An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability
Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 4 vom: 01. Apr., Seite 1728-1742 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Folkes, Oakleigh M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.12.2020 Date Revised 29.03.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI131752 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304742708 |
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| 100 | 1 | |a Folkes, Oakleigh M |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Neuroscience | |
| 650 | 4 | |a Psychiatric diseases | |
| 650 | 7 | |a Endocannabinoids |2 NLM | |
| 650 | 7 | |a Microfilament Proteins |2 NLM | |
| 650 | 7 | |a Nerve Tissue Proteins |2 NLM | |
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| 700 | 1 | |a Báldi, Rita |e verfasserin |4 aut | |
| 700 | 1 | |a Kondev, Veronika |e verfasserin |4 aut | |
| 700 | 1 | |a Marcus, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Hartley, Nolan D |e verfasserin |4 aut | |
| 700 | 1 | |a Turner, Brandon D |e verfasserin |4 aut | |
| 700 | 1 | |a Ayers, Jade K |e verfasserin |4 aut | |
| 700 | 1 | |a Baechle, Jordan J |e verfasserin |4 aut | |
| 700 | 1 | |a Misra, Maya P |e verfasserin |4 aut | |
| 700 | 1 | |a Altemus, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Grueter, Carrie A |e verfasserin |4 aut | |
| 700 | 1 | |a Grueter, Brad A |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Sachin |e verfasserin |4 aut | |
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