Abstract
Telencephalic cognitive and emotional circuits/functions are strongly modulated by subcortical inputs. The main focus of past research on the nature of this modulation has been on the widespread monoamine projections to the telencephalon. However, the nucleus incertus (NI) of the pontine tegmentum provides a strong GABAergic and peptidergic innervation of the hippocampus, basal forebrain, amygdala, prefrontal cortex, and related regions; and represents a parallel source of ascending modulation of cognitive and emotional domains. NI GABAergic neurons express multiple peptides, including neuromedin-B, cholecystokinin, and relaxin-3, and receptors for stress and arousal transmitters, including corticotrophin-releasing factor and orexins/hypocretins. A functional relationship exists between NI neurons and their associated peptides, relaxin-3 and neuromedin-B, and hippocampal theta rhythm, which in turn, has a key role in the acquisition and extinction of declarative and emotional memories. Furthermore, RXFP3, the cognate receptor for relaxin-3, is a Gi/o protein-coupled receptor, and its activation inhibits the cellular accumulation of cAMP and induces phosphorylation of ERK, processes associated with memory formation in the hippocampus and amygdala. Therefore, this review summarizes the role of NI transmitter systems in relaying stress- and arousal-related signals to the higher neural circuits and processes associated with memory formation and retrieval.
Highlights
Forebrain function is driven by subcortical ascending connections resulting in arousal activation allowing cognitive and emotional processes
Nucleus Incertus and Relaxin-3/RXFP3 Signaling in Memory from the pontine-mesencephalic reticular projections to the thalamus were initially proposed as the central core of the Ascending Reticular Activating Systems (ARAS) (Steriade and Glenn, 1982)
The nucleus incertus (NI) projection to the septohippocampal system is strongly implicated as a key component of the subcortical system driving hippocampal theta rhythm
Summary
Forebrain function is driven by subcortical ascending connections resulting in arousal activation allowing cognitive and emotional processes. While research over the last two decades has implicated the relaxin-3/RXFP3 system in a wide variety of functions, including modulation of stress, anxiety, foraging, and addictive and social behaviors (see Ma et al, 2017b; Olucha-Bordonau et al, 2018), for this review we examined the evidence for a specific role of NI transmitter systems, relaxin-3/RXFP3, in relaying stress- and arousal-related signaling to higher neural centers associated with memory formation and retrieval. It is possible, given the transient nature of MAPK activation, that these approaches are likely to have missed the complete direct increase of pERK in RXFP3-expressing neurons due to RXPF3 agonist activation These results support the hypothesis that experimental timing is crucial to determine the role and adequately delimit the downstream pathways which mediate relaxin-3/RXFP3 induced neuronal plasticity. More experiments are needed to fully understand the dynamics of the NI/relaxin-3/ GABA system
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