dc.contributor.advisor | Winder, Danny G | |
dc.contributor.advisor | Patel, Sachin | |
dc.creator | Folkes, Oakleigh Marie | |
dc.date.accessioned | 2020-09-22T21:32:46Z | |
dc.date.created | 2020-01 | |
dc.date.issued | 2020-01-17 | |
dc.date.submitted | January 2020 | |
dc.identifier.uri | http://hdl.handle.net/1803/15997 | |
dc.description.abstract | Deficits in social interaction (SI) are a core symptom of Autism Spectrum Disorders (ASD), 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 ASD. 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 (eCB) signaling reduced BLA-NAc glutamatergic activity, and that pharmacological 2-AG augmentation via administration of JZL184 blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit significantly increased SI in the Shank3B-/-, an ASD model with substantial SI impairment, without affecting SI in wild-type 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 feedforward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASD and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | Endocannabinoids, Basolateral Amygdala, Nucleus Accumbens, Autism, Shank3 | |
dc.title | Investigations of the role of the basolateral amygdala-nucleus accumbens circuit and endocannabinoid regulation of social interaction behavior in the Shank3B-/- model of autism spectrum disorder | |
dc.type | Thesis | |
dc.date.updated | 2020-09-22T21:32:46Z | |
dc.type.material | text | |
thesis.degree.name | PhD | |
thesis.degree.level | Doctoral | |
thesis.degree.discipline | Pharmacology | |
thesis.degree.grantor | Vanderbilt University Graduate School | |
local.embargo.terms | 2021-01-01 | |
local.embargo.lift | 2021-01-01 | |
dc.creator.orcid | 0000-0001-9664-5783 | |