Control of arousal through neuropeptide afferents of the locus coeruleus

Zitnik, Gerard

doi:10.1016/j.brainres.2015.12.010

Cited by 44 publications

(25 citation statements)

References 178 publications

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“…The tPBN injections also did not affect the LC: Numerous enkephalin receptors on LC dendrites 37 and the involvement of the LC in multiple regulatory functions including arousal and nociception 54 make the LC a theoretical target during our opioid protocols. The importance of awake drive for respiratory rate has recently been shown in pediatric patients 55 .…”

Section: Discussionmentioning

confidence: 97%

A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits

et al. 2017

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Background The efficacy of opioid administration to reduce postoperative pain is limited by respiratory depression. We investigated whether clinically relevant opioid concentrations altered the respiratory pattern in the parabrachial nucleus, a pontine region contributing to respiratory pattern generation, and compared these effects with a medullary respiratory site, the pre-Bötzinger complex. Methods Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjections elicited tachypnea. Two protocols were performed in separate sets of animals. First, bilateral microinjections of the μ-opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (100 μM) into the “tachypneic area” determined the effect of maximal μ-opioid receptor activation. Second, respiratory rate was decreased with continuous IV infusions of remifentanil. The opioid antagonist naloxone (1 mM) was then microinjected bilaterally into the “tachypneic area” of the parabrachial nucleus to determine whether the respiratory rate depression could be locally reversed. Results Average respiratory rate was 27 ± 10 breaths/min. First, [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin injections decreased respiratory rate by 62 ± 20% in young and 45 ± 26% in adult rabbits (both P < 0.001). Second, during IV remifentanil infusion, bilateral naloxone injections into the “tachypneic area” of the parabrachial nucleus reversed respiratory rate depression from 55 ± 9% to 20 ± 14% in young and from 46 ± 20% to 18 ± 27% in adult rabbits (both P < 0.001). The effects of bilateral [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin injection and IV remifentanil on respiratory phase duration in the “tachypneic area” of the parabrachial nucleus was significantly different from the pre-Bötzinger complex. Conclusions The “tachypneic area” of the parabrachial nucleus is highly sensitive to μ-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids.

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Section: Discussionmentioning

confidence: 97%

A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits

et al. 2017

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“…Interestingly, in addition to sexual dimorphism of LC morphology and stress responsiveness, there are also sex differences in LC intracellular signaling induced by CRF: specifically, CRFR1 is more strongly coupled to β -arrestin in males, promoting receptor internalization and potentially blunted responsiveness to CRF in the future. In females, however, CRFR1 is more strongly coupled to Gs signaling pathways, which promotes increased LC discharge and dendritic proliferation, potentially increasing future sensitivity to stress by providing more space for synaptic contacts with CRF-positive afferents [ 63 , 133 ]. In this way, the male and female LC may be differentially aligned to respond to stress with specific neuroplastic adaptations that promote disease.…”

Section: Lc/ne Synaptic Plasticity Changes During Stressmentioning

confidence: 99%

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

2018

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Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder.

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“…However, their firing frequency is strongly modulated by conventional neurotransmitters (Cherubini et al, 1988; Singewald and Philippu, 1998). Often co-expressed with GABAergic and glutamatergic inputs are an assortment of neuropeptides which either exert direct effects on LC neuronal excitability or modulate the effects of the co-released neurotransmitters, and are thus considered as neuromodulators (Zitnik, 2016). In contrast, the role of another LC afferent system, distinguished by the expression of the neurohormone AVP (Rood and De Vries, 2011) is relatively poorly understood in terms of its contribution to LC function.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Modulation of Mouse Locus Coeruleus Neurons by Vasopressin 1a and 1b Receptors

et al. 2018

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The locus coeruleus (LC) is a brainstem nucleus distinguished by its supply of noradrenaline throughout the central nervous system. Apart from modulating a range of brain functions, such as arousal, cognition and the stress response, LC neuronal excitability also corresponds to the activity of various peripheral systems, such as pelvic viscera and the cardiovascular system. Neurochemically diverse inputs set the tone for LC neuronal activity, which in turn modulates these adaptive physiological and behavioral responses essential for survival. One such LC afferent system which is poorly understood contains the neurohormone arginine-vasopressin (AVP). Here we provide the first demonstration of the molecular and functional characteristics of the LC-AVP system, by characterizing its receptor-specific modulation of identified LC neurons and plasticity in response to stress. High resolution confocal microscopy revealed that immunoreactivity for the AVP receptor 1b (V1b) was located on plasma membranes of noradrenergic and non-noradrenergic LC neurons. In contrast, immunoreactivity for the V1a receptor was exclusively located on LC noradrenergic neurons. No specific signal, either at the mRNA or protein level, was detected for the V2 receptor in the LC. Clusters immunoreactive for V1a-b were located in proximity to profiles immunoreactive for GABAergic and glutamatergic synaptic marker proteins. AVP immunopositive varicosities were also located adjacent to labeling for such synaptic markers. Whole-cell patch clamp electrophysiology revealed that the pharmacological activation of V1b receptors significantly increased the spontaneous activity of 45% (9/20) of recorded noradrenergic neurons, with the remaining 55% (11/20) of cells exhibiting a significant decrease in their basal firing patterns. Blockade of V1a and V1b receptors on their own significantly altered LC neuronal excitability in a similar heterogeneous manner, demonstrating that endogenous AVP sets the basal LC neuronal firing rates. Finally, exposing animals to acute stress increased V1b, but not V1a receptor expression, whilst decreasing AVP immunoreactivity. This study reveals the AVP-V1a-b system as a considerable component of the LC molecular architecture and regulator of LC activity. Since AVP primarily functions as a regulator of homeostasis, the data suggest a novel pathway by modulating the functioning of a brain region that is integral to mediating adaptive responses.

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Control of arousal through neuropeptide afferents of the locus coeruleus

Cited by 44 publications

References 178 publications

A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits

A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Dynamic Modulation of Mouse Locus Coeruleus Neurons by Vasopressin 1a and 1b Receptors

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