Modulation of forebrain function by nucleus incertus and relaxin-3/RXFP3 signaling

Abstract

The nucleus incertus (NI) in the pontine tegmentum sends ascending projections to the midbrain, hypothalamus, amygdala, basal forebrain, hippocampus, and prefrontal cortex, and has a postulated role in modulating several forebrain functions. A substantial population of GABAergic NI neurons expresses the neuropeptide, relaxin-3, which acts via the G_i/o -protein-coupled receptor, RXFP3, present throughout the forebrain target regions. Broad and specific manipulations of these systems by activation or inhibition of the NI or modulating RXFP3 signaling have revealed key insights into the likely influence of the NI/relaxin-3/RXFP3 system on modalities including arousal, feeding, stress responses, anxiety and addiction, and attention and memory. This range of actions corresponds to a likely impact of NI/(relaxin-3) projections on multiple integrated circuits, but makes it difficult to draw conclusions about a generalized function for this network. This review will focus on the key physiological process of oscillatory theta rhythm and the neural circuits that promote it during behavioral activation, highlighting the ability of NI and relaxin-3/RXFP3 signaling systems to modulate these circuits. A better understanding of these mechanisms may provide a way to therapeutically adjust malfunction of forebrain activity present in several pathological conditions.

Keywords: GABA; arousal; brainstem; feeding; hippocampus; septum; social interaction; theta rhythm.

Figure 1

Morphological features of the rat nucleus incertus (NI). A, A Giemsa‐stained section of the pontine tegmentum at the level of the floor of the 4th ventricle (IV). The NI (outlined) is composed of the pars compacta in the midline (NIc) and the pars dissipata (NId), just dorsal to the medial longitudinal fasciculus (mlf), with the posterodorsal tegmentum (PDTg) and the sphenoid nucleus (Sph) dorsolateral to the NI at this level. B, An injection site (is) for the retrograde tracer, fluorogold (FG) in the dentate gyrus of the caudo‐ventral hippocampus, displaying some retrograde labeling in the entorhinal cortex (Ent). C, Retrograde labeling in the ipsilateral NI resulting from the injection in (B), with some retrograde labeling in the contralateral NI. D, Immunohistochemical detection of relaxin‐3 (RLN3) in the NI. E, Immunohistochemical detection of cholecystokinin (CCK) in the NIc. Calibration bars in A, C, D and E, 200 μm, and B, 500 μm

Figure 2

Two schematic models of NI connectivity. A, Based on their anatomical mapping studies, Goto et al11 proposed a strong neural circuit between the median raphe (MR), the interpeduncular nucleus (IPN) and the NI and proposed that from this circuit, ascending projections could reach the ventral tegmental area (VTA), supramammillary nucleus (SuM), hypothalamus (Hyp), medial septum (MS), hippocampus (Hip), and the medial prefrontal cortex (mPFC). B, In subsequent studies, Olucha‐Bordonau et al12 proposed a series of overlapping ascending projections from the NI to the hippocampus, in which each progressive step recapitulated previous projections on route to the hippocampus. This scheme also incorporated the bed nucleus of the stria terminalis (ST) and the amygdala (Amy). Descending projections from the septum, hypothalamus, and lateral habenula (LHb) are also illustrated, which constitute a bidirectional pathway13

Figure 3

Organization of the connections of the NI and its specific targets. A loop in the brainstem exists where the median raphe induces theta desynchronization, and the reticularis pontis oralis (RPO) is the source for tonic firing during somatosensory stimulation and may relay on the NI. The NI can integrate stress‐related information to activate arousal, emotion, and learning and memory mechanisms in a set of ascending connections. At the next level, the supramammillary nucleus (SuM) modulates NI firing to regulate rhythmic output to the septum, which is a primary regulator of rhythmic input to the hippocampus. Several neural circuit loops can be anatomically defined. (1) The central processing loop is composed of the lateral habenula (LHb), the interpeduncular nuclei (IPN) and the NI. (2) The NI also receives hypothalamic projections from corticotropin‐releasing factor (CRF) and orexin (Orx) peptidergic projections and also from GABAergic projections arising from the septal area. (3) The NI receives projections from the RPO which is responsible for driving theta from somatosensory stimulation. (4) The NI then sends ascending connections to the median raphe (MR), supramammillary nucleus (SuM), medial septum/diagonal band (MS/DB), and hippocampus, which largely underlie subcortically‐driven theta rhythm. (5) NI projections also innervate the extended amygdala, which is important for emotionally‐driven behaviors, including addictive behaviors and anxiety. (6) Some of these behaviors, such as feeding, could be modulated by NI projections to hypothalamic nuclei and interactions with other peptidergic systems (Pep)