Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear

Pereira, Celia W.; Santos, Fábio Neves dos; Sánchez-Pérez, Ana María; Otero-García, Marcos; Marchioro, Murilo; Ma, Sherie; Gundlach, Andrew L.; Olucha-Bordonau, Francisco E.

doi:10.1016/j.bbr.2013.03.025

Cited by 30 publications

(27 citation statements)

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“…Rats in which CRF‐R1‐positive NI neurones were selectively lesioned using a CRF‐conjugated saporin toxin, exhibited significantly prolonged freezing behaviour following the presentation of a cue previously associated with footshock and during the 5 min after cue presentation offset, although there were no impairments in conditioned learning . Similarly, electrolytic lesion of the NI has been reported to significantly delay the extinction of conditioned fear behaviour, whereby rats exhibit significantly more freezing during conditioned cue presentations . Because NI activity appears related to active locomotor components of behavioural responses, these findings suggest ablation of the NI results in impairment of active locomotor responses that would normally be associated with active aversion/withdrawal from a potential threat and/or during the extinction process, which involves new learning that a cue is no longer associated with a threat .…”

Section: Activation Of Ni Neurones By Neurogenic Stressors and Crf: Mmentioning

confidence: 88%

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

Gundlach

2015

J Neuroendocrinology

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Arousal is a process that involves the activation of ascending neural pathways originating in the rostral pons that project to the forebrain through the midbrain reticular formation to promote 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 extrahypothalamic 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 arousal and motivated behaviours and has begun to identify the associated mechanisms. Future research that should help to better clarify the connectivity and function of the NI in major experimental species and humans is also discussed.

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Section: Activation Of Ni Neurones By Neurogenic Stressors and Crf: Mmentioning

confidence: 88%

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

Gundlach

2015

J Neuroendocrinology

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“…Considerable evidence supports a role for oxytocin in the hypothalamic coordination of metabolic signals (Ganella, Ma, & Gundlach, ) and indicates that it is likely to be an effector of relaxin‐3/RXFP3 receptor signalling based on the robust expression of these receptors in the hypothalamic nuclei that synthesize oxytocin, the PVN and the SON, and the role of oxytocin in modulating anxiety, fear, and stress responses (Carter, ; McCarthy, McDonald, Brooks, & Goldman, ; Viero et al, ). It was further reported that central infusion of CRH or exposure to neurogenic stressors directly or indirectly activates NI neurons (Ryan, Ma, Olucha‐Bordonau, & Gundlach, ), and electrolytic lesioning of the NI (Pereira et al, ) and selective ablation of CRF1 receptor‐positive NI neurons using CRH‐saporin (Lee, Rajkumar, & Dawe, ) cause a deficit in fear conditioning. Moreover, serotoninergic afferents are dispersed across multiple regions of the amygdala (Bonn, Schmitt, Lesch, Van Bockstaele, & Asan, ), and stress during fear conditioning induces an increase in serotonin concentrations in the amygdala.…”

Section: Discussionmentioning

confidence: 99%

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Marwari

Poulsen

Shih

et al. 2019

British J Pharmacology

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Background and PurposeDepression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin‐3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug‐like properties. We proposed that a hydrocarbon‐stapled mimetic of relaxin‐3, when administered intranasally, might be uniquely applicable to the treatment of these disorders.Experimental ApproachWe designed a series of hydrocarbon‐stapled relaxin‐3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin‐3 and the lead stapled mimetic in rat models of anxiety and depression.Key ResultsWe developed an i,i+7 stapled relaxin‐3 mimetic that manifested a stabilized α‐helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin‐3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant‐like activity in anxiety‐ and depression‐related behaviour paradigms.Conclusions and ImplicationsOur preclinical findings demonstrate that targeting the relaxin‐3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin‐3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

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“…Previously published data suggest that this effect of the CNR1+ interneurons might be related to dysfunction of both the cortical and the amygdalar circuitry: CNR1 is highly expressed in the amygdala (Katona et al, 2001) and it is known that the amygdala significantly contributes to cue based memory, while contextual memory is largely hippocampal-dependent (Amano et al, 2011; Phillips and LeDoux, 1992). Furthermore, both CNR1 antagonists (Ganon-Elazar and Akirav, 2009) or disruption of GABA in the amygdala also lead to loss of extinction (Ehrlich et al, 2009; Pereira et al, 2013). Our work suggests that inactivation of CNR1+ interneurons is sufficient to block extinction, highlighting the important role of this interneuronal subclass in the response to cannabinoid activation and subsequent behavior.…”

Section: Discussionmentioning

confidence: 99%

The role of cannabinoid 1 receptor expressing interneurons in behavior

Brown¹,

Horváth²,

Garbett³

et al. 2014

Neurobiology of Disease

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Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kD a protein isoform of glutamic acid decarboxylase (GAD67), is a hallmark of the disease, and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.

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Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear

Cited by 30 publications

References 48 publications

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

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

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

The role of cannabinoid 1 receptor expressing interneurons in behavior

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