Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.

Background: Older adults with Type 2 diabetes (T2D) are more likely to be frail, which increases the risk for disability and mortality. Objectives: To determine the feasibility of a behavioral lifestyle intervention, enhanced with mobile health technology for self-monitoring of diet and activity, to improve frailty in overweight/obese older adults (≥65 years) diagnosed with T2D. Design, Setting, and Participants: Single arm, 6-month study of a behavioral lifestyle intervention in 20 overweight/obese (BMI>25) older adults (≥ 65 years) with self-reported T2D diagnosis who owned a smartphone. A Fitbit tracker was provided to all participants for self-monitoring of diet and physical activity. Our primary outcome of feasibility was measured by session attendance, adherence to Fitbit usage to self-monitor diet and physical activity, and study retention. Secondary outcomes included the preliminary efficacy of the intervention on frailty, physical function, quality of life, and T2D-related outcomes. Results: Eighteen participants completed the study. The mean age was 71.5 (SD ± 5.3) years, 56% were female, and half were Hispanic. At baseline, 13 (72%) were pre-frail, 4 (22%) were frail, and 1 (6%) were non-frail. At follow-up, frailty scores improved significantly from 1.61 ± 1.15 to 0.94 ± 0.94 (p=0.01) and bodyweight improved from 205.66 ± 45.52 lbs. to 198.33 ± 43.6 lbs. (p=<0.001). Conclusion: This study provides evidence for the feasibility of a behavioral lifestyle intervention in overweight/obese older adults with T2D and preliminary results support its potential efficacy in improving frailty score.

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