Contribution of the co-chaperone FKBP51 in the ventromedial hypothalamus to metabolic homeostasis in male and female mice.

OBJECTIVE: Steroidogenic factor 1 (SF1) expressing neurons in the ventromedial hypothalamus (VMH) have been directly implicated in whole-body metabolism and in the onset of obesity. The co-chaperone FKBP51 is abundantly expressed in the VMH and was recently linked to type 2 diabetes, insulin resistance, adipogenesis, browning of white adipose tissue (WAT) and bodyweight regulation. METHODS: We investigated the role of FKBP51 in the VMH by conditional deletion and virus-mediated overexpression of FKBP51 in SF1-positive neurons. Baseline and high fat diet (HFD)-induced metabolic- and stress-related phenotypes in male and female mice were obtained. RESULTS: In contrast to previously reported robust phenotypes of FKBP51 manipulation in the entire mediobasal hypothalamus (MBH), selective deletion or overexpression of FKBP51 in the VMH resulted in only a moderate alteration of HFD-induced bodyweight gain and body composition, independent of sex. CONCLUSIONS: Overall, this study shows that animals lacking and overexpressing Fkbp5 in Sf1-expressing cells within the VMH display only a mild metabolic phenotype compared to an MBH-wide manipulation of this gene, suggesting that FKBP51 in SF1 neurons within this hypothalamic nucleus plays a subsidiary role in controlling whole-body metabolism.

Certainty and uncertainty of the future changes planning and sunk costs.

Many foraging experiments have found that subjects are suboptimal in foraging tasks, waiting out delays longer than they should given the reward structure of the environment. Additionally, theories of decision-making suggest that actions arise from interactions between multiple decision-making systems and that these systems should depend on the availability of information about the future. To explore suboptimal behavior on foraging tasks and how varying the amount of future information changed behavior, we ran rats on two matching neuroeconomic foraging tasks, Known Delay (KD) and Randomized Delay (RD), with the only difference between them being the certainty of the cost of future opportunities. Rats' decision-making strategies differed significantly based on the amount of future certainty. Rats on both tasks still showed suboptimality in decision-making through a sensitivity to sunk costs; however, rats on KD showed significantly less sensitivity to sunk costs than rats on RD. Additionally, on neither task did the rats account for travel and postreward lingering times as heavily as prereward foraging times providing evidence problematic for the Marginal Value Theorem model of foraging behavior. This suggests that while future certainty reduced decision-making errors, more complex decision-making processes unaffected by future certainty were involved and likely produced these decision-making errors within subjects on these foraging tasks. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Repair of nuclear ruptures requires barrier-to-autointegration factor.

Cell nuclei rupture following exposure to mechanical force and/or upon weakening of nuclear integrity, but nuclear ruptures are repairable. Barrier-to-autointegration factor (BAF), a small DNA-binding protein, rapidly localizes to nuclear ruptures; however, its role at these rupture sites is unknown. Here, we show that it is predominantly a nonphosphorylated cytoplasmic population of BAF that binds nuclear DNA to rapidly and transiently localize to the sites of nuclear rupture, resulting in BAF accumulation in the nucleus. BAF subsequently recruits transmembrane LEM-domain proteins, causing their accumulation at rupture sites. Loss of BAF impairs recruitment of LEM-domain proteins and nuclear envelope membranes to nuclear rupture sites and prevents nuclear envelope barrier function restoration. Simultaneous depletion of multiple LEM-domain proteins similarly inhibits rupture repair. LEMD2 is required for recruitment of the ESCRT-III membrane repair machinery to ruptures; however, neither LEMD2 nor ESCRT-III is required to repair ruptures. These results reveal a new role for BAF in the response to and repair of nuclear ruptures.