Surface anatomy of the floor of the Fourth ventricle, with the nucleus incertus labeled

The nucleus incertus is a brainstem region of the pontine brainstem, just ventral to the 4th ventricle.[1] The term was coined by George Streeter (Latin for "uncertain nucleus") based on its unknown function at the time to name a group of cells he observed near the midline of the floor of the 4th ventricle.[2] It sometimes called the 'nucleus O'.[3]

The nucleus incertus is a bilateral structure which sits near the brainstem, in front of the nucleus prepositus hypoglossi.[4] It consists of mostly ascending GABAergic projection neurons and glutamatergic neurons[5] which innervate a broad range of forebrain regions involved in behavioural activation.

It is part of the theta network acting as a relay from the reticularis pontis oralis nucleus to the septo-hippocampal system.[6] The stimulation of the nucleus incertus activates the hippocampal theta rhythm and either its lesion or inhibition suppress the theta oscillation induced by brainstem stimulation.[7] The nucleus incertus itself presents theta oscillations coupled to the hippocampal theta rhythm.[8]

In addition to hippocampal theta rhythms, the nucleus incertus is involved in the control of locomotor speed and arousal,[9] response to stress[3] and integrating the vestibulo-ocular reflex and gaze holding with hippocampal navigation.[6]

Neuroanatomy and Neurochemistry

The NI consists of GABAergic and glutamatergic neurons that project widely to other regions of the brain, including the septum, hippocampus, hypothalamus, amygdala, interpeduncular nucleus and prefrontal cortex.[1] One of the defining neurochemical characteristics of NI GABAergic neurons is their expression of relaxin-3, a neuropeptide that acts via the G-protein-coupled receptor, known as RXFP3 in various brain regions, but can also activate RXFP1. The primary effect of RXFP3 receptor activation is the suppression of neuronal activity, which occurs mainly through the opening of M-channels, allowing an outward flow of potassium ions.[4]

The relaxin-3/RXFP3 system has been extensively studied since its discovery in 2002 due to its involvement in stress and arousal-related functions.[5] This peptidergic system is preserved throughout vertebrate evolution and is present in zebrafish and several other species, including human.[6][7] Relaxin-3 (RLN3) is detected in at least two neuronal clusters in both teleosts and mammals, in the periaqueductal grey (PAG) and the NI. However, while in the teleosts the PAG/RLN3 projections target extensive areas of the forebrain and optic tectum, the NI/RLN3 projection is concentrated in the interpeduncular nucleus. By contrast, in mammals, PAG/RLN3 projections are restricted to the brainstem and diencephalon, while NI/RLN3 projections display a wide pattern of ascending projections to areas ranging from the nearby interpeduncular nucleus to the more distant hippocampus and prefrontal cortex. In both teleosts and mammals, the RLN3 signaling system plays a central role in arousal control.[9][10]

In addition to relaxin-3, NI GABAergic neurons express other neuromodulators such as cholecystokinin (CCK) and neuromedin-B (NMB). These neurons also express receptors for corticotropin-releasing factor (CRF), orexins (hypocretins), melanin- concentrating hormone (MCH), serotonin (5-HT) and glutamate; and this diverse receptor expression profile suggests that the NI integrates signals from multiple neurotransmitter systems.[11]

Functional roles

The NI plays a role in various behavioral states, particularly arousal and stress responses. It is implicated in the modulation of theta rhythm, a type of brain oscillation that occurs during active behaviors and is critical for cognitive functions of learning, memory, and attention. NI neurons project strongly to the septohippocampal system, which is crucial for the generation and maintenance of theta rhythms, suggesting a modulatory role in cognitive processes.[12]

Involvement in Stress Control

NI neurons are highly sensitive to stress-related stimuli and a high density of CRF receptor-1 (CRF-R1) in the NI likely mediate these responses.[13][14] CRF-R1 are expressed by virtually all relaxin-3 positive neurons in the rat NI, and these relaxin-3 neurons are activated by both CRF and different stressors .[15][16] Stress evoked activation of CRF-R1 in the NI activity impairs plasticity in the hippocampo-medial prefrontal cortical pathway.[17] Studies have shown that activation of NI neurons can influence anxiety-like behaviors, linking the NI to stress and emotional regulation.[18]

Stress and Alcohol Abuse

RLN3 and RXFP3 play a critical role in regulating stress-induced alcohol preference and the reinstatement of alcohol-seeking behavior in rodents. Central antagonism of RXFP3 effectively prevents stress-induced relapse, highlighting its potential as a target for interventions in alcohol addiction.[19] Within this process, CRF-R1 in the NI has a central role, as intra-NI injections of CRF-R1 antagonists significantly attenuated stress-induced reinstatement of alcohol-seeking behavior.[20] These findings indicate the crucial role of the RLN3/RXFP3 systems and CRF-R1 signaling within the NI in mediating addiction-related behaviors, especially under stress.

Involvement in Sleep-Wake Regulation

Emerging research has highlighted the role of the NI in sleep-wake cycles. The NI is active during wakefulness and has been proposed to promote arousal through its projections to the hypothalamus and forebrain. [21][22] Experimental activation of the NI increases waking states, while its inhibition promotes sleep. Mice in which the relaxin-3 gene has been deleted display a hypoactive phenotype on free-access voluntary running wheels[23] and mice with the RXFP3 gene deleted display an identical phenotype, suggesting this effect is mediated via the relaxin-3/RXFP3 and GABAergic signaling systems.[24]

Cognitive and Behavioral Effects

The NI also plays a role in cognition, motivation, and reward-related behaviors via its widespread projections. Some studies have suggested a role for the NI in motivational states and appetitive behaviors, possibly through interactions with dopaminergic systems in reward-related brain regions such as the ventral tegmental area (VTA). Consistently, central administration of a relaxin-3 agonist peptide results in an immediate increase of food intake in satiated rats.[25]

Moreover, relaxin-3/RXFP3 signaling in the hippocampus has been shown to influence learning and memory. Mice with RXFP3 deleted in the hippocampus demonstrate impairments in spatial memory, further supporting the idea that the NI modulates cognitive functions through its peptidergic pathways.[26]

References

  1. ^ a b Goto M, Swanson LW, Canteras NS (September 2001). "Connections of the nucleus incertus". The Journal of Comparative Neurology. 438 (1): 86–122. doi:10.1002/cne.1303. PMID 11503154.
  2. ^ Streeter GL (1903). "Anatomy of the floor of the fourth ventricle. (The relations between the surface markings and the underlying structures.)". American Journal of Anatomy. 2 (3): 299–313. doi:10.1002/aja.1000020303. ISSN 1553-0795.
  3. ^ a b Ryan PJ, Ma S, Olucha-Bordonau FE, Gundlach AL (May 2011). "Nucleus incertus--an emerging modulatory role in arousal, stress and memory". Neuroscience and Biobehavioral Reviews. 35 (6): 1326–41. doi:10.1016/j.neubiorev.2011.02.004. PMID 21329721. S2CID 24464719.
  4. ^ a b Cheron, Guy; Ris, Laurence; Cebolla, Ana Maria (2023). "Nucleus incertus provides eye velocity and position signals to the vestibulo-ocular cerebellum: a new perspective of the brainstem–cerebellum–hippocampus network". Frontiers in Systems Neuroscience. 17. doi:10.3389/fnsys.2023.1180627. ISSN 1662-5137. PMC 10248067. PMID 37304152.
  5. ^ a b Cervera-Ferri A, Rahmani Y, Martínez-Bellver S, Teruel-Martí V, Martínez-Ricós J (May 2012). "Glutamatergic projection from the nucleus incertus to the septohippocampal system". Neuroscience Letters. 517 (2): 71–6. doi:10.1016/j.neulet.2012.04.014. PMID 22521581. S2CID 32163510.
  6. ^ a b c Teruel-Martí V, Cervera-Ferri A, Nuñez A, Valverde-Navarro AA, Olucha-Bordonau FE, Ruiz-Torner A (July 2008). "Anatomical evidence for a ponto-septal pathway via the nucleus incertus in the rat". Brain Research. 1218: 87–96. doi:10.1016/j.brainres.2008.04.022. PMID 18514169. S2CID 5519042.
  7. ^ a b Nuñez A, Cervera-Ferri A, Olucha-Bordonau F, Ruiz-Torner A, Teruel V (May 2006). "Nucleus incertus contribution to hippocampal theta rhythm generation". The European Journal of Neuroscience. 23 (10): 2731–8. doi:10.1111/j.1460-9568.2006.04797.x. PMID 16817876.
  8. ^ Cervera-Ferri A, Guerrero-Martínez J, Bataller-Mompeán M, Taberner-Cortes A, Martínez-Ricós J, Ruiz-Torner A, Teruel-Martí V (June 2011). "Theta synchronization between the hippocampus and the nucleus incertus in urethane-anesthetized rats". Experimental Brain Research. 211 (2): 177–92. doi:10.1007/s00221-011-2666-3. PMID 21479657. S2CID 23444954.
  9. ^ a b Lu L, Ren Y, Yu T, Liu Z, Wang S, Tan L, et al. (January 2020). "Control of locomotor speed, arousal, and hippocampal theta rhythms by the nucleus incertus". Nature Communications. 11 (1): 262. Bibcode:2020NatCo..11..262L. doi:10.1038/s41467-019-14116-y. PMC 6959274. PMID 31937768.
  10. ^ Olucha-Bordonau, Francisco E.; Teruel, Vicent; Barcia-González, Jorge; Ruiz-Torner, Amparo; Valverde-Navarro, Alfonso A.; Martínez-Soriano, Francisco (2003-09-08). "Cytoarchitecture and efferent projections of the nucleus incertus of the rat". The Journal of Comparative Neurology. 464 (1): 62–97. doi:10.1002/cne.10774. ISSN 0021-9967. PMID 12866129.
  11. ^ Ryan, Philip J.; Ma, Sherie; Olucha-Bordonau, Francisco E.; Gundlach, Andrew L. (2011-05-01). "Nucleus incertus—An emerging modulatory role in arousal, stress and memory". Neuroscience & Biobehavioral Reviews. 35 (6): 1326–1341. doi:10.1016/j.neubiorev.2011.02.004. ISSN 0149-7634. PMID 21329721.
  12. ^ Kania, Alan; Szlaga, Agata; Sambak, Patryk; Gugula, Anna; Blasiak, Ewa; Micioni Di Bonaventura, Maria Vittoria; Hossain, Mohammad Akhter; Cifani, Carlo; Hess, Grzegorz; Gundlach, Andrew L.; Blasiak, Anna (2020-06-12). "RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior". The Journal of Neuroscience. 40 (28): 5362–5375. doi:10.1523/jneurosci.2895-19.2020. ISSN 0270-6474. PMC 7343322. PMID 32532885.
  13. ^ Burazin, Tanya C. D.; Bathgate, Ross A. D.; Macris, Mary; Layfield, Sharon; Gundlach, Andrew L.; Tregear, Geoffrey W. (2002-09-09). "Restricted, but abundant, expression of the novel rat gene-3 (R3) relaxin in the dorsal tegmental region of brain". Journal of Neurochemistry. 82 (6): 1553–1557. doi:10.1046/j.1471-4159.2002.01114.x. ISSN 0022-3042. PMID 12354304.
  14. ^ Donizetti, Aldo; Grossi, Mario; Pariante, Paolo; D'Aniello, Enrico; Izzo, Gaia; Minucci, Sergio; Aniello, Francesco (2008-11-04). "Two neuron clusters in the stem of postembryonic zebrafish brain specifically express relaxin-3 gene: First evidence of nucleus incertus in fish". Developmental Dynamics. 237 (12): 3864–3869. doi:10.1002/dvdy.21786. ISSN 1058-8388. PMID 18985751.
  15. ^ Blasiak, Anna; Gugula, Anna; Gundlach, Andrew L.; Olucha-Bordonau, Francisco E.; Aniello, Francesco; Donizetti, Aldo (2022-10-05). "Relaxin ligand/receptor systems in the developing teleost fish brain: Conserved features with mammals and a platform to address neuropeptide system functions". Frontiers in Molecular Neuroscience. 15. doi:10.3389/fnmol.2022.984524. ISSN 1662-5099. PMC 9580368. PMID 36277494.
  16. ^ Ávila, Camila de; Gugula, Anna; Trenk, Aleksandra; Intorcia, Anthony J.; Suazo, Crystal; Nolz, Jennifer; Plamondon, Julie; Khatri, Divyanshi; Tallant, Lauren (2023-09-09). "Unveiling a Novel Memory Center in Humans: Neurochemical Identification of theNucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology". doi.org. doi:10.1101/2023.09.08.556922. Retrieved 2025-03-05.
  17. ^ Spikol, Emma D.; Cheng, Ji; Macurak, Michelle; Subedi, Abhignya; Halpern, Marnie E. (2024-05-14). "Genetically defined nucleus incertus neurons differ in connectivity and function". doi:10.7554/elife.89516.2. PMID 38819436. {{cite web}}: Missing or empty |url= (help)
  18. ^ Nasirova, Nailyam; Quina, Lely A.; Morton, Glenn; Walker, Andrew; Turner, Eric E. (2020-10-14). "Mapping Cell Types and Efferent Pathways in the Ascending Relaxin-3 System of the Nucleus Incertus". eNeuro. 7 (6): ENEURO.0272–20.2020. doi:10.1523/eneuro.0272-20.2020. ISSN 2373-2822. PMC 7643772. PMID 33055197.
  19. ^ Ma, Sherie; Allocca, Giancarlo; Ong-Pålsson, Emma K. E.; Singleton, Caitlin E.; Hawkes, David; McDougall, Stuart J.; Williams, Spencer J.; Bathgate, Ross A. D.; Gundlach, Andrew L. (2016-05-20). "Nucleus incertus promotes cortical desynchronization and behavioral arousal". Brain Structure and Function. 222 (1): 515–537. doi:10.1007/s00429-016-1230-0. ISSN 1863-2653. PMID 27206427.
  20. ^ Ma, Sherie; Smith, Craig M; Blasiak, Anna; Gundlach, Andrew L (2016-12-04). "Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain". British Journal of Pharmacology. 174 (10): 1034–1048. doi:10.1111/bph.13659. ISSN 0007-1188. PMC 5406293. PMID 27774604.
  21. ^ Olucha-Bordonau, Francisco E.; Teruel, Vicent; Barcia-González, Jorge; Ruiz-Torner, Amparo; Valverde-Navarro, Alfonso A.; Martínez-Soriano, Francisco (2003-07-10). "Cytoarchitecture and efferent projections of the nucleus incertus of the rat". Journal of Comparative Neurology. 464 (1): 62–97. doi:10.1002/cne.10774. ISSN 0021-9967. PMID 12866129.
  22. ^ Nuñez, A.; Cervera-Ferri, A.; Olucha-Bordonau, F.; Ruiz-Torner, A.; Teruel, V. (2006-05-09). "Nucleus incertus contribution to hippocampal theta rhythm generation". European Journal of Neuroscience. 23 (10): 2731–2738. doi:10.1111/j.1460-9568.2006.04797.x. ISSN 0953-816X. PMID 16817876.
  23. ^ Bittencourt, Jackson C.; Sawchenko, Paul E. (2000-02-01). "Do Centrally Administered Neuropeptides Access Cognate Receptors?: An Analysis in the Central Corticotropin-Releasing Factor System". The Journal of Neuroscience. 20 (3): 1142–1156. doi:10.1523/jneurosci.20-03-01142.2000. ISSN 0270-6474. PMC 6774165. PMID 10648719.
  24. ^ Tanaka, Masaki; Iijima, Norio; Miyamoto, Yasumasa; Fukusumi, Shoji; Itoh, Yasuaki; Ozawa, Hitoshi; Ibata, Yasuhiko (2005-03-08). "Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress". European Journal of Neuroscience. 21 (6): 1659–1670. doi:10.1111/j.1460-9568.2005.03980.x. ISSN 0953-816X. PMID 15845093.
  25. ^ Ma, Sherie; Blasiak, Anna; Olucha-Bordonau, Francisco E.; Verberne, Anthony J. M.; Gundlach, Andrew L. (July 2013). "Heterogeneous responses of nucleus incertus neurons to corticotrophin-releasing factor and coherent activity with hippocampal theta rhythm in the rat". The Journal of Physiology. 591 (16): 3981–4001. doi:10.1113/jphysiol.2013.254300. ISSN 0022-3751. PMC 3764641. PMID 23671163.
  26. ^ Kumar, Jigna Rajesh; Rajkumar, Ramamoorthy; Jayakody, Tharindunee; Marwari, Subhi; Hong, Jia Mei; Ma, Sherie; Gundlach, Andrew L; Lai, Mitchell K P; Dawe, Gavin S (2016-09-06). "Relaxin' the brain: a case for targeting the nucleus incertus network and relaxin-3/RXFP3 system in neuropsychiatric disorders". British Journal of Pharmacology. 174 (10): 1061–1076. doi:10.1111/bph.13564. ISSN 0007-1188. PMC 5406295. PMID 27597467.
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