publications

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model

MAGEL2 (patho‐)physiology and Schaaf–Yang syndrome

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