MR effects on neuronal activity in rodent models
Nuclear MR-mediated effects set the reactivity of neurons to (stress-related) stimuli. Non-genomic MR detects changes in glucocorticoid levels (by ultradian pulsing or from a stress stimulus) and translates them into functional adaptations (Karst, 2005). As such, mEPSC frequency in dorsal hippocampal CA1 neurons follows the CORT pulse amplitude (Sarabdjitsingh et al. , 2016) necessary for neuronal electrical activity (Sarabdjitsingh et al. , 2014). Early studies in the dorsal hippocampal CA1 demonstrated subsequent genomic GR-mediated effects on excitability are opposite to those by genomic MR. In L-type calcium currents, absence of CORT produced high amplitude that gradually reduced with low CORT doses and increased following high CORT application (Joels, 2006; Diamond et al. , 2007). Such findings form the basis of considerations on the importance of an MR/GR balance (de Kloet et al. , 2018). However, in the amygdala a rapid MR-dependent increase in excitability occurs by cooperation with nuclear GR and is prolonged with noradrenalin exposure (as seen in stress; (Karst and Joƫls, 2016).
MR effects on cognitive and emotional function
MR mediates emotional and cognitive reactivity by affecting the appraisal of novel situations, learning strategies, and response selection (Vogel et al. , 2016). Pharmacological water maze studies demonstrated that MR affected search-escape strategies and behavioural reactivity to spatial novelty (Oitzl and de Kloet, 1992; Oitzl, Fluttert and Ron de Kloet, 1994; Zhou et al. , 2011). The stress induced switch from hippocampal to dorsal striatal based habit learning was further demonstrated to depend on MR (Vogel et al.,2016; Arp et al. , 2014; Ter Horst et al. , 2014) and enhanced MR expression facilitated this learning shift to guide behaviour under stress (Wirz et al 2017). Genetically modified MR-deficient models showed reduced learning and memory performance, and behavioural adaptation in strategic contexts (Berger et al. , 2006; Brinks et al. , 2009; Schwabe et al. , 2010; ter Horstet al. , 2013). These were improved by overexpressing MR (Laiet al. , 2007; Rozeboom, Akil and Seasholtz, 2007; Mitra, Ferguson and Sapolsky, 2009). Combined increased MR and decreased GR expression improved spatial memory and behavioural flexibility (Harris et al. , 2013). Prolonged stress in adulthood or early life stress (ELS) shifted hippocampal dependent contextual learning to fear learning (Kanatsou et al. , 2015, 2017), which was somewhat prevented by overexpressing forebrain MR, likely by neuronal and synapse regeneration in granular cells of the DG. Thus, MR is involved in behavioral reactivity in rodents as dependent on the substantial occupancy pre-stress, and the rapid non-genomic signalling in the early phases of a stress response. All this work was performed under the implicit assumption that antagonist effects acted on the GC-preferring MRs. Interpretation of interactions between MR expression and the effects of ELS is challenging in relation to the time at which MR is required. Interesting, these effects show sex differences, similarly to the consequence of human genetic variants of the MR gene ((Bonapersonaet al. , 2019), see below)