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Activation of locus coeruleus-projecting enkephalin neurons in the nucleus PGi. A, Scatterplot showing the percentage of FG-c-fos-labeled neurons that were also immunolabeled for ENK for individual control, SL, and LL rats. Lines through the points indicate the group mean. B, Representative immunofluorescence photomicrograph from a long latency rat showing c-fos profiles (blue), FG labeling (green), ENK-immunoreactivity (red), and triple-labeled neurons (yellow). Arrows point to single-labeled neurons and arrowheads point to triple-labeled neurons. Scale bar, 10 m. C, High-magnification photomicrographs illustrating activated LC-projecting ENK neurons in the PGi of a LL rat. FG, c-fos, and ENK panels show single labeling for the retrograde tracer, FG (green), c-fos immunoreactivity (blue), and ENK immunoreactivity (red), respectively. The merged image shows all labels. Thin arrows point to the same triple-labeled neuron in all images. Scale bar, 10 m.
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Stress increases vulnerability to psychiatric disorders, partly by affecting brain monoamine systems, such as the locus coeruleus (LC)-norepinephrine system. During stress, LC activity is coregulated by corticotropin-releasing factor (CRF) and endogenous opioids. This study identified neural circuitry that regulates LC activity of intruder rats dur...
Citations
... We previously reported that the LC-NAergic system regulates subchronic social stress-induced decrease in passive stress coping in postpartum female mice [11]. The LC is also associated with stress coping in non-postpartum females and males in rats [27,61]. Projection from the LC plays an important role in stress-induced modulation of mPFC function [24]. ...
The prevalence of depression in women increases during the postpartum period. We previously reported that subchronic exposure to social stress decreased passive coping in postpartum female mice. This study aimed to investigate whether noradrenaline regulation might regulate coping styles in mice. We first determined whether a different type of stress, subchronic physical stress, decreases passive coping in postpartum females. Postpartum female, virgin female, and male mice were exposed to subchronic restraint stress (restraint stress for 4 h for 5 consecutive days). Subchronic restraint stress decreased passive coping in postpartum females but not in virgin females and males in the forced swim and tail suspension tests. We next examined the neuronal mechanism by which subchronic stress decreases passive coping in postpartum female mice. Neuronal activity and expression of noradrenergic receptors in the medial prefrontal cortex (mPFC) were analyzed using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction, respectively. The mPFC was manipulated using chemogenetics, knockdown, or an α2A adrenergic receptor (AR) antagonist. Immunohistochemistry revealed that subchronic restraint stress increased glutamatergic neuron activation in the mPFC via forced swim stress and decreased α2A AR expression in postpartum females. Chemogenetic activation of glutamatergic neurons in the mPFC, knockdown of α2AAR in the mPFC, and the α2A AR receptor antagonist atipamezole treatment decreased passive coping in postpartum females. Subchronic restraint stress decreased passive coping in postpartum females by increasing glutamatergic neuron activity in the mPFC through α2A AR attenuation. The noradrenergic regulation of the mPFC may be a new target for treating postpartum depression.
... While the NacS receives noradrenergic inputs from the A2 noradrenergic population of the Nucleus of the Solitary tract (NTS) and the Locus Coeruleus (LC) [60], the acquisition of coping responses has been associated with the LC-NA system [61][62][63][64][65] which has also been suggested to be involved in the expression of polydipsic adjunctive water drinking [66]. ...
... The results of the present study show that the development of compulsive adjunctive behaviour under SIP is associated with a decrease in Arc mRNA levels in the LC, and more particularly in a LC Arc+/TH+/zif268-neuronal ensemble. This new cellular signature of compulsive coping behaviour in the LC is in agreement with previous evidence of the involvement of this monoaminergic nucleus of the brainstem in stress [62] and coping strategies [61,64], and in which originate the neurons whose projections to the NacS, further characterised in the present study, contribute to the regulation of the high impulsivity trait that confers and increased vulnerability to developing compulsive adjunctive behaviours under SIP [40,59]. ...
Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviours and their subsequent compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline-dependent system in stress and related excessive behaviours, we hypothesised that neuroplastic changes in the LC may be associated with the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behaviour, and the ensuing development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behaviour was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268− neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behaviour, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice, while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+/zif268− LC neurons represents a signature of the tendency to develop compulsive coping behaviours.
... The locus coeruleus-noradrenergic (LC-NA) system is considered the central system responsible for processing stress stimuli (Itoi and Sugimoto 2010), including physical (Pirnik et al. 2004) and social stressors (Reyes et al. 2019). The LC-NA system regulates adaptation to stress (Valentino and Van Bockstaele 2008), and is associated with stress coping (Reyes et al. 2015(Reyes et al. , 2019. In mice, unfamiliar males are recognized as a social threat by postpartum females (Hahn-Holbrook et al. 2011) because they often attack newborns (Isogai et al. 2018). ...
... The activity of LC-NA neurons is coregulated by corticotropin-releasing factor and enkephalin, which increase and decrease the activity of LC-NA neurons, respectively . Higher resilience to social defeat stress is associated with enkephalin from the nucleus paragigantocellularis in nonpostpartum females and males of rats (Reyes et al. 2019(Reyes et al. , 2015. Enkephalin decreases LC-NA neuronal activity as anti-stress neuromodulator . ...
Stress-coping strategies have been implicated in depression. The control of stress coping may improve the symptom and higher prevalence of depression during the postpartum period in women. However, the neuronal mechanisms underlying stress coping remain to be fully elucidated in postpartum women. In this study, we examined how locus coeruleus-noradrenergic (LC-NA) neurons, which have been associated with both stress coping and depression, regulate changes in coping style induced by subchronic exposure to unfamiliar male mice as a social threat in postpartum female mice. In contrast to virgin females, dams exposed to unfamiliar males daily for four consecutive days showed reduced immobility duration in the forced swim test, indicating that exposure to unfamiliar males decreased passive stress coping in dams. Exposure to unfamiliar males also decreased sucrose palatability in the sucrose preference test and suppressed the crouching behavior in the maternal care test but did not affect anxiety-like behavior in the hole-board test in dams. In fiber photometry analyses, LC-NA neurons showed differential activity between dams and virgin females in response to unfamiliar males. Chemogenetic inhibition of LC-NA neurons during exposure to unfamiliar males prevented the social threat-induced decrease in immobility duration in the forced swim test in dams. Furthermore, inhibition or activation of LC-NA neurons exacerbated crouching behavior in dams. These results indicate that LC-NA neurons regulate the social threat-induced decrease in passive stress coping and relieve social threat-induced inhibition of maternal care in postpartum female mice.
... The results of the present study show that the development of compulsive adjunctive polydipsic behavior under SIP is associated with a decrease in Arc mRNA levels especially, but not restricted to TH+zif268-neurons in the LC, a monoaminergic nucleus long suggested to be involved in stress [51] and, more recently, in coping strategies [50,53]. While the overall population of rats exposed to SIP developed a polydipsic response over time, in agreement with previous studies [46,93], individual differences emerged from the first week of training, with some individuals, namely HD rats, losing control over their coping response and developing very high levels of polydipsic drinking, the time course and magnitude of which is in line with that reported in previous studies from our laboratory and others [44,46,84,94]. ...
Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviors and their ensuing compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline dependent system in stress and related excessive behaviors, we hypothesised that neuroplastic changes in the LC may be involved in the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behavior, and the subsequent development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behavior was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268- neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behavior, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+zif268- LC neurons represents a signature of the tendency to develop compulsive coping behaviors.
... Tasks that apply both appetitive and aversive stimuli might better uncover the nature of signals observed in this region and how it relates to attentional signals observed in ACC in both social and non-social contexts. Finally, the locus coeruleus (LC) -a region with widespread projections throughout the entire central nervous system -consists of neurons that synthesize norepinephrine and play a major role in arousal and attention (Breton-Provencher et al., 2021) is also thought to contribute to social stress (Reyes et al., 2015). Future studies should investigate how norepinephrine release in ACC might modulate attention to social cues. ...
In 2014, we participated in a special issue of Frontiers examining the neural processing of appetitive and aversive events. Specifically, we reviewed brain areas that contribute to the encoding of prediction errors and value versus salience, attention and motivation. Further, we described how we disambiguated these cognitive processes and their neural substrates by using paradigms that incorporate both appetitive and aversive stimuli. We described a circuit in which the orbitofrontal cortex (OFC) signals expected value and the basolateral amygdala (BLA) encodes the salience and valence of both appetitive and aversive events. This information is integrated by the nucleus accumbens (NAc) and dopaminergic (DA) signaling in order to generate prediction and prediction error signals, which guide decision-making and learning via the dorsal striatum (DS). Lastly, the anterior cingulate cortex (ACC) is monitoring actions and outcomes, and signals the need to engage attentional control in order to optimize behavioral output. Here, we expand upon this framework, and review our recent work in which within-task manipulations of both appetitive and aversive stimuli allow us to uncover the neural processes that contribute to the detection of outcomes delivered to a conspecific and behaviors in social contexts. Specifically, we discuss the involvement of single-unit firing in the ACC and DA signals in the NAc during the processing of appetitive and aversive events in both social and non-social contexts.
... These findings indicate that enkephalinergic signaling at DORs within LC both reduces anxietylike behavior and may be related to reward-related learning. While the role of the pro-stress effector CRF in driving behavior through its actions in LC have been well characterized [8,13,23,30,39], the role of enkephalin, and DORs in particular, has been comparatively understudied. This is an important area for investigation because CRF and endogenous opioids act in concert in LC to respond to a stressor: first, CRF is released onto LC causing depolarization and increased discharge and anxiety-like behavior, and upon stressor termi-nation, endogenous opioids act on their receptors to suppress LC output and facilitate a return to a more normative behavioral state [25,32]. ...
... Although these studies did not specifically investigate if the enkephalinergic projection to LC becomes engaged in animals that show reduced anxiety-like behavior in response to stress, previous studies have provided indirect evidence that the CRF-positive and enkephalinergic projections to LC become engaged under specific circumstances and aid in driving particular behavioral phenotypes [30]. Specifically, there is evidence for increased activation of the CRF-positive CeA→LC circuit in animals that are stress-susceptible passive copers, and increased activation of the enkephalinergic PGi→LC circuit in animals that are stress-resilient active copers. ...
The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. LC is also innervated by several structures that synthesize and release the endogenous opioid peptide enkephalin onto LC upon stressor termination. While the role of CRF neurotransmission within LC in mediating anxiety-like behavior and the behavioral response to stress has been well characterized, the role of enkephalinergic signaling at LC-expressed δ-opioid receptors has been comparatively understudied. We have previously shown that acute stressor exposure increases LC activity and anxiety-like behavior for at least one week. Here, we extend these findings by showing that these effects may be mediated at least in part through stress-induced downregulation of DORs within LC. Furthermore, overexpression of DORs in LC blocks the effects of stress on both LC firing properties and anxiety-like behavior. In addition, intra-LC infusions of enkephalin blocked stress-induced freezing behavior and promoted conditioned place preference. These findings indicate that enkephalinergic neurotransmission at DORs within LC is an important component of the behavioral response to stress and may drive reward-related behavior as well.
... Kataoka et al. [37] reported that the rostral modulatory raphe and the dorsomedial hypothalamus mediated SIH. However, the locus coeruleus (LC), a small brainstem nucleus, is considered the primary site for norepinephrine production in the brain, which is implicated in the etiology of anxiety or stress [38,39]. Furthermore, LC dendrites receive input from excitatory terminals containing CRF [40]. ...
The objective of this study was to determine the effects of centrally administered taurine on rectal temperature, behavioral responses and brain amino acid metabolism under isolation stress and the presence of co-injected corticotropin-releasing factor (CRF). Neonatal chicks were centrally injected with saline, 2.1 pmol of CRF, 2.5 μmol of taurine or both taurine and CRF. The results showed that CRF-induced hyperthermia was attenuated by co-injection with taurine. Taurine, alone or with CRF, significantly decreased the number of distress vocalizations and the time spent in active wakefulness, as well as increased the time spent in the sleeping posture, compared with the saline- and CRF-injected chicks. An amino acid chromatographic analysis revealed that diencephalic leucine, isoleucine, tyrosine, glutamate, asparagine, alanine, β-alanine, cystathionine and 3-methylhistidine were decreased in response to taurine alone or in combination with CRF. Central taurine, alone and when co-administered with CRF, decreased isoleucine, phenylalanine, tyrosine and cysteine, but increased glycine concentrations in the brainstem, compared with saline and CRF groups. The results collectively indicate that central taurine attenuated CRF-induced hyperthermia and stress behaviors in neonatal chicks, and the mechanism likely involves the repartitioning of amino acids to different metabolic pathways. In particular, brain leucine, isoleucine, cysteine, glutamate and glycine may be mobilized to cope with acute stressors.
... Neurons in the locus coeruleus (LC) release NE to regulate baseline arousal and to facilitate a variety of sensory-motor and behavioral functions (Aston- Jones and Cohen, 2005;Sara, 2009;Sara and Bouret, 2012;Poe et al., 2020). Dysfunction in the LC-NE system has been implicated in the etiology of ADHD (Arnsten, 2011), schizophrenia (Friedman et al., 1999), anxiety or stress (Valentino and Van Bockstaele, 2008;Arnsten et al., 2015;Reyes et al., 2015), and depression (Delgado and Moreno, 2000), as well as in the cognitive decline observed in aging and Alzheimer's disease (Weinshenker, 2008). ...
The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions, and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE to control arousal, but also in the context of a variety of sensory-motor and behavioral functions. Despite its brain-wide effects, much about the role of LC-NE in behavior and the circuits controlling LC activity is unknown. New evidence suggests that the modular input-output organization of the LC could enable transient, task-specific modulation of distinct brain regions. Future work must further assess whether this spatial modularity coincides with functional differences in LC-NE subpopulations acting at specific times, and how such spatiotemporal specificity might influence learned behaviors. Here, we summarize the state of the field and present new ideas on the role of LC-NE in learned behaviors.
... enkephalin-containing axon terminals converge on some of the same LC dendrites as CrF-containing axon terminals and have opposing effects on LC discharge 199,200 during stress, implicating enkephalin afferents to the LC (acting at µ-opioid receptors) as an important stresscoping and recovery system. acute stressors engage both CrF and enkephalin afferents to regulate LC activity 201,202 . although CrF excitation of LC activity predominates during acute stress, µ-opioid receptor antagonism results in a greater magnitude of LC activation and delays recovery 201 . ...
The locus coeruleus (LC) has long been underappreciated for its role in the pathophysiology of Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative disorders. While AD and PD are distinct in clinical presentation, both are characterized by prodromal protein aggregation in the LC, late-stage degeneration of the LC, and comorbid conditions indicative of LC dysfunction. Many of these early studies were limited to post-mortem histological techniques due to the LC’s small size and location deep in the brainstem. Thus, there is a growing interest in utilizing in vivo imaging of the LC as a predictor of preclinical neurodegenerative processes and biomarker of disease progression. Simultaneously, neuroimaging in animal models of neurodegenerative disease holds promise for identifying early alterations to LC circuits, but has thus far been underutilized. While still in its infancy, a handful of studies have reported effects of single gene mutations and pathology on LC function in disease using various neuroimaging techniques. Furthermore, combining imaging and optogenetics or chemogenetics allows for interrogation of network connectivity in response to changes in LC activity. The purpose of this article is twofold: (1) to review what magnetic resonance imaging (MRI) and positron emission tomography (PET) have revealed about LC dysfunction in neurodegenerative disease and its potential as a biomarker in humans, and (2) to explore how animal models can be used to test hypotheses derived from clinical data and establish a mechanistic framework to inform LC-focused therapeutic interventions to alleviate symptoms and impede disease progression.
... Enkephalin-containing axon terminals converge on some of the same LC dendrites as CRF-containing axon terminals and have opposing effects on LC discharge 199,200 during stress, implicating enkephalin afferents to the LC (acting at μ-opioid receptors) as an important stresscoping and recovery system. Acute stressors engage both CRF and enkephalin afferents to regulate LC activity 201,202 . Although CRF excitation of LC activity predominates during acute stress, μ-opioid receptor antagonism results in a greater magnitude of LC activation and delays recovery 201 . ...
The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.
