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)