Impulsive Choice in Mice Lacking Paternal Expression of Grb10 Suggests Intra-Genomic

Genetics: Early Online, published on March 21, 2018 as 10.1534/genetics.118.300898 1 Impulsive choice in mice lacking paternal expression of Grb10 suggests intra-genomic 2 conflict in behavior 3 Claire L. Dent*, Trevor Humby†, Katie Lewis*, Andrew Ward‡, Reiner Fischer-Colbrie§, 4 LawrenCe S. Wilkinson*,†, Jon F Wilkins** & Anthony R. Isles*, †† 5 *Behavioural GenetiCs GrouP, MRC Centre for NeuroPsyChiatriC GenetiCs and GenomiCs, 6 NeurosCienCe and Mental Health ResearCh Institute, Cardiff University, Hadyn Ellis Building, 7 Maindy Road, Cardiff, United Kingdom 8 †Behavioural GenetiCs GrouP, SChool of PsyChology, Cardiff University, Tower Building, 9 Cardiff, United Kingdom 10 ‡DePartment of Biology and BioChemistry, University of Bath, Bath, United Kingdom 11 §DePartment of PharmaCology, InnsbruCk MediCal University, InnsbruCk, Austria 12 **Ronin Institute, Montclair, NJ 07043, USA 13 ††Author for CorresPondenCe: Anthony R. Isles, E-mail [email protected] 14 15 Running title: Intragenomic conflict and impulsivity 16 Keywords: genomiC imPrinting; NesP55; delayed reinforCement; intra-genomiC ConfliCt; 17 Grb10 18 19 20 21 1 Copyright 2018. 1 Abstract 2 ImPrinted genes are exPressed from one Parental allele only as a ConsequenCe of ePigenetiC 3 events that take Place in the mammalian germ line and are thought to have evolved through 4 intra-genomiC ConfliCt between Parental alleles. We demonstrate, for the first time, 5 oPPositional effeCts of imPrinted genes on brain and behavior. SPeCifiCally, here we show 6 that miCe lacking Paternal Grb10 make fewer impulsive choices, with no dissoCiable effeCts 7 on a seParate measure of imPulsive action. Taken together with Previous work showing that 8 miCe lacking maternal NesP55 make more imPulsive ChoiCes this suggests that imPulsive 9 ChoiCe behavior is a substrate for the action of genomiC imPrinting. Moreover, the 10 Contrasting effeCt of these two genes suggests imPulsive ChoiCes are subjeCt to intra- 11 genomiC ConfliCt and that maternal and Paternal interests Pull this behavior in oPPosite 12 direCtions. Finally, these data may also indiCate that an imbalanCe in exPression of imPrinted 13 genes Contributes to PathologiCal Conditions suCh as gambling and drug addiCtion, where 14 impulsive behavior beComes maladaptive. 2 1 INTRODUCTION 2 ImPrinted genes are exPressed from one Parental allele only as a ConsequenCe of ePigenetiC 3 events that take Place in the mammalian germ line (FERGUSON-SMITH 2011). FunCtionally, 4 imPrinted genes Converge on sPeCifiC biologiCal ProCesses that have Prominent imPortanCe 5 in mammals, suCh as in utero growth, metabolism and behavior (PETERS 2014; WILKINS et al. 6 2016). Many of the effeCts that maternally- and Paternally-exPressed imPrinted genes have 7 on in utero growth and during the early Post-natal Period are oPPositional in direCtion (HAIG 8 AND GRAHAM 1991; MADON-SIMON et al. 2014), lending suPPort to the theory that imPrinting 9 has evolved as a ConsequenCe of intra-genomiC ConfliCt (MOORE AND HAIG 1991; WILKINS AND 10 HAIG 2003). 11 Grb10 is Currently a unique examPle of an imPrinted gene that is exPressed from the 12 maternal allele only in some tissues, and the Paternal allele only in others (ARNAUD et al. 13 2003; HIKICHI et al. 2003; MONK et al. 2009). Consequently, different Parental alleles of Grb10 14 mediate distinCt PhysiologiCal funCtions (GARFIELD et al. 2011). Maternal Grb10 is expressed 15 in many PeriPheral body tissues, whilst being exCluded from the Central nervous system 16 (GARFIELD et al. 2011), and Plays a Prominent role in Controlling Placental funCtion 17 (CHARALAMBOUS et al. 2003; CHARALAMBOUS et al. 2010) and metabolism (SMITH et al. 2007). In 18 Contrast, Paternal Grb10 is essentially restriCted to the brain alone and imPacts on 19 behavioral PhenotyPes, including soCial dominanCe (GARFIELD et al. 2011). Grb10 exPression 20 in the brain is neuronal, showing a Pattern of exPression in disCrete brain regions that is 21 shared with the maternally exPressed imPrinted gene Nesp (PLAGGE et al. 2005). This overlap 22 in brain exPression of maternal Nesp (encoding Nesp55) and Paternal Grb10 has led to 23 sPeCulation that these two genes may influenCe common adult behaviors, Possibly in an 3 1 oPPosite manner (GARFIELD et al. 2011; DENT AND ISLES 2014), whiCh would be Consistent with 2 the PrediCtion from the intra-genomiC ConfliCt theory of genomiC imPrinting evolution (HAIG 3 2000). 4 Here, we address this question direCtly. We have shown that miCe lacking maternal NesP55 m/+ 5 (Nesp ) make more imPulsive ChoiCes (DENT et al. 2016). In Contrast, here we show that 6 Grb10+/P mice make less impulsive choiCes relative to their littermate Controls. Furthermore, 7 there were no dissoCiable effeCts on a seParate measure of imPulsive action, ComPletely m/+ 8 matching the sPeCifiCity of effeCts seen Previously in Nesp mice (DENT et al. 2016). Our 9 data Provide new findings on Grb10 funCtion in brain and reveal oPPosite effeCts of 10 maniPulating Grb10 and Nesp exPression on disCrete asPeCts of imPulsive resPonding. Taken 11 together these data are Consistent with the ConfliCt theory of the evolution of imPrinted 12 genes and as suCh Provide the first direCt evidenCe for intra-genomiC ConfliCt imPacting 13 adult behavior. 14 15 RESULTS AND DISCUSSION 16 Grb10+/p mice make less impulsive choices 17 We used the delayed-reinforCement task to examine imPulsive ChoiCe behavior (ISLES et al. 18 2003), where subjeCts made a ChoiCe between reCeiving a small food reward after a short 19 (1s) delay, or a larger reward after a longer delay (1, 8 or 16s). The extent to whiCh subjeCts 20 make imPulsive ChoiCes is indexed by a PreferenCe for Choosing the immediate but smaller 21 reward, versus a larger delayed reward (delayed gratifiCation). InCreasing the delay to the 22 larger reward within session deCreased the likelihood of Choosing that reward across all 2 23 subjeCts (Figure 1A; main effeCt of DELAY, F2,42=9.20, p=0.001, Partial η =0.37). However, 4 1 Grb10+/P miCe were signifiCantly more tolerant of an increased delay to the larger reward 2 than wild-tyPe (WT) littermate miCe (Figure 1A; main effeCt of GENOTYPE, F1,21=6.45, 3 p=0.019, Partial η2=0.25). However, whilst the data indiCate that the exPerimental grouP 4 diverges from wild-tyPe inCreasingly as the delay inCreases, this effeCt failed to result in a 5 signifiCant interaction between GENOTYPE and DELAY (Figure 1A; F2,42=0.56, p=0.946, Partial 6 η2=0.003), due largely to a Pre-existing grouP differenCe in the first 1s delay bloCk. 7 A standard Control measure to assess the extent to whiCh behavior is sensitive to delay is a 8 task maniPulation where any differential delay assoCiated with the larger and smaller 9 reward was equalized (1s) across all three bloCks. Here, all subjeCts now demonstrated the 10 exPeCted PreferenCe for the larger reward throughout the session (Figure 1B; no main effeCt 2 11 of DELAY, F1.7,35.1=1.88, p=0.17, Partial η =0.08); that is under these task Conditions there 12 were no differences in Choice-bias between Grb10+/P and WT miCe (no main effeCt of 2 13 GENOTYPE, F1,21=0.63, p=0.44, Partial η =0.03). Furthermore, there was no differenCe in the 14 sessions taken to achieve a stable baseline in these Conditions (WT 9 ±0.8; Grb10+/P 8 ±0.5; 15 t21=1.51, P=0.15). 16 The Contrasting Patterns of ChoiCe behavior between the Grb10+/P and WT miCe was also not 17 due to any differenCes between the grouPs in terms of basiC motivation to Carry out the task 18 as Grb10+/P animals acquired the task at the same rate as WT littermates (sessions to last +/P 19 day of baseline; WT 50.4 ±1.1 SEM, Grb10 47.7 ±1.2 SEM t21=1.73, p=0.10). Additionally, 20 variability between Grb10+/P and WT miCe was not related to differenCes in exPerienCing the 21 information trial ContingenCies. In the ‘forCed’ trials (where no ChoiCe was available), both 22 Grb10+/P and their WT littermates made equal resPonses to the large and small reward- 23 related stimuli at all delays (no interaction GENOTYPE x DELAY x CHOICE, F2,42=0.44, 5 1 p=0.649; data not shown). Finally, there was no differenCe between Grb10+/P and WT miCe 2 on general measures of task PerformanCe (see SuPPlemental Information). 3 Figure 1 Grb10+/p mice make less impulsive choices on a delayed-reinforcement task. Behavior of both Grb10+/P and WT miCe Changed across session bloCks (blk) with inCreasing delay, suCh that ChoiCe bias moved away from the resPonse leading to the large reward towards the small reward, with inCreasing delay (A). However, there were systematiC differenCes between the grouPs in their behavior, suCh that Grb10+/P animals switched their ChoiCe to the small, less delayed reward less quiCkly than WT miCe. When the delay assoCiated with the large and small rewards was equal (1s) throughout the session (B), ChoiCe bias was Consistently high (large reward Chosen apProximately 80% of the time). Under these task Conditions there were no differenCes in ChoiCe bias between Grb10+/P and WT miCe. Data shows mean ±SEM of three ConseCutive stable sessions; * rePresents P<0.05 main effeCt of GENOTYPE; ## rePresents P<0.01 main effeCt of DELAY. 4 6 1 In large Part Choice bias behavior in delayed reinforCement tasks is governed by three 2 Potentially interacting PsyChologiCal ProCesses; the PerCeived value of the rewards, and the 3 perCeived length and aversive nature of the delay (HO et al. 1999). The difference in choice 4 between Grb10+/P and WT miCe in the first bloCk of the task (where delay for the larger and 5 smaller rewards are both 1s) may suggest a Contribution to behavior in the Grb10+/P from a 6 relatively more less PronounCed generalized Conditioned Place aversion to the delayed 7 larger reward resPonse (see ISLES et al.

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