Mice lacking paternal expression of imprinted Grb10 are risk‐takers

Abstract

The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting task in an opposite manner. A recently developed theory suggests that this pattern of behavior may be representative of predicted effects of imprinted genes on tolerance to risk. Here we examine whether mice lacking paternal expression of Grb10 show abnormal behavior across a number of measures indicative of risk‐taking. Although Grb10+/p mice show no difference from wild type (WT) littermates in their willingness to explore a novel environment, their behavior on an explicit test of risk‐taking, namely the Predator Odor Risk‐Taking task, is indicative of an increased willingness to take risks. Follow‐up tests suggest that this risk‐taking is not simply because of a general decrease in fear, or a general increase in motivation for a food reward, but reflects a change in the trade‐off between cost and reward. These data, coupled with previous work on the impulsive behavior of Grb10+/p mice in the delayed reinforcement task, and taken together with our work on mice lacking maternal Nesp, suggest that maternally and paternally expressed imprinted genes oppositely influence risk‐taking behavior as predicted.

Paternal early life stress exerts intergenerational effects on male C57Bl/6J offspring risk-taking behaviors and predator scent-induced c-Fos expression

“…Unexpectedly, no significant difference in hypothalamus Grb10 gene expression was detected between the groups ( t = 1.586, P =0.135) ( Figure 2 A). This was surprising since it had been reported that paternal expression of imprinted Grb10 directly regulates risk-taking behavior in the PORT task [ 19 ], so we extended our profiling to other imprinted genes. In contrast, Igf2 levels were significantly increased in PatMS offspring ( t = 4.381, P <0.001) ( Figure 2 B), consistent with a previous finding in a model of paternal generalized daily stress [ 11 ].…”

“…The PORT protocol was adapted from Dent et al, 2020 [ 19 ] and represented in Figure 1 A. Two to four mice per litter from four control and four PatMS litters were trained for PORT.…”

“…1% TMT solutions were prepared and stored at 4°C for up to 4 weeks before testing. TMT-scented bedding was prepared in individual sealable bags, in which 250 μl of 1% TMT was added to 200 g of bedding, equivalent to the TMT-bedding concentration previously published [ 19 ]. The bags were thoroughly mixed and prepared 2 days before the final test days, and kept in a cool dark space.…”

“…Disruption of maternal Grb10 expression in the periphery is associated with Silver–Russell syndrome [ 16 , 17 ], a condition that manifests a range of metabolic and growth disruptions [ 18 ]. In the absence of paternal Grb10, mice failed to adapt by increasing their hesitancy to enter an area marked with TMT, a chemical scent mimicking fox odor [ 19 ]. It is presently unknown whether the expression of paternal Grb10 is subject to intergenerational modification and, if so, whether that would result in maladaptive behavioral responses to predator odors.…”

Noncanonical genomic imprinting in the monoamine system determines naturalistic foraging and brain-adrenal axis functions

“…We previously found that the Prader-Willi syndrome imprinted gene, Magel2, significantly affects foraging modules ( Hörndli et al, 2019 ), building on studies by others showing that Magel2 affects anxiety-like responses, feeding, activity, and 5-HT signaling ( Kozlov et al, 2007 ; Mercer et al, 2009 ). Moreover, Grb10 impacts impulsive choice and risk-taking behaviors ( Dent et al, 2016 , 2018 , 2020 ). Grb10 is a canonical imprinted gene that resides next to Ddc, and it is paternally expressed in the mouse and human brain and maternally expressed in the body ( Arnaud et al, 2003 ; Menheniott et al, 2008 ; Sanz et al, 2008 ).…”