Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms

Abstract

Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.

Sex differences in behavioral responding and dopamine release during Pavlovian learning

“…Female subjects display a faster acquisition rate and elevated responding during drug self-administration (Lynch and Carroll, 1999;George et al, 2021). Females exhibit higher levels of conditioned freezing relative to males during fear conditioning (Dubroqua et al, 2011). Sex differences have also been identified in Pavlovian conditioning tasks employing food rewards (Stringfield et al, 2019).…”

“…The aforementioned research was primarily performed in male subjects, however increasing evidence highlights sex differences in dopamine neuron activity and release (Xiao and Becker, 1994;Walker et al, 2000;McArthur et al, 2007;Becker and Chartoff, 2019;Brundage et al, 2021;Zachry et al, 2021). These differences in dopamine transmission between males and females could account for the observed sex differences in dopamine-dependent behaviors (Lynch and Carroll, 1999;Dubroqua et al, 2011;Eubig et al, 2014;Pitchers et al, 2015;Stringfield et al, 2019;Zachry et al, 2019;Kutlu et al, 2020;Chen et al, 2021;George et al, 2021). While certain forms of Pavlovian conditioned responding can differ between males and females (Stringfield et al, 2019), it is not known if sex differences during Pavlovian learning is accompanied by distinct patterns of dopamine signaling.…”

Sex Differences in Behavioral Responding and Dopamine Release during Pavlovian Learning

“…The aforementioned research was primarily performed in male subjects; however, increasing evidence highlights sex differences in behavioral responding. Across studies, female subjects display augmented behavioral responses compared with males, including higher locomotor activity, faster latency, and elevated conditioned responding ( Lynch and Carroll, 1999 ; Dubroqua et al, 2011 ; Eubig et al, 2014 ; Scholl et al, 2019 ; Stringfield et al, 2019 ; Zachry et al, 2019 ; Kutlu et al, 2020 ; Bishnoi et al, 2021 ; Chen et al, 2021 ; George et al, 2021 ; Knight et al, 2021 ). Furthermore, prior research has identified sex differences in dopamine neuron activity and release ( Xiao and Becker, 1994 ; Walker et al, 2000 ; McArthur et al, 2007 ; Becker and Chartoff, 2019 ; Brundage et al, 2021 ; Zachry et al, 2021 ).…”

Sex differences in the effects of a combined behavioral and pharmacological treatment strategy for cocaine relapse prevention in an animal model of cue exposure therapy

“…Sex differences also occurred for the behavioral effects of genetic deletion of forebrain GlyT-1. During extinction of appetitive Pavlovian conditioning (nose pokes during conditioned stimulus presentations in absence of reward), male mice with genetic deletion of GlyT-1 exhibited facilitated extinction compared to male control mice, whereas female mice with genetic deletion of GlyT-1 exhibited resistance to extinction compared to female control mice [81]. In terms of the NMDA receptor, female rats were shown to have higher levels of the NR2B subunit (glutamate binding site) in the hippocampus and higher levels of the NR1 subunit (glycine binding site) in the hippocampus, prefrontal cortex, and amygdala compared to male rats [82].…”