Neuroendocrinology and Pituitary

MON-042 - Heightened Food Reward Motivation and Reduced Opioid Sensitivity and Molecular Shifts in the Orexinergic and Ghrelin Systems Following Developmental Thyrotoxicosis

Monday, June 15, 2026

9:00 AM - 2:00 PM CT

Location: ENDOExpo; Poster Floor

Abstract Poster Presenter(s)

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Logan Teresa Douglas, B.S.

Maine Health Institute for Research
Biddeford, ME, United States

Senior Author/Primary Investigator(s)

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Arturo Hernandez, PhD

MaineHealth Institute for Research
Scarborough, United States

Co-Author(s)

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Arturo Hernandez, PhD

MaineHealth Institute for Research
Scarborough, United States

To investigate the role of gestational thyroid hormone (TH) in programming adult reward systems, we utilized global Dio3 knockout (KO) mice, which model developmental TH excess due to the loss of the TH-inactivating enzyme, DIO3. We hypothesize that developmental TH excess programs adult behaviors, hormone physiology and gene expression of relevance to the reward system.

Methods: We used adult male and female WT and Dio3 KO littermates bred on a hybrid C57BL/6J × 129X1/SvJ background, including reciprocal crosses to assess parent-of-origin effects. Food reward motivation was measured using a palatable food reward self-administration runway assay and palatable food conditioned place preference (CPP). Opioid sensitivity was assessed using twice-daily morphine injections over 72 hours with nociceptive testing (hot-plate tail-flick latency) at baseline and 30 minutes post-morphine, followed by naloxone-precipitated withdrawal scoring. We measured serum acyl and total ghrelin by ELISA. We also quantified reward-related gene expression in hypothalamus, striatum, and amygdala, as well as gene expression responses to a 16 h fasting.

Results: Dio3 KO mice exhibited increased palatable food motivation and significant resistance to extinction in the palatable food reward self-administration runway. Dio3 KO mice with a C57BL/6J paternal background also showed an increased CPP for palatable food reward. In the opioid assay, Dio3 KO mice exhibited higher tail-flick latency after three days of morphine treatment, consistent with reduced tolerance, and displayed significantly fewer total jumps following naloxone administration. Notably, the subset of Dio3 KO mice that jumped were all female, with no Dio3KO males showing withdrawal-dependent jumping. Serum acyl ghrelin trended lower in Dio3 KO mice, and the acyl:total ghrelin ratio was significantly reduced, most prominently in animals with a C57BL/6J paternal background. In the hypothalamus of fasted mice, Ghsr, which functions as the ghrelin receptor, expression was significantly lower in fasted Dio3 KO mice compared with WT, and Dio3 KO mice did not exhibit the expected post-prandial decrease in orexin (Hcrt, also hypocretin). Molecular analyses revealed a complex remodeling of the orexinergic and dopaminergic systems. In the amygdala, Hcrt was downregulated while Hcrtr1 was upregulated, which was confirmed via RNAscope. RNA-seq and RNAscope further showed sex-specific dysregulation of addiction-linked genes, such as Ppp1r1b and Gpr88 within the amygdala and striatum.

Conclusion: Developmental TH excess leads in adulthood to heightened palatable food motivation and attenuated opioid tolerance and withdrawal, reward-related behaviors that were associated with significant brain and serum alterations in the ghrelin and orexin systems.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*