Ascending Control of Arousal and Motivation: Role of Nucleus Incertus and Its Peptide Neuromodulators in Behavioural Responses to Stress S

Journal of Neuroendocrinology, 2015, 27, 457–467 REVIEW ARTICLE © 2015 British Society for Neuroendocrinology Ascending Control of Arousal and Motivation: Role of Nucleus Incertus and its Peptide Neuromodulators in Behavioural Responses to Stress S. Ma*† and A. L. Gundlach*†‡ *Neuropeptides Division, The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. †Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia. ‡Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia. Journal of Arousal is a process that involves the activation of ascending neural pathways originating in Neuroendocrinology the rostral pons that project to the forebrain through the midbrain reticular formation to pro- mote the activation of key cortical, thalamic, hypothalamic and limbic centres. Established modulators of arousal include the cholinergic, serotonergic, noradrenergic and dopaminergic networks originating in the pons and midbrain. Recent data indicate that a population of largely GABAergic projection neurones located in the nucleus incertus (NI) are also involved in arousal and motivational processes. The NI has prominent efferent connections with distinct hypothalamic, amygdalar and thalamic nuclei, in addition to dense projections to key brain regions associated with the generation and pacing of hippocampal activity. The NI receives strong inputs from the prefrontal cortex, lateral habenula and the interpeduncular and median raphe nuclei, suggesting it is highly integrated in circuits regulating higher cognitive behaviours (hippocampal theta rhythm) and emotion. Anatomical and functional studies have revealed that the NI is a rich source of multiple peptide neuromodulators, including relaxin-3, and may mediate extra- hypothalamic effects of the stress hormone corticotrophin-releasing factor, as well as other key modulators such as orexins and oxytocin. This review provides an overview of earlier studies and highlights more recent research that implicates this neural network in the integration of Correspondence to: Dr S. Ma and Dr A.L. Gundlach, arousal and motivated behaviours and has begun to identify the associated mechanisms. Future The Florey Institute of Neuroscience research that should help to better clarify the connectivity and function of the NI in major and Mental Health, 30 Royal Parade, experimental species and humans is also discussed. Parkville, Victoria 3052, Australia (e-mail: sherie.ma@florey.edu.au Key words: nucleus incertus, arousal, stress, relaxin-3, motivation, corticotrophin-releasing and factor, orexin, oxytocin andrew.gundlach@florey.edu.au). doi: 10.1111/jne.12259 neural inputs and projection targets of these subregions are quite Introduction similar (4,5). In the mouse (6) and macaque (2), the neuroanatomi- The nucleus incertus (NI) was first identified in the human brain by cal definition of NIc and NId are less clear and the descriptions George Streeter in 1904 (1), who coined the name, which is Latin provided here will refer to the nucleus as a whole. for ‘uncertain’ nucleus, based on its unknown function. In the non- In terms of connectivity, although there are some similarities in human primate (2) and other mammals examined to date (3), the the neural projections of NI and caudal dorsal raphe (DRc) neuro- NI consists of a midline, bilateral cluster of large, multipolar neurones with regard to the initial course of axons/fibres through the nes in the central grey which lie immediately posterior to the dorsal pontine reticular core, their terminal fields in forebrain regions such raphe nucleus (DR) and are bordered laterally by the dorsal teg- as the septum, nucleus accumbens and hippocampus are quite dis- mental nucleus and ventrally by the medial longitudinal fascicular tinct (4). Therefore, although reports in the literature have often white matter tracts. In the rat, there are two distinct subregions of mistakenly regarded the NI as a caudal extension of the DRc or the NI based on cytoarchitecture - midline columns of compact even as other brain structures (7–9), it is important that the dis- neurones termed NI pars compacta (NIc) and lateral wings of distinct anatomical characteristics and functional roles of the NI persed neurones termed the NI pars dissipata (NId), although the should be recognised and evaluated separately. 458 S. Ma and A. L. Gundlach RSC mPFC Hip SC LHb Thal MS DRC 5-HT NI MR LHorexin IPN RPO MCH Fig. 1. Major neural inputs and outputs of the nucleus incertus. Schematic representation of the major neural inputs to and outputs from the nucleus incertus (NI) in the rat brain (see text and Table 1) (4,5). Putative glutamatergic inputs are indicated in green, inhibitory inputs in red, and unknown in blue; and major ascending NI output pathways assessed by anterograde tract-tracing studies are indicated in yellow. DRC, caudal part of dorsal raphe nucleus; Hip, hippocampus; IPN, interpeduncular nucleus; LH, lateral hypothalamus; LHb, lateral habenula; MCH, melanin-concentrating hormone; mPFC, medial prefrontal cortex; MR, median raphe nucleus; MS, medial septum; NI, nucleus incertus; RPO, reticularis pontis oralis; RSC, retrosplenial cortex; SC, superior colliculus; 5-HT, 5-hydroxytryptamine. In rat brain, the major neural inputs to NI (Fig. 1 and Table 1) field, and continues through to the IPN and rostrally into the hypo- arise from cortical prelimbic (and to a lesser extent the infralimbic), thalamus, innervating various hypothalamic regions via the medial anterior cingulate, medial and ventral orbital areas, generally from forebrain bundle, including lateral and medial mammillary and su- pyramidal neurones of layer V (4). Other major inputs arise from pramammillary nuclei, and the lateral hypothalamic and lateral pre- neurones in medial regions of the lateral habenula (9), which are optic areas. A branch of these fibres courses dorsally to innervate densely innervated by dopamine and neurotensin fibres (10,11) and the mediodorsal, centromedial, centrolateral and paraventricular express serotonin-2c receptors (12). Neurones in the medial part of thalamic regions. A substantial group of fibres ascend through the the lateral habenula also provide projections to the intermediate hypothalamus to innervate the nucleus of the diagonal band and part of the interpeduncular nucleus (IPN) (13) and median raphe MS, and pass through the fornix and fimbria to innervate the dorsal nucleus (MR) (9) and may play a role in the maintenance of rapid- and ventral hippocampus, as well as the amygdala. Finally, a fibre eye movement (REM) sleep (14). Notably, neurones of the IPN and bundle continues rostrally from the hypothalamus to innervate the MR also provide dense inputs to the NI (4), suggesting there are infralimbic, prelimbic and anterior cingulate cortex. Some of these strong bidirectional (reciprocal) neural circuits between the NI, lat- fibres extend through the midline cingulum bundle, providing inner- eral habenula, MR and IPN. vation of the anterior cingulate and posterior retrosplenial cortices Moderate neural inputs to the rat NI arise from inhibitory neuro- (4,5) (Fig. 1 and Table 1). The cell types innervated by NI remain to nes in the medial septum (MS) and diagonal band (4,15) and, be characterised, although recent histological studies have started because the septum is a principal target of NI projections (4,5), this to assess this in the densely innervated MS, and indicate that NI input may provide an inhibitory feedback regulation of a ponto- terminations are located on both cholinergic neurones and inhibi- septohippocampal network (16). Other neural inputs stem from the tory neurones expressing parvalbumin and calbindin (19), including lateral preoptic and lateral hypothalamic areas, particularly the peri- those that provide further projections to the dorsal hippocampus, fornical region (4,17), periaqueductal grey (PAG) and DRc, although suggesting broad modulatory actions of the septohippocampal net- cell types are unknown (4). In the brainstem, small and medium work. neurones within a region immediately caudal to the laterodorsal By contrast to the detailed analysis in the rat, there have not tegmental nucleus are also retrogradely labelled from the NI, which been any equivalent focused studies of the connectivity of the NI is a source of cholinergic neurones interacting with habenular and in the mouse, which is the other major experimental species being meso-dopaminergic circuits underlying motivated behaviours (18). used in related functional studies of the NI and its peptide neuro- Furthermore, NI neurones also appear to send projections to their modulators. Although the NI is recognised in major anatomical contralateral equivalent, suggesting the existence of a local inhibi- atlases of the mouse brain (20) (also termed ‘nucleus O’ and ‘cen- tory microcircuit (4). tral grey alpha’) (21) and several histological studies (6,22), the dis- With regard to NI outputs, anterograde tracing studies in the rat tribution of neural projections from and inputs to the mouse NI demonstrate that NI ascending projections are long-range and arise has not been described, apart from some data available in the pub- as two major fibre bundles (4,5) (Fig. 1 and Table 1). The first effer- lic access Allen Brain Institute Atlas (http://www.brain-map.org), ent projection group courses through the pontine periventricular which reveals, for example, a strong innervation of the NI region

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