Nucleus incertus—An emerging modulatory role in arousal, stress and memory

Ryan, Phil; Ma, Sherie; Olucha-Bordonau, Francisco E.; Gundlach, Andrew L.

doi:10.1016/j.neubiorev.2011.02.004

Cited by 95 publications

(115 citation statements)

References 122 publications

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“…(B) There was no significant effect on inactive lever presses for cue-induced reinstatement in sucrose-trained rats (F (2,44) = 0.68, P = 0.51). (C) Although there was a significant effect of treatment on active lever presses for stress-induced reinstatement in sucrose-trained rats (F (2,22) = 16.60, P < 0.0001), post hoc tests indicated that the lever pressing for vehicleinjected rats was not significantly different from lever pressing of R3(B1-22) R-treated rats. However, there was a significant difference between vehicleinjected rats and lever pressing during extinction (P < 0.001) and between R3 (B1-22)R-treated rats and lever pressing during extinction (P < 0.01); n = 12 rats.…”

Section: Discussionmentioning

confidence: 92%

“…Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels of RXFP3 (11,15,(17)(18)(19)(20)(21)(22). This pattern of innervation, along with findings that relaxin-3 can modulate (i) food intake (23)(24)(25), (ii) responses to stress (20,26,27), (iii) arousal (28,29), and (iv) interactions with the corticotropin-releasing factor (CRF) systems (20,26), led us to hypothesize that relaxin-3 may modulate aspects of behavior related to substance use and abuse.…”

Section: Addiction | Dependencementioning

confidence: 99%

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Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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114

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Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

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Section: Discussionmentioning

confidence: 92%

Section: Addiction | Dependencementioning

confidence: 99%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

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“…Furthermore, the change in hippocampal activation correlated significantly with subjective fatigue levels, rather than subsequent recognition performance. Therefore, we suggest that activation differences in the right hippocampus may more likely reflect the involvement of this area in differences in arousal/fatigue state (e.g., via the nucleus incertus: Ryan, Ma, Olucha-Bordonau, & Gundlach, 2011) between responders and non-responders than cortisol-induced blockade of memory encoding processes.…”

Section: Discussionmentioning

confidence: 93%

Cortisol and induced cognitive fatigue: Effects on memory activation in healthy males

Klaassen¹,

Groot²,

Evers³

et al. 2013

Biological Psychology

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a b s t r a c tWe investigated the relationship between individual differences in acute fatigue and endogenous cortisol changes elicited by the sustained performance of cognitively demanding tasks (fatigue condition). Healthy males provided salivary cortisol measurements and subjective fatigue ratings, and were scanned (functional magnetic resonance imaging) during memory encoding and recognition tasks in fatigue and control conditions. A group of 15 'responders' showed significantly higher cortisol levels in the fatigue condition than 12 'non-responders'. Responders showed higher subjective fatigue and reduced encoding and recognition activation than non-responders in the fatigue condition. An interaction in activation changes in the right hippocampus during encoding reflected decreased activation in responders, but somewhat increased activation in non-responders in the fatigue compared to control condition. Moreover, decreased hippocampal activation in responders was associated with increased subjective fatigue. Findings are consistent with a central role for the hippocampus in differences between responders and non-responders and also implicate the right hippocampus in individual differences in induced cognitive fatigue effects.

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“…This highly conserved structure consists mainly of GABAergic projection neurons, innervates many forebrain regions 3 and has been implicated in various behaviours including arousal and responses to stress 2,4 . NI neurons express CRF receptor type 1 (CRFR1) protein and mRNA in abundance 5 , and electrophysiological characterization in vitro and in vivo has revealed that CRF depolarizes NI cells via postsynaptic CRFR1 in a long-lasting and non-desensitizing manner 6 .…”

mentioning

confidence: 99%

“…Central infusion of CRF, or exposure to neurogenic stressors (including behavioural or pharmacological stressors), directly or indirectly activates NI neurons 4 . Electrolytic lesioning of the NI 8 and selective ablation of CRFR1-positive NI neurons using CRFsaporin 9 cause deficits in fear extinction without impairing initial conditioning.…”

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confidence: 99%

CRF and the nucleus incertus: a node for integration of stress signals

Lawrence

2016

Nat Rev Neurosci

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We recently read with interest the timely and scholarly Review by Henckens et al. (Regionspecific roles of the corticotropin-releasing factor-urocortin system in stress. Nat. Rev. Neurosci. 17, 636-651 (2016)) 1 on the regionspecific actions of the corticotropin-releasing factor (CRF)-urocortin system in stress neuro biology. However, we note an inadvertent but important omission: a role for CRF signalling in the nucleus incertus.The nucleus incertus (NI; also known as the 'nucleus O') is located in the pons, below the fourth ventricle 2 . This highly conserved structure consists mainly of GABAergic projection neurons, innervates many forebrain regions 3 and has been implicated in various behaviours including arousal and responses to stress 2,4 . NI neurons express CRF receptor type 1 (CRFR1) protein and mRNA in abundance 5 , and electrophysiological characterization in vitro and in vivo has revealed that CRF depolarizes NI cells via postsynaptic CRFR1 in a long-lasting and non-desensitizing manner 6 . Substantial evidence confirms the importance of CRF signalling in the NI in relation to various stress-related disorders, such as anxiety (reviewed in REFS 2,7).Central infusion of CRF, or exposure to neurogenic stressors (including behavioural or pharmacological stressors), directly or indirectly activates NI neurons 4 . Electrolytic lesioning of the NI 8 and selective ablation of CRFR1-positive NI neurons using CRFsaporin 9 cause deficits in fear extinction without impairing initial conditioning. Moreover, selective pharmacogenetic activation of NI neurons causes enhanced arousal, locomotion, vigilance and active responding behaviours during fear conditioning 10 . CRF infusion into, or electrical stimulation of, the NI impairs long-term potentiation (LTP) of hippocampal-medial prefrontal cortical synapses 11 , whereas intra-NI infusion of the CRFR1 antagonist antalarmin reversed stress-induced suppression of LTP in this pathway 12 . Intra-NI infusion of the CRFR1 antagonist CP-376395, but not the CRFR2 antagonist astressin 2B, considerably reduced the reinstatement of alcohol seeking in rats that was induced by administration of the pharmacological stressor yohimbine 13 -an effect that is probably mediated by CRFR1 activation of relaxin-3-positive NI neurons 6,14 . The NI is therefore a stressresponsive nucleus and, through CRFR1, contributes to memory and learning, stressinduced reward seeking, impairments in neuronal plasticity, and arousal behaviours 9-13 .The lateral preoptic area sends CRFcontaining projections to the NI 6 ; however, other CRF-positive regions that do the same require further clarification. Given the close proximity of the NI to the fourth ventricle, CRF may activate NI neurons through volume transmission from the cerebrospinal fluid 15 . Furthermore, it has recently been discovered that Crf mRNA and CRF protein are expressed in the rodent NI 13 , therefore, CRF release intrinsic to the NI cannot be ruled out, although the phenotype and function of these CRF-positive cells require elucidat...

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Nucleus incertus—An emerging modulatory role in arousal, stress and memory

Cited by 95 publications

References 122 publications

Relaxin-3/RXFP3 system regulates alcohol-seeking

Relaxin-3/RXFP3 system regulates alcohol-seeking

Cortisol and induced cognitive fatigue: Effects on memory activation in healthy males

CRF and the nucleus incertus: a node for integration of stress signals

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