# Role of the locus coeruleus-noradrenergic system in stress-related psychopathology and resilience: Clinical and pre-clinical evidences

Déa Slavova, Vanesa Ortiz, Maud Blaise, Marya Bairachnaya, Bruno Giros, Elsa Isingrini

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## To cite this version:

Déa Slavova, Vanesa Ortiz, Maud Blaise, Marya Bairachnaya, Bruno Giros, et al.. Role of the locus coeruleus-noradrenergic system in stress-related psychopathology and resilience: Clinical and pre-clinical evidences. Neuroscience and Biobehavioral Reviews, 2024, 167, pp.105925. 10.1016/j.neubiorev.2024.105925. hal-05380442

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# Role of the locus coeruleus-noradrenergic system in stress-related psychopathology and resilience: Clinical and pre-clinical evidences

Déa Slavova<sup>a</sup>, Vanesa Ortiz<sup>a</sup>, Maud Blaise<sup>a</sup>, Marya Bairachnaya<sup>b</sup>, Bruno Giros<sup>a,b</sup>,
Elsa Isingrini<sup>a,*</sup>

## ARTICLE INFO

### Keywords:

Stress

stress modalities

major depressive disorder

post-traumatic stress disorder

individual variability

resilience

noradrenaline

locus coeruleus

## ABSTRACT

Stressful events, from daily stressors to traumatic experiences, are common and occur at any age. Despite the high prevalence of trauma, not everyone develops stress-related disorders like major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), a variation attributed to resilience, the ability to adapt and avoid negative consequences of significant stress. This review examines the locus coeruleus-norepinephrine (LC-NE) system, a critical component in the brain's stress response. It discusses the LC-NE system's anatomical and functional complexity and its role in individual variability in stress responses. How different etiological factors and stress modalities affect the LC-NE system, influencing both adaptive stress responses and psychopathologies, are discussed and supported by evidence from human and animal studies. It also explores molecular and cellular adaptations in the LC that contribute to resilience, including roles of neuropeptide, inflammatory cytokines, and genetic modulation, and addresses developmental and sex differences in stress vulnerability. The need for a multifaceted approach to understand stress-induced psychopathologies is emphasized and pave the way for more personalized interventions for stress-related disorders.

## 1. Introduction

Every individual experiences stressful events in their lifetime, which can manifest as daily life stressors (e.g., work harassment, dysfunctional relationships, grinding stress of poverty) or traumatic events (e.g., death of a loved one, accidents, natural disasters, terrorist attacks, war trauma). These stressors can occur early in life (e.g., child maltreatment, bullying) or during adulthood. In the general population, the lifetime prevalence of trauma and adversity is extremely high, ranging from

50 % to 84 % (Benjet et al., 2016; Bürgin et al., 2020). Such threatening life experiences can compromise the psychological and physical well-being of some individuals, leading to the emergence of emotional psychiatric disorders, particularly major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) (Caspi et al., 2003). However, the global prevalence of major depression varies from 5 % to 23 % depending on the country (Smith, 2014) and for PTSD is 7.1 % and 3.6 %, indicating that not all individuals experiencing threatening life experience will develop mental illness (Horn et al., 2016; Rutter, 2012,

Abbreviations: ACTH, AdrenoCorticoTropic Hormone; AMY, Amygdala; AR, Adrenoceptors; ASR, Acoustic Startle Response; BLA, Basolateral Amygdala; CeA, Central Amygdala; CKO, Conditional Knock-Out; CNS, Central Nervous System; COMT, Catechol-O-MethylTransferase; CRF, Corticotropin-Releasing Factor; CSDS, Chronic Social Defeat Stress; DA, Dopamine; DBH, Dopamine-β-Hydroxylase; DEGs, Differentially-Expressed Genes; DL, Dorsolateral; DRD1, Dopamine Receptor D1; Egr1, Early growth response 1; EPM, elevated plus maze; FST, Forced Swimming Test; Gal, Galanin; GalR, Galanin Receptor; HPA, Hypothalamic-Pituitary-Adrenal; HPC, Hippocampus; HYP, Hypothalamus; Ih, Hyperpolarization-activated cation currents; IL-1β, Interleukine; KO, Konck-Out; LC, Locus Coeruleus; LH, Learned Helplessness; LL, Longer Latency; MAO, Monoamine Oxidase; MDD, Major Depressive Disorder; MGluR, Metabotropic glutamate receptor; NAc, nucleus accumbens; NE, Noradrenaline; NET, Noradrenaline Transporter; NPY2R, Neuropeptide Y Receptor type 2; NRI, Noradrenaline Reuptake Inhibitors; NPY, Neuropeptide-Y; Oprk1, Opioid Receptor Kappa 1; PFC, Prefrontal Cortex; PSS, Predator Scent Stress; PTSD, Post-Traumatic Stress Disorder; PVN, ParaVentricular Nucleus; RDoC, Research Domain of Criteria; VM, Ventromedial; SL, Short Latency; Sh-RNA, Short hairpin RNA; SON, SupraOptic Nucleus; SPS, Single Prolonged Stress; SSRI, Serotonin Selective Reuptake Inhibitors; TERS, Traumatic Experience with Reminders of Stress; TH, Tyrosine hydroxylase; TNF-α, Tumor necrosis factor; UCMS, Unpredictable Chronic Mild Stress; VTA, Ventral Tegmental Area; HPSC, human pluripotent stem cells; VMAT, Vesicular Monoamine Transporter.

<footnote><sup>a</sup> Université Paris Cité, INCC UMR 8002, CNRS, Paris F-75006, France</footnote>

<footnote><sup>b</sup> Douglas Research Center Institute, McGill University, Montreal, Canada</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: elsa.isingrini@parisdescartes.fr (E. Isingrini).</footnote>
2006). This phenomenon is known as resilience to trauma, defined as the ability to adapt successfully in response to a significant stress and avoid its negative consequences, in contrast to susceptibility.

Despite the availability of well-defined and evidence-based strategies for addressing psychiatric disorders, particularly major depression, less than half of the patients achieve remission with current treatments, including medications and psychotherapies. Major explanations for this failure include:

i) **the heterogeneity of the disease**, in which clinical manifestation emerged from a multitude of environmental and individuals' factors that shape the cognitive and emotional treatment of an individual in response to stressful life experiences,

ii) **the complexity of neurobiological underpinning** of these disorders which involve complex interactions from individual brain regions to larger neural networks and,

iii) **the inter-individual variability** observed in response to stress and adversity, add another layer of complexity.

Until recently, research primarily focused on understanding the pathogenic mechanisms of mental illnesses. However, in the last decade, there has been increased interest in the phenomenon of resilience. Understanding the processes underlying inter-individual variability in response to adversity is crucial for developing more effective treatments and innovative therapies aimed at preventing stress-related disorders. Investigating the neurobiological mechanisms of resilience can help identify natural processes that enable some individuals to maintain normal psychological and physiological states in the face of adversity.

The main objective of this review is to explore the locus coeruleus-noradrenergic (LC-NE) system, a critical component of the brain's first response to stress, and to elucidate its role in the variability of individual responses to stress and trauma. The first part of the review will discuss the anatomical and functional complexity of the LC-NE system, emphasizing the need to consider this complexity when targeting the LC-NE system for treatment. We will examine how etiological factors and stress modalities significantly influence the response of the LC-NE system. The review will then focus on how the LC-NE system, situated at the interface of integrating somatosensory information related to stress and processing this information at emotional and cognitive levels, could be a major driver of resilient responses.

## 2. The LC-NE system: a complex system involved in the adaptive stress response

### 2.1. Description of the LC-NE system

The noradrenergic (NE) system comprises clusters of neurons through in the pons of the central nervous system (CNS), with the locus coeruleus (LC) being the largest nucleus. The LC-NE system is conserved across vertebrate species, from amniotes to amniotes, or from fish to mammals (Smeets and González, 2000; Wang et al., 2022). In the simplest vertebrates, such as zebrafish, the LC system contains up to 20 NE neurons (Farrar et al., 2018). In rodents, this number increases to around 3000 (Sara, 2009), and in non-human primates, it ranges from 10,000 to 35,000 depending on the species (Sharma et al., 2010). In humans, the LC contains approximately 45,000–50,000 noradrenergic cells (German et al., 1988; Mouton et al., 1994). In rodents, two types of NE cells have been identified: multipolar cells (approximately 35 µm in the ventral LC) and fusiform cells (approximately 20 µm in the dorsal LC) (Schwarz and Luo, 2015; Swanson, 1976). In humans, four main types have been described: large multipolar, large bipolar, small multipolar and small bipolar, with the latter two predominantly found in the rostral, middle, and caudal regions of the human LC (Chan-Palay and Asan, 1989).

The LC region is composed of two regions, the LC “core” composed of NE cell bodies and the pericoeruleus “shell” region containing mainly

GABAergic cells (Bangasser et al. 2016a, Breton-Provencher V. et al. 2021). The pericoeruleus region or peri-LC can be divided in the dorsolateral (DL) and ventromedial (VM) parts (Bangasser et al., 2016a). NE acts on adrenoreceptors (AR), which are ubiquitously present post-synaptically and pre-synaptically on neurons, glia, and blood vessels. There are three families of NE receptors: α2-AR (high affinity for NE), α1-AR (intermediate affinity), and β-AR (low affinity) (Atzori et al., 2016). Depending on the AR targeted, NE can have excitatory (α1 and β1, β2, β3) or inhibitory (α2 and in some cases β2) effects on neural activity through Gα-mediated signaling. However, the modulatory effect of NE is more complex than merely triggering an excitatory or inhibitory response. In numerous target areas, NE enhances the efficacy of synaptic transmission (either excitatory or inhibitory) while decreasing the spontaneous activity of the same neuron (Berridge and Waterhouse, 2003; Woodward et al., 1979). This complexity makes it difficult to predict how NE modulates the activity of brain circuits.

The LC in rodents and humans is organized similarly, with extensive projections to various brain regions, and comparable distribution patterns and functional roles (Manger and Eschenko, 2021; Wang et al., 2022). The LC-NE system receives afferent projections from a broad array of regions and sends projections to nearly all regions of the brain (Aston-Jones and Waterhouse, 2016; Berridge and Waterhouse, 2003; Cedarbaum and Aghajanian, 1978; Jones and Moore, 1977; Moore and Bloom, 1979; Samuels and Szabadi, 2008; Szabadi, 2013). Its extensive projections throughout the CNS make this system ideally positioned at the interface of physiological, cognitive, and emotional processing. NE response has been shown to modulate a wide range of behavioral orientations, including arousal, learning and memory, as well as emotion, motivation, and fear (Breton-Provencher et al., 2022, 2021; Harley, 1987; Holland et al., 2021; Isingrini et al., 2023). Interestingly, recent studies suggest that the temporal activation patterns of LC-NE neurons (phasic vs. tonic) can recruit distinct downstream circuits in the same target region, leading to diverse behaviors (Ghosh et al., 2021; Harley and Yuan, 2021; McCall et al., 2017).

Multiple reports have provided evidence of an efferent topography within the LC, indicating a spatial organization of cells in the LC nucleus with respect to their terminal field targets (Berridge and Waterhouse, 2003; Mejías-Aponte et al., 2009). Although early retrograde tracing and antidromic activation studies revealed that single LC neurons branch to innervate different brain regions, other studies indicate that individual LC neurons collateralize to innervate functionally related circuits (Chandler et al., 2014; Simpson et al., 1997; Steindler, 1981). A heterogeneous organization of LC projections has been described, and distinct LC sub-circuits have been defined. For example, while the activation of LC-NE projections to the amygdala (AMY) is involved in the formation of fear memory, the activation of those projecting to the prefrontal cortex (PFC) contributes to the formation of extinction memory and the reduction of aversive memory expression. This demonstrates a modular organization of the LC, with projection- and behavior-specific cell populations (Uematsu et al., 2017).

Regarding the neuronal populations in the LC, 90% are NE cells, while serotonergic and GABAergic neurons represent the remaining 10% (Iijima, 1989; McLean et al., 1989). In addition to NE, the LC generates and releases neuropeptides, including vasopressin, somatostatin, galanin, neuropeptide Y, enkephalin, neurotensin, and corticotropin-releasing hormone (Olpe and Steinmann, 1991). Furthermore, NE neurons co-express galanin and neuropeptide Y (Olpe and Steinmann, 1991; Schwarz and Luo, 2015). This varied expression of peptides and co-neurotransmission contributes to the LC's complexity and its modulation in target regions.

The molecular, cellular, and systemic heterogeneity of the LC-NE system, as well as its different modes of activity, highlight the complexity of this system as a neuromodulator of behavior. In the next section, we will provide a non-exhaustive overview of the role of the LC-NE system in the physiological stress response in human and animal studies of stress-related psychopathologies (For review see (Ross and
Van Bockstaele, 2021). We will discuss how the anatomical and func-
tional complexity of the LC-NE system is a crucial factor to consider in
understanding how the stress response is influenced by different stress
modalities.

## 2.2. The LC-NE system in the adaptive stress response

The physiological stress response is characterized by complex and
synchronized autonomic, behavioral, endocrine, and immunological
responses (Bangasser and Valentino, 2014). Known as allostasis, this
response is necessary for survival as it triggers adaptive reflexes that
protect the individual from potential threats. Two major hallmarks of
this adaptive response are the activation of the
hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous
system (McEwen, 2007).

In response to stress, activation of the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus (HYP) leads to the release of corticotropin-releasing factor (CRF), vasopressin, and oxytocin (Jacobson and Sapolsky, 1991; Spiess et al., 1981). This triggers the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which causes the release of cortisol from the adrenal cortex. Cortisol alters the functioning of a variety of central and peripheral processes involved in arousal, alertness, and vigilance, leading to elevated heart rate, respiratory rate, and gluconeogenesis, thereby enhancing the availability of vital substrates (Chrousos and Gold, 1992; McEwen, 1998).

Another major hallmark of the adaptive stress response is the activation of the LC-NE/sympathetic systems (Pardon et al., 2002). Previous research has demonstrated that the release of NE increases during stress (Cecchi et al., 2002; Jacobs et al., 1991; Rasmussen et al., 1986) leading to elevated extracellular NE concentrations in its projection areas, including the AMY, hippocampus (HPC), striatum, and PFC (Finlay et al., 1995; Galvez et al., 1996; Steven M. Southwick et al., 1999). This correlates with enhanced reactivity to salient stressful stimuli (Aston-Jones et al., 1999; Jacobson and Sapolsky, 1991; Ziegler et al., 1999).

The LC is thought to play a critical role in the cognitive aspects of the stress response (Valentino et al., 1993; Valentino and Van Bockstaele, 2008). It modulates the likelihood that a stimulus will elicit a behavioral response by acting as an arousal and alerting system, thereby governing the responsivity of target regions. The LC's stress response is regulated by CRF (Curtis et al., 1999, 1995) and the interaction of CRF with the NE system allows for the integration of endocrine and autonomic responses to stress (Aston-Jones et al., 1999; Pardon et al., 2002; Valentino et al., 1993). While the stress response is protective for the organism, a negative autoregulation loop (mediated by cortisol negative feedback inhibition) ensures that once the threat has passed, the stress response is inactivated, allowing the restoration of homeostasis (Chrousos and Gold, 1992; Munck et al., 1984; Yehuda and LeDoux, 2007). Although the physiological stress response is adaptive, extreme stress exposure or trauma, characterized by highly intense and overwhelming stressors that far exceed an individual's normal coping abilities, can lead to psychopathologies such as depression and PTSD.

## 3. The LC-NE system in psychopathology: Evidence in human and animal models

While the response to stress is an adaptive and complex reaction of
the organism, it can become maladaptive and lead to pathological states
when stress becomes excessive or chronic. In the following sections, we
will delve deeper into the evidence from human and animal models to
better understand the role of the LC-NE system in psychopathology,
highlighting both consistent findings and areas of ongoing debate.

### 3.1. Evidences in human's depression and PTSD

Stress and trauma are leading causes for the development of psy-
chiatric disorders, including MDD, anxiety, and PTSD. The symptoms
resulting from these pathologies are believed to reflect stress-induced
changes in neurobiological systems and/or inadequate adaptation of
these systems in response to stress or trauma.

While MDD is defined as an affective disorder associated with anhedonia, lack of motivation, pessimistic and suicidal thoughts, PTSD is characterized by a cluster of symptoms including re-experiencing, avoidance, alterations in cognition and mood, and alterations in arousal and reactivity. Re-experiencing the traumatic event is a key symptom of PTSD and can be conceptualized within the framework of fear memory extinction (Pitman et al., 2012) which remains persistent in these patients. Common core symptoms of these psychopathological conditions are mood alterations.

The catecholamine hypothesis of affective disorders proposes that depression is associated with a decrease in catecholamines, especially serotonin and NE. This hypothesis was first advanced with the discovery that reserpine, which induces monoaminergic depletion, leads to clinical depression (Chandley and Ordway, 2012; Schildkraut, 1995). Moreover, the therapeutic effect of antidepressant drugs is to increase NE neurotransmission by acting on NE reuptake or degradation (e.g., serotonin selective reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (NRIs), and monoamine oxidase inhibitors (MAOIs)) (Dell'Osso et al., 2011; Pinder, 2005).

In contrast, the understanding of the involvement of the NE system in PTSD emerged from studies demonstrating increased peripheral sympathetic nervous system activity. This was confirmed in clinical trials showing that prazosin, a clinically available antagonist of the post-synaptic α1 noradrenergic receptor (α1-AR), was effective for both nighttime and daytime symptoms of PTSD. Historically, this evidence suggests a decrease in NE tone in depression and increased reactivity of the LC-NE system in PTSD. However, inconsistencies observed in the literature (Table 1) can explain the high rate of treatment resistance associated with these pathologies.

This discrepancy among clinical studies might be explained by dif-
ferences in basal versus evoked LC responses, the samples used (urine,
plasma, arterial plasma), unequal percentages of women versus men in
each study (considering gender's influence on noradrenergic system
function), and the different approaches employed (protein level versus
cell counts). At the molecular level, evidence is controversial, and the
appearance of adaptive compensatory mechanisms needs to be clarified.
It is also important to note the limitations of human post-mortem
studies, including the limited number of patients and the potential
impact of medication and drugs found at the time of death.

## 3.2. LC-NE system in animal models of stress-induced psychopathologies

Because chronic stress and trauma exposure are the main etiological
factors for the development of MDD and PTSD, multiple laboratory
animal models of stress and traumatic exposure have been developed to
reproduce the symptomatology of these diseases and to better under-
stand their neurobiological underpinnings.

In the field of psychiatric disorders, three criteria were established by
Willner in 1984 to validate an animal model as representative of a
human disease (Willner, 1997): face validity (the etiological factors
should be reminiscent of those inducing the pathology in humans), 2)
construct validity (how well the animal model reproduces behavioral
and neuropathological symptoms), and 3) predictive validity (whether
pharmacological agents validated in humans can reverse the symptoms
developed by the animal). Different variants of these criteria exist, and
for exhaustive information, see the relevant literature (Belzung and
Lemoine, 2011). Since 2009, a vast community of researchers developed
the RDoC (Research Domain Criteria) initiative with the objective to
integrate biological and behavioral measurements to assess certain
<table><caption>**Table 1**
LC-NE studies in human depression and PTSD.</caption><thead><tr><th></th><th>Promoting increase LC-NE</th><th>Promoting decrease LC-NE</th></tr></thead><tbody><tr><td><strong>Depression</strong></td><td></td><td></td></tr><tr><td>Postmortem</td><td><strong>Increased TH expression level in LC</strong><br>Ordway et al. (1994a), Zhu et al. (1999)<br>Lei Guo et al. (2019)</td><td>Decreased number of TH+ neurons in LC<br>Chan-Palay and Asan (1989), Biegon et al. 1992</td></tr><tr><td>Decreased NET binding in LC (no effect in other structure)</td><td>Klimek et al. (1997)</td><td>Increased sensibility;<br>Increased expression of α2 AR in PFC<br>Gonsalez et al. 2004, Escribá et al. (2004)</td></tr><tr><td>Biochemical</td><td><strong>Increased CSF MHPG</strong><br>Koslow et al. (1983)<br>Ehnvall et al. (2003)</td><td>Increased α2 binding in LC<br>Ordway et al. (1994b, 2003)</td></tr><tr><td>Imaging</td><td><strong>Elevated levels of urinary epinephrine (E) and metanephrine (MET)</strong><br>Davis et al. (1988)</td><td>fMRI: Alteration in LC-ACC connectivity<br>Neuromelanin-MR: Decreased contrast ratio of the LC<br>Ines del Cerro et al. (2020)<br>Shibata et al. (2007, 2008)</td></tr></tbody></table>

<table><caption>**Table 1 (continued)**</caption><thead><tr><th></th><th>PTSD</th><th></th><th></th></tr></thead><tbody><tr><td>Postmortem</td><td></td><td>Lower number of TH+ neurons in LC</td><td>Arango et al., (1996), Bracha et al., (2005)</td></tr><tr><td>Biochemical</td><td><strong>Increased urinary NE level</strong><br>Higher plasma NE at baseline, and exaggerated responses to combat sounds<br>Higher CSF NE concentration<br>Increased pupil dilatation<br>Increased NE activity in response to stressors but not during rest</td><td><strong>Kosten et al. (1987), Young and Breslau, (2004), Wingenfeld et al. (2015)</strong><br>Liberzon et al. (1999)<br><br><strong>Geraciotti et al. (2001)</strong><br><br><strong>Kimble et al. (2010), Cascardi et al. (2015)</strong><br>Pitman and Orr, (1990)<br>Southwick et al. (1999)</td><td><strong>Lower basal arterialized plasma levels of NE, Lower rates of NE appearance into plasma</strong></td><td>Murburg et al. (1995)</td></tr></tbody></table>

<table><thead><tr><th></th><th>PTSD</th></tr></thead><tbody><tr><td>Imaging</td><td>Increased LC connectivity with AMY, striatum and insula during direct threatening eye gaze<br>Higher LC and insula BOLD responses to fearful stimuli<br><br>Steuwe et al., (2015)<br><br>Morey et al., (2015)</td></tr></tbody></table>

diseases (Cuthbert, 2022). The RDoC framework analyzes construct assessment across different dimensions: 1) from childhood to adulthood, focusing on various domains (e.g., arousal, valence, sensorimotor processes, and social processes), 2) units of analysis (e.g., genes, molecules, cells, circuits, physiology, behavior, self-reports, paradigms), and 3) environments. The primary goal of the face-construct-predict (FCP) validity framework is to establish a valid translational approach between human psychiatric disorders and animal models in research with the aim of encompassing a broader range of symptoms associated with each pathology, particularly through the use of current treatments (e.g., antidepressant drugs). The RDoC framework offers a 'DSM-5'-like tool for non-psychiatrists researchers enabling them to contribute new insights to the field by focusing on specific symptoms rather than the entire pathology. This approach is particularly valuable because assessing the full pathology is often challenging in both rodents and humans, as diagnoses are frequently based on subjective criteria (Anderzhanova et al., 2017). Individual symptoms, however, tend to be more objective and are often shared across different pathologies. Models of MDD and PTSD can both be used to study various symptoms. In this discussion, we will explore well-known animal models used to study MDD and PTSD.

The unpredictable chronic mild stress (UCMS), chronic social defeat stress (CSDS), and learned helplessness (LH) paradigms are validated models for studying depressive-like behavior according to Willner's criteria (Fig. 1). UCMS induces anhedonia and sleep disturbances, while CSDS is known to reduce locomotor activity, increase anxiety, induce social avoidance, reduce food intake, and cause anhedonia following social defeat (for review: Song and Kim, 2021). LH-induced traumatic stress can impair memory, and reproduces another important symptom of MDD—acceptance of a stressful situation without attempting to escape. The single prolonged stress (SPS), predator scent stress (PSS), and traumatic experience with reminders of stress (TERS) paradigms are used to study symptoms of PTSD (Fig. 1). However, the classification of these models as specific to depression or PTSD is not well-defined, and often these models allow for the study of comorbidity between these stress-related disorders.

The involvement of the LC-NE system in these models is undeniable (Table 2). This overview of studies in animal models demonstrates the complexity of responses involved in stress-induced psychopathologies (For review: Chandley and Ordway, 2012; Seki et al., 2018; Southwick et al., 1999). Three important points to consider are: i) Spontaneous and evoked responses are important aspects, as numerous studies have found a lower baseline response that increases significantly following a challenge; ii) The nature of the stressors used (modality, predictability, intensity, context, duration) greatly influences the reactivity of the LC-NE system. Moreover, while the animal models described here have been previously categorized as models of PTSD or depression, this segregation is insufficient to explain the contradictory hypotheses about the involvement of the LC-NE system in response to chronic stress; iii) Consideration of LC-NE modulatory circuits is also crucial. Studies using
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Animal models and behavioral Paradigms in psychopathologies and Resilience. Created in BioRender. Sla, D. (2024) BioRender.com/q47s025. Illustration of the different animal models of stress established in laboratories to mimic symptoms of psychiatric diseases, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), measured through various behavioral paradigms. The role of the locus coeruleus-noradrenergic (LC-NE) system in these psychopathologies, as well as in resilience against stress, has been evaluated using these models. The stressors employed in these models can be categorized based on their nature: environmental (yellow), psychosocial (blue), and physical (pink). MDD is primarily associated with environmental stressors (yellow), whereas PTSD is mainly linked to physical stressors (pink). However, all three types of stressors—environmental, physical, and psychosocial—are present to varying degrees in both pathologies. When a specific model is illustrated in one color, it signifies that the model involves a single type of stressor (e.g., PSS involves only psychosocial stress, while LH involves only physical stress). When a model is depicted in two different colors (e.g., UCMS, CSDS, SPS, TERS), it indicates that the model involves multiple stressors. For instance, UCMS involves environmental and psychosocial stress, CSDS and SPS involve psychosocial and physical stress, and TERS involves both environmental and physical stress. The behavioral paradigms used to assess the effects of chronic stress mimic symptoms of psychiatric disorders, as outlined by the RDoC framework. In MDD, resignation and anhedonia are the primary behavioral characteristics, assessed using tests such as the Forced Swim Test (FST) and Sucrose Preference Test (SPT). In PTSD, fear- and anxiety-related behaviors are evaluated using paradigms like Fear Conditioning and the Elevated Plus Maze (EPM), while social interaction is measured in both MDD and PTSD. "UCMS: Unpredictable Chronic Mild Stress, PSS: Predator Scent Stress, CSDS: Chronic Social Defeat Stress, LH: Learned Helplessness, TERS: traumatic Experience with Reminder of Stress, SPS: Single Prolonged Stress.</figcaption></figure>

the same model (e.g., social defeat stress) but examining different LC-NE projecting pathways have shown evidence for either increased NE in some areas (HPC, PFC, AMY) or decreased NE in others (HYP).

In summary, while animal models have provided significant insights into the role of the LC-NE system in stress-related psychopathologies, the complexity of the system's response to stress highlights the need for a nuanced understanding of its function across different contexts and conditions.

## 4. Transition toward resilience: the LC-NE system in stress-induced inter-individual variability

Discrepancies in the increase or decrease of LC-NE system activity in response to stress among both clinical and pre-clinical studies suggest a hypothesis explaining poor treatment responses in stress-related disorders. An intriguing strategy to improve treatment and discover new targets is to consider the inter-individual variability in response to stress and study the cellular and molecular mechanisms underlying resilience to stress and psychopathology. In this section, we will discuss the role of

the LC-NE system in stress resilience in both humans and animals, while considering stress modalities and the complexity of the LC network.

### 4.1. What is resilience in the context of psychiatric disorders?

The concept of resilience in psychology was first introduced in 1973 by Garmezy, who observed that some children actively coped with stress and adapted faster (Dean, 1973). Garmezy defined resilience as "the ability to adapt quickly to adversity," and the study of psychological resilience has since focused on the capacity to resist stress. Over time, this notion has found its place in the field of psychiatric disorder development (Luthar, 1991; Luthar and Zigler, 1991; Werner, 2016), with increasing attention over the last few decades.

Considering recent biological and psychological studies, a more detailed definition of resilience has emerged. Resilience to stress is now understood as a biological-behavioral process that actively regulates neurobiological systems to maintain homeostasis following a stressful event, rather than merely the absence of pathological responses in more susceptible individuals (Russo et al., 2012). In other words,
<table><caption>**Table 2**
LC-NE studies in animal model of depression and PTSD.</caption><thead><tr><th>Animal model</th><th colspan="2">Promoting increase LC-NE</th><th colspan="2">Promoting decrease LC-NE</th></tr></thead><tbody><tr><td><strong>Neuronal activity</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Single prolonged stress (SPS)</td><td>Higher evoked response of LC-NE neurons</td><td>George SA et al. Eur J Neurosci. (2013)</td><td>Lower spontaneous activity of LC-NE neurons</td><td>George SA et al. Eur J Neurosci. (2013)</td></tr><tr><td>Chronic cold stress</td><td>Higher evoked response of LC-NE neurons<br>CRH-evoked increase in LC neuron activity was enhanced</td><td>Mana and Grace, Neuroscience. (1997)<br>Jedema HP et al, Biol psy. (2001)</td><td>Lower spontaneous activity of LC-NE neurons</td><td>Mana and Grace, Neuroscience. (1997)</td></tr><tr><td>Traumatic experience with reminder of stress</td><td>Increased c-fos expression after FST</td><td>Olson VG, biol psy. (2011)</td><td></td><td></td></tr><tr><td><strong>Biochemical activity</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>SPS</td><td>Increased TH mRNA at baseline in LC and in response to acute stressors</td><td>George SA et al. Eur J Neurosci. (2013)<br>Serova L et al. Neurosci. (2013)</td><td>Lower TH mRNA in LC at baseline</td><td>George SA et al. Eur J Neurosci. (2013)</td></tr><tr><td>Long term repeatedly immobilized stress</td><td>Increased TH mRNA at baseline in LC and in response to acute stressors</td><td>Rusnák M et al. Brain Res. (2001)</td><td></td><td></td></tr><tr><td>Chronic cold stress</td><td></td><td></td><td>Decreased NE released in the brain;<br>Increased alpha2 binding sites</td><td>Morilak et al. Neuropsychopharmacol Biol Psy. (2005)</td></tr><tr><td>Chronic social defeat</td><td>Increased DBH mRNA and protein expression in the LC;<br>Increased DBH protein expression in the HPC, PFC and AMY<br>Increased NET mRNA and protein levels in the LC;<br>Increased NET protein levels in the HPC, PFC and AMY.</td><td>Fan Y et al. Synapse. (2013)</td><td></td><td></td></tr><tr><td>Chronic restraint stress</td><td>Decreased NET availability in both the LC and limbic areas</td><td>Zafar et al. Brain res bull. (1997)</td><td>Decreased NE level in the HYP</td><td>Favoretto et al. Psychopharmacol. (2020)</td></tr><tr><td>Repeated novel stressor model</td><td></td><td>Tejani-Butt et al. Brain res. (1994)</td><td></td><td></td></tr><tr><td>Predator exposure</td><td>Long sensitization of α1 receptors</td><td>Rajbhandari et al. J Neurosci. (2015)</td><td></td><td></td></tr><tr><td>chronic mild stress</td><td>Increased NE level in the hippocampus</td><td>Wang et al. J. Chromatogr B Analyt Technol Biomed Life Sci. (2019)</td><td>Decreased NE analytics in the serum and cerebral cortex</td><td>Wang et al. J Chromatogr B Analyt Technol Biomed Life Sci. (2019)</td></tr><tr><td>Chronic force running stress</td><td></td><td></td><td>Axonal LC degeneration in the PFC</td><td>Nakamura et al. Neurosci Lett. (1989), Brain Res Bull. (1991)</td></tr></tbody></table>

psychological resilience results from compensatory mechanisms at the molecular, hormonal, cellular, and behavioral levels that promote heightened adaptability following stressful events.

Clinical research on resilience to stress has mainly focused on correlational or phenomenological studies. Neuroendocrine and neuro-imaging changes predicting resilience have been described (Bremner et al., 2003; Fani et al., 2012), as well as genetic variations linked with resilience outcomes (Cahill et al., 2022). Although correlational analyses provide valuable information, they do not explain causality. Therefore, neurobiological mechanisms of psychological resilience have been intensively studied in animal models that allow investigation of individual sensitivity to stressors (Fig. 1). In rodents, vulnerability and resilience are distinguished by differential behavioral outcomes following stressful events, such as social avoidance, acoustic startle response, anxiety, and anhedonia. Animals that display an absence of deficits in key behavioral domains but still present some deleterious symptoms in response to stress are considered resilient (Russo et al., 2012).

Given the critical role of the LC-NE system in the stress response and the development of MDD and PTSD, neuroadaptations in this pathway underlying the resilience phenomenon are expected. This section discusses clinical and preclinical evidence related to the participation of the LC-NE system in the neurobiological basis of resilience.

## 4.2. Evidence in humans

Operationalizing human resilience in a clinical setting is challenging due to two major artifacts. First is the variation in risk exposure, meaning that defining resilience must consider the nature or type of risk (environmental, physical, emotional), the severity or degree of this risk,

and the cumulative effect of stressors. Second, resilience encapsulates many divergent behavioral phenotypes, and apparent resilience might result from measuring too narrow a range of outcomes. Human studies of resilience need to use similar risks and compare the same behavioral outcomes, which is easier regarding PTSD in defined at-risk populations. Additionally, stress susceptibility has rarely been investigated before potentially traumatic stressors are experienced, making it difficult to identify factors that genuinely predispose individuals to resilience when they subsequently face adverse events.

Despite these challenges, evidence shows the participation of the LC-NE system in this adaptive process. Highland et al. (2015) studied physiological markers of PTSD resilience among post-deployment service members (Highland et al., 2015). They found that lower blood NE levels within two months after deployment were associated with lower combat-related PTSD symptoms three months later, particularly with symptom intensity and avoidance symptoms. Another study, however, found no significant differences in urinary-derived NE and E metabolites between PTSD-exposed and non-PTSD-exposed participants (Breen et al., 2019).

Naegeli et al. (2018) performed a study including PTSD participants and trauma-exposed participants without PTSD. They analyzed functional resonance imaging (fMRI), pupillometry, and peripheral psychophysiological assessments following a loud sound in both groups. Despite all subjects finding the noises similarly intense and unpleasant, increased autonomic hyper-responsiveness was associated with a larger response of the LC to a loud sound only in PTSD subjects (Naegeli et al., 2018). This suggests that differential LC activity mediates the impact of an unpleasant stimulus in PTSD vs. non-PTSD subjects, indicating that susceptibility and resilience to PTSD involve neuroadaptations in the LC.

Whether changes in the LC-NE system represent a risk or
consequence of developing PTSD following trauma has been investi-
gated in military soldiers before and after deployment to combat zones.
Higher post-combat training stress symptoms were associated with
increased LC hyperactivation between pre- and post-combat training
during an interpersonal anger-provoking game (Gilam et al., 2017). In a
recent study, the mood state of medical residents before and after a
stressful emergency room shift was tested in relation to LC activity using
fMRI and pupil dilation during an emotional conflict task. Participants
with high stress-related changes in depressive scores exhibited stronger
LC responsivity than those with low symptom severity change. This
study showed that greater activation of the LC system during upregu-
lation is associated with elevated symptoms of depression and anxiety
after real-world stress, whereas lower LC activation predicts resilience.
Simultaneously acquired pupil-dilation measures, associated with
LC-NE firing, corroborate LC responsivity as a reliable predictor for
stress-related psychopathology and provide insights into the noradren-
ergic basis of conflict generation and adaptation (Grueschow et al.,
2021). In other words, this study suggests that vulnerability to devel-
oping depression and anxiety-related behaviors is correlated with LC
activation, whereas reduced LC-NE responsivity appears to offer pro-
tection against severe stress-related behaviors.

4.3. Evidence in rodents

This section discusses LC-NE system activity in resilient rodents (Fig. 1) and how genetic and pharmacological manipulations before, during, and after stress protocols strengthen the assumption that the LC-NE system plays a key role in the active adaptive process defining resilience (Fig. 2, Table 3).

4.3.1. *Noradrenergic system activity in resilient rodents: differential effect of stress modalities*

The impact of susceptibility versus resilience on the LC-NE system
has been well-documented in terms of LC-NE neuronal activity and NE
transmission in the brain. However, the effects on neural network ac-
tivity vary depending on the paradigm and the nature of the stressor. For
instance, in the CSDS paradigm, a notable correlation was observed
between c-Fos positive LC-NE neurons projecting to the ventral
tegmental area (VTA) and social preference, which was associated with
increased NE release in the VTA of resilient mice (Isingrini et al., 2016).
This finding was further supported by Zhang et al. (2019) who noted an
increase in the firing and bursting activity of LC-NE neurons in resilient
animals compared to control and susceptible mice (Zhang et al., 2019).

<figure><img src="image_6.png" /></figure>

**Fig. 2. Differential Noradrenergic Response in Susceptible vs. Resilient Phenotype According to Stress Modalities.** Created in BioRender. Sla, D. (2024) BioRender.com/a05q188. This figure showcases animal models of stress (CSDS: Chronic Social Defeat Stress, LH: Learned Helplessness, TERS: Traumatic Experience with Reminder of Stress, SPS: Single Prolonged Stress) used to study the noradrenergic system in susceptibility (red) and resilience (green). The response to stress observed in the noradrenergic system varies between "resilient" and "susceptible" phenotypes following specific stressors. In the resilient phenotype following CSDS, there is increased firing (schematically represented by 3 action potentials (AP) compared to a basal level of 2) and bursting activity of LC-NE neurons projecting to the VTA (ventral tegmental area), associated with elevated NE (noradrenergic) levels in the VTA. In LH/TERS or SPS paradigms, the resilient phenotype is characterized by a decreased firing rate of LC neurons (1 AP compared to a basal level of 2) and reduced NE turnover in the amygdala. Conversely, the susceptible phenotype following the TERS or SPS models shows increased expression of c-fos in the locus coeruleus (3 neurons compared to a basal level of 2) and higher concentrations of NE in the amygdala and hippocampus. The LC-NE system was manipulated before, during, or after stress to promote resilience or reverse the susceptible phenotype. Genetically modified mice with NET promoter modifications (NET-KO/NET-Sh-RNA) or chronic reboxetine administration foster a resilient phenotype following CSDS/UCMS/CRS (Chronic Restraint Stress). In VMAT2DBHCre mice, NE depletion promotes resilience to the LH paradigm. Post-stress manipulation that reverses the susceptible phenotype into a resilient one was performed following CSDS and TERS paradigms. After chronic social defeat stress, treatments with Idazoxan (alpha2-R antagonist), Reboxetine (NET inhibitor), chronic optogenetic stimulation of LC neural projections into the VTA, or alpha1/beta-3 adrenergic receptor agonist infusion reverse the susceptible phenotype. Following traumatic experience with a reminder of stress, injections of Clonidine (alpha2-AR agonist) or Prazosin (alpha-1 aR antagonist) promote behaviors associated with the resilient phenotype.
<table><caption>**Table 3**
LC-NE studies in resilience from animal models of various stress modalities.</caption><thead><tr><th colspan="4">Noradrenergic system activity in resilient rodents</th></tr><tr><th>Model</th><th>Behavioural outputs</th><th>Effect on LC-NE in resilience</th><th>References</th></tr></thead><tbody><tr><td>CSDS</td><td>Social Interaction</td><td>Increased NE release in the VTA<br/>Increased firing and bursting activity</td><td>Increased NE transmission</td></tr><tr><td>LH</td><td>Escape behavior</td><td>Lower c-Fos expression<br/>Decreased firing and bursting activity<br/>Reduced NE turnover in AMY<br/>Reduced LC α2-AR expression</td><td>Decreased NE transmission</td></tr><tr><td>TERS</td><td>Acoustic startle response</td><td>Decreased c-Fos expression</td><td>Isingrini et al., (2016) Zhang et al., (2019)</td></tr><tr><td>SPS</td><td>Fear response Open field test</td><td>Lower NE level in the HPC and AMY</td><td>Kim et al., (2016)<br/>Isingrini et al., (2020)</td></tr><tr><td>SPS</td><td>Hyperarousal</td><td>higher LC NET expression</td><td>Muneoka et al., 2020<br/>Taneja et al., (2011)<br/>Olson et al., (2011)<br/>Skorzewska et al., 2020<br/>Nwokafor et al., (2021)</td></tr></tbody></table><table><thead><tr><th colspan="6">LC-NE system manipulations before and/or during stress protocol</th></tr><tr><th>Models</th><th>Behavioural output</th><th>LC-NE system manipulation</th><th>Behavioural effects</th><th>References</th></tr></thead><tbody><tr><td>Chronic restraint / CSDS</td><td>Forced swimming Sucrose preference Social interaction</td><td>NET-KO mice<br/>Chronic Reboxetine</td><td>Increased NE transmission</td><td>Promoted resilience</td></tr><tr><td>UMCS</td><td>Forced swimming test Open field test Sucrose preference</td><td>NET-Sh-RNA in LC</td><td>Decreased NE transmission</td><td>Blocked resilience</td></tr><tr><td>CSDS</td><td>Social interaction</td><td>NE-depleted mice (VMAT2<sup>DBHcre</sup> KO)</td><td>Decreased NE transmission</td><td>Isingrini et al., (2016)</td></tr><tr><td>LH</td><td>Escape behavior</td><td>NE-depleted mice (VMAT2<sup>DBHcre</sup> KO)</td><td>Decreased NE transmission</td><td>Isingrini et al., (2020)<br/>Martinho et al., (2021)</td></tr><tr><td>Fear conditioning</td><td>Fear memory Elevated Plus Maze Open field</td><td>Inhibiting Dopamine-β-hydroxylase (DBH)</td><td>Decreased NE transmission</td><td>Martinho et al., (2021)</td></tr></tbody></table><table><thead><tr><th colspan="5">LC-NE system manipulation after stress</th></tr><tr><th>Models</th><th>Behavioural output</th><th>LC-NE system manipulation</th><th>Behavioural effects</th><th>References</th></tr></thead><tbody><tr><td>CSDS</td><td>Social interaction</td><td>Chronic Idazoxan or Reboxetine<br/>Chronic optogenetic stimulation of NE release in the VTA</td><td>Increased NE transmission</td><td>Reversed susceptibility</td></tr><tr><td>TERS</td><td>Acoustic startle response<br/>Social Interaction Resident-Intruder</td><td>Intra-VTA infusion of α1- and β3-ARs agonists<br/>Clonidine or Prozasin</td><td>Decreased NE transmission</td><td>Reversed susceptibility</td></tr></tbody></table>

Conversely, in the LH paradigm, higher c-Fos expression was reported in LC neurons of susceptible mice as opposed to resilient ones (Kim et al., 2016). Additionally, using in vivo single unit electrophysiology, preliminary results from our team indicate a decrease in firing rate and bursting activity of LC-NE neurons in resilient mice compared to control and susceptible animals in the LH model (Isingrini et al., 2020). Similarly, Muneoka et al. (2020) observed reduced NE turnover in the AMY of LH resilient rats, suggesting decreased LC-NE activity in response to physical stress (Muneoka et al., 2020a, 2020b). In relation to NE transmission within the LC, Taneja et al. (2011) demonstrated reduced expression of LC α2-AR in LH resilient rats (Taneja et al., 2011). However, this finding appears inconsistent with reduced NE transmission in LH resilient animals, considering that pre-synaptic activation of α2-AR inhibits NE release and neuron firing. Further studies are needed to confirm the cell-type-specific expression of α2-AR at the pre- and post-synaptic levels and its impact on NE inhibition within the LC.

Other stress paradigms used as PTSD models, including TERS and SPS models, have shown similar effects to the LH paradigm. Olson et al., (2011) demonstrated increased c-Fos expression after swim stress in susceptible mice in the TERS model (Olson et al., 2011). Skórzewska et al. (2020) described higher NE concentrations in the HPC and AMY of PTSD+ (susceptible) compared to PTSD- (resilient) animals in the SPS model (Skórzewska et al., 2020). A recent study found a negative correlation between hyperarousal and NE transporter (NET) mRNA expression in the LC of rats subjected to the SPS paradigm, suggesting that resilience to PTSD is associated with higher LC NET expression (Nwokafor et al., 2021).

Collectively, these studies clearly demonstrate the involvement of the LC-NE system in stress resilience. However, NE cell activity varies depending on the stress modality: social stress tends to promote

activation, while physical stress leads to decreased function of the LC-NE system in resilient animals. Specifically, resilient mechanisms related to stress-induced social avoidance are linked to hyperactivity of the NE system (Isingrini et al., 2019; Zhang et al., 2019). In contrast, resilience to anxiety, fear responses, escape, and hyperarousal behaviors is associated with decreased NE activity (Kim et al., 2016; Isingrini et al., 2020; Muneoka et al., 2020; Taneja et al., 2011; Olson et al., 2011; Skorzewska et al., 2020; Nwokafor et al., 2021).

### 4.3.2. LC-NE system manipulations before and/or during stress protocol: predict or result from resilience

Studies manipulating the LC-NE system before and/or during stress paradigms, using genetically modified mice or pharmacological treatments, have shown significant impacts on behavioral outcomes to stress. Strategies that promote increased NE release, such as using NET-KO mice, NET-Sh-RNA expression in the LC, or chronic Reboxetine administration, have induced resilience to anhedonia, social avoidance and immobility in the FST following CSDS, UCMS, and chronic restraint stress (Du et al., 2020; Haenisch et al., 2009). Conversely, whole-brain NE-depleted mice (VMAT2<sup>DBHcre</sup> KO mice was associated with an increased proportion of resilient mice in the LH paradigm, suggesting a pro-resilient effect of NE depletion in the escape behaviour following physical stress (Isingrini et al., 2020). This observation was supported by another study where decreased NE synthesis, induced by inhibiting

However, stress modalities differentially regulate the neurobiological endpoints of resilience. Preliminary results from our group show that NE depletion in VMAT2<sup>DBHcre</sup> KO mice was associated with an increased proportion of resilient mice in the LH paradigm, suggesting a pro-resilient effect of NE depletion in the escape behaviour following physical stress (Isingrini et al., 2020). This observation was supported by another study where decreased NE synthesis, induced by inhibiting
Dopamine-β-hydroxylase (DBH), reversed PTSD-related fear memory and anxiety state by reducing NE in the PFC, but not in the HPC/AMY (Martinho et al., 2021).

### 4.3.3. LC-NE system manipulation after stress: antidepressant/anti-PTSD or pro-resilient effect

Studies manipulating the LC-NE system after stress-induced psychopathological behaviors aim to reverse a susceptible phenotype. These studies can be categorized based on stress modalities.

In the CSDS procedure, mimicking the LC-NE effect observed in resilient individuals counteracted maladaptive behavior in susceptible animals. One-week pharmacological increases of NE release using Ida-zoxan (α2-AR antagonist) or Reboxetine (NET inhibitor), but not acute treatment, in susceptible mice after 10 days of stress reversed the susceptible phenotype to induce resilience (Isingrini et al., 2016). Similarly, chronic optogenetic stimulation of NE release in the VTA or intra-VTA infusion of α1- and β3-ARs agonists in susceptible mice abolished social aversion (Isingrini et al., 2016; Zhang et al., 2019). These studies highlighted the antidepressant effects by increasing NE neurotransmission, particularly in the VTA, or by mimicking NE post-synaptic effects in the VTA. Altogether, these results indicate that post-stress manipulations promoting increased NE release, reverses the social avoidance behavior in susceptible animals. This effect has been confirmed in numerous studies manipulating the LC-NE system after stress without segregating susceptible and resilient groups of animals. For example, Haenisch et al. (2009) demonstrated that 21 days of Reboxetine treatment during the CSDS procedure decreased immobility in the forced swim test (FST) and increased sucrose preference (Haenisch et al., 2009).

Considering stress modalities, other studies have found that decreasing NE transmission can reverse the susceptible phenotype observed after stress. Olson et al. (2001) have reported that Clonidine (α2-AR agonist) or Prozasin (α1-AR antagonist) treatments decreased NE release in susceptible animals subjected to the TERS model, resulting in decreased acoustic startle response (ASR) and aggression, along with increased social interaction behaviour (Olson et al., 2011).

Even if studies manipulating the LC-NE system after stress utilize neurobiological effects observed in resilient animals to counteract susceptibility, it is crucial to clarify whether the reversion of maladaptive stress-related behaviors results from activating resilient mechanisms (pro-resilient effect) or reestablishing activity levels observed in unstressed mice (antidepressant effect). In the CSDS paradigm, active pro-resilient mechanisms appear to be involved. The hyper-excitability of VTA-DA neurons in susceptible animals, mediated in part by the induction of hyperpolarization-activated cation currents (Ih), has been well documented. In resilient mice, a compensatory increase in K+ channels counteracts the increased Ih function to normalize firing rate (Friedman et al., 2014). Isingrini et al. (2016) uncovered an inhibitory action of LC-NE projections on VTA-DA neuron activity, suggesting that the behavioral effect of optogenetic NE release activation in the VTA might be mediated by its impact on VTA-DA neuron activity (Isingrini et al., 2016). This hypothesis was confirmed by Zhang et al. (2019) demonstrating that optogenetic stimulation of LC-NE in susceptible mice reestablishes the balance between Ih current and K+ channels, thereby abolishing the hyper-excitability of VTA-DA neurons (Zhang et al., 2019).

## 5. Resilience-related molecular and cellular adaptations into LC (Fig. 3)

In this section, the neurochemical adaptations into the LC underlying resilient phenotype are presented, to provide hypothetical mechanisms by which NE neurons promote resistance to stress-deleterious effects.

### 5.1. Neuropeptide-Y (NPY)

Neuropeptide Y (NPY) is the most abundant neuropeptide in the human brain, playing a crucial role in the stress response and exhibiting anxiolytic-like effects (Adrian et al., 1983). Numerous reviews (Enman et al., 2015; Reichmann and Holzer, 2015) have consolidated studies, evidences, and hypothesis regarding NPY's involvement in mediating stress responses.

NPY receptors (Y1, Y2, and Y5) are densely expressed in the LC, with NPY co-expressed in 20-40% of LC-NE neurons in the rat brain (Everitt et al., 1984; Heilig and Widerlöv, 1990; Holets et al., 1988; Smialowska, 1988; Theisen et al., 2018; Wolak et al., 2003). NPY appears to be present in similar proportions in both rats and humans. In human pluripotent stem cells (hPSC), Tao et al. (2023) reported that 30% of NE neurons express NPY after 30 days of culture (Tao et al., 2023). However, NPY expression notably differs between rats and mice. A recent study by Caramia et al. (2023), using single-cell sequencing and in situ hybridization in mice, found that NPY and its receptors are exclusively located in the GABAergic cells surrounding the LC (Caramia et al., 2023). Conversely, a preprint publication found that while NPY was not expressed in TH+ cells of the LC, NPY receptor expression was present in 4% of TH+ cells (with 74.5% of TH+ cells being Y1+/Y2+, 8% being Y1+/Y2-, and 7.4% being Y1-/Y2+) (Riga et al., 2023). The age difference between the two studies (young vs adult) may explain these contradictory results.

Studies in the previous decade have characterized the potential link between the LC and NPY in mediating stress and psychopathologies. NPY inhibits the firing rate of NE neurons in the LC and potentiates the effect of NE on presynaptic autoinhibition of neuronal firing, according to an electrophysiology study (Enman et al., 2015). Clinical and preclinical studies have reported that NPY is associated with reduced stress responses and the reversal of maladaptive behaviors following chronic stress (Reichmann and Holzer, 2015). In depressed individuals who committed suicide, NPY transcript levels were found to be approximately eight times higher in females than in males, though elevated expression of NPY and NPYR1 in the LC was observed in both sexes (Barde et al., 2024). In rats, chronic air puff stress increases NPY gene expression (McDougall et al., 2005), while acute foot shocks stress decreases it (de Lange et al., 2008). Moreover, using SPS as a model of PTSD in rats, reduced mRNAs for NPY and Y2 receptors were observed into the LC (Serova et al., 2019). In mice, acute electrical foot-shocks engages peri-LC NPY neurons, increasing their excitability and suppressing LC noradrenergic neuron activity via an NPY1R receptor-mediated mechanism (Riga et al., 2023).

Regarding stress resilience, a single intranasal NPY administration reversed the SPS-elicited anxiety response in the elevated plus maze (EPM) in male rats, but not in females, demonstrating NYP role in the treatment against PTSD-related behaviors (Sabban, 2015). This effect was linked to reduced expression of the LC-NE biosynthesis enzyme tyrosine hydroxylase (TH) in SPS-stressed male rats treated with NPY (Sabban, 2015; Serova et al., 2014). In the article of Cohen et al., 2011, the authors reverse PTSD like-behaviour (EPM and acoustic startle response) with a microinjection of 10 µg of NPY into the HPC 1 h post PSS (Cohen et al., 2011). More precisely, it completely abolished the development of extreme behavioural response following PSS.

These findings suggest that NPY's effect on the brain modifies LC-NE synthesis, possibly through NPY modulation of LC inputs. In line with this, the presence of NPY5R receptor, as well as the administration of NPY into the LC region, decreased anxiety-like behavior in the EPM. However, in the same study, no effect was observed with NPY1R receptor (Reichmann and Holzer, 2016).

The studies discussed highlight the significant interaction of NPY with the LC and its role in mediating stress responses. Future research should aim to further elucidate NPY's role in resilience and its potential for treating stress-related disorders. The differential expression of NPY and its receptors in the LC, as well as the species- and sex-specific
variations observed, indicate that more comprehensive studies are needed Fig. 3.

## 5.2. Galanin

Galanin is a neuromodulatory peptide and trophic factor co-expressed in over 80% of LC-NE neurons in rats and in almost all TH+ neurons in mice and humans (Caramia et al., 2023; Holmes et al., 1995; Tillage et al., 2020; Weinshenker and Holmes, 2016). In situ hybridization studies have reported expression of galanin receptor GalR1 in 20% of LC-NE, with higher expression of transcripts in GABA cells of the peri-LC region (46% of colocalization with GAD1+ neurons). GalR2 levels were detected at low levels in the LC, and GalR3 expression were even lower in rodents, though GalR3 is more expressed in humans (Caramia et al., 2023). Galanin receptors (GalR1 and GalR2) appear to be present in the postsynaptic LC neurons of rats (Vila-Porcile et al., 2009). Galanin receptors are GPCRs expressed in the LC and its brain targets, such as the VTA (GalR2), medial PFC (GalR1 and GalR2), AMY, and HPC (GalR1, GalR2, and GalR3 in rats) (Weinshenker and Holmes, 2016).

It has been found that galanin is released from LC dendrites and

soma, modulating LC neuron activity through GalR1 receptors in an autocrine manner (Pieribone et al., 1995; Vila-Porcile et al., 2009). Galanin is released when NE is highly activated, which in turn decreases the firing activity of the LC (Sevcik et al., 1993; Xu et al., 2005). Galanin-induced LC inhibition is primarily linked to GalR1 receptor activation, which promotes hyperpolarization of NE neurons and enhances α2-adrenergic receptor activity (Ma et al., 2001; Pieribone et al., 1995; Seutin et al., 1989).

Physical exercise has been shown to be protective with both anti-depressant and anxiolytic effects in rodents (Duman et al., 2008; Kingston et al., 2018; Mul, 2018; Nowacka-chmielewska et al., 2022; Sciolino et al., 2012; Tanner et al., 2019), and NE-derived galanin is involved. Increased galanin expression into LC-NE neurons following voluntary exercise in rats has been found with pharmacological modulations (Holmes et al., 2006; Murray et al., 2010; Neal et al., 2001; Sciolino et al., 2015; Tillage et al., 2020). Furthermore, the effect of exercise on anxiety was mimicked by galanin overexpression in LC-NE neurons, preventing anxiety-like responses in the elevated zero maze induced by optogenetic stimulation of the LC in mice (Tillage et al., 2020). A recent study reported that pharmacological activation of galanin signaling during foot-shock stress normalized the anxiety-like response in the

<figure><img src="image_7.png" /></figure>

**Fig. 3.** Heterogeneous coping adaptation in the locus coeruleus and surrounding in resilience against stress. Created in BioRender. Sla, D. (2024) BioRender.com/a43w644. Following chronic stress the heterogeneous structure of the locus coeruleus (LC) and its surroundings can contribute to several adaptations associated with resilience. The locus coeruleus (LC) region is divided into two parts: the LC, which primarily contains noradrenergic cells (NE, depicted in blue), and the peri-LC, which includes GABAergic neurons (depicted in grey). Within the noradrenergic cells, NE is synthesized through the conversion of Tyrosine (Tyr) to DOPA (3,4-dihydroxyphenylalanine), then to Dopamine (DA), and finally to NE, which is released into the synaptic cleft. NE primarily acts on four types of receptors: α1, β1, β2, and α2 (an auto receptor). The degradation of NE occurs via the enzymes COMT (postsynaptic) and MAO-A (presynaptic) after reuptake by the NET transporter. Notably, a lower COMT mRNA expression is observed in the peripheral blood of individuals with a resilient phenotype. NE also interacts with microglia and astrocytes through β1 and/or β2 receptors and α1 receptors, respectively. In resilient individuals, this interaction reduces the expression of inflammatory cytokines such as IL-1β. NE cells simultaneously secrete Galanin (GAL), Neuropeptide Y (NPY), and corticolerine (CRF) acting on GAL1R, various NPY receptors (Y1, Y2, Y5), and CRF1R respectively. In mice, NPY is exclusively secreted by GABAergic cells in the peri-LC. In humans and rats, about 30% of NE cells co-secrete NPY with NE, inhibiting the firing rate of NE neurons. Recent studies indicate that NPY receptors (Y1, Y2, Y5) are expressed exclusively in GABAergic cells in the peri-LC, although their presence in NE neurons remains controversial. Following optostimulation of LC-NE cells, overexpression of Galanin prevents anxiety-like behaviour, persistent depression-like symptoms in the learned helplessness are highlighted in GALR1 knock-out mice. NPY administration reverse PTSD symptoms in the single prolonged stress model and predator scent model. CRF is also released during stress-related NE secretion and acts on CRF1R, with down-regulation of this receptor observed in resilient phenotypes.
elevated zero maze 24 hours later in KO mice for galanin exclusively in NE cells expressing DBH (GalcKO-Dbh mice) (Tillage and Foster, 2021). These results suggest that this neuropeptide has a protective effect against stress-induced anxiogenic states.

Regarding LC-derived galanin expression associated with depressive-like behaviors, the evidence is controversial, with chronic antidepressant administration promoting either reduced or enhanced expression of galanin mRNA in the LC (Holmes et al., 2006; Lu et al., 2005; Rovin et al., 2012). Moreover, GalR2 participation has been studied in animal models of depression. Using the LH paradigm, Lu and Bartfai (2009) found more persistent depressive-like responses in GalR2-KO mice (Lu and Bartfai, 2009). These animals displayed increased immobility in the tail suspension test and increased anxiety-like behavior. This work indicated an antidepressant-like effect of GalR2 signaling, in accordance with the fact that decreasing NE transmission in the LH paradigm promotes resilience (Isingrini et al., 2020). In human post-mortem tissues, Barde et al. (2016) reported increased gene expression of GAL in the LC of both male and female depressed subjects, but no differences for GAL1R mRNA. Decreased CpG1 and CpG2 methylation of individual sites of CpG (cytosine followed by guanine from 5' to 3' sites of genome; 80 % of these sites are methylated) of the GAL gene was observed in both males and females with depression (Barde et al., 2016).

Although these findings collectively show a role of galanin in resilience to non-social and acute stress effects, more studies are required to decipher how galanin modulates NE neuron activity in resilient rodents following both chronic social and non-social stress.

### 5.3. Inflammatory cytokines

The role of central and peripheral inflammation in psychiatric disorders has been well described, with an increased peripheral immune response observed in patients with anxiety and/or mood disorders (Caruso et al., 2023; Peruzzolo et al., 2022). Evidence suggests a key role of the NE system in this process (Fourrier et al., 2019; Rhie et al., 2020; Tsyglakova et al., 2019; for review Dantzer et al., 2018). Inflammation in the body is detected through pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which activate immune responses. In the brain, these cytokines are primarily synthesized and secreted by activated microglia and astrocytes (Smith et al., 2012; Wang et al., 2015). The NE system is a crucial modulator of neuroinflammation, mainly by regulating the function of microglia and astrocytes and activating beta-adrenergic receptors (ADRβ1 and ADRβ2) (Evans et al., 2022; Sugama et al., 2019).

IL-1β plays an important role in initiating the immune response in the central nervous system. It acts on IL-1RI (type I receptor) for activation, which is inhibited by IL-1ra (receptor antagonist) and IL-1RII (type 2 receptor) for inhibition. Noradrenaline has been shown to induce the production of IL-1ra and IL-1RII in primary rat mixed cell cultures (McNamee et al., 2010). In 2002, Borsody and Weiss studied the electrophysiological properties of NE neurons in rats following the local microinjection of IL-1β. They observed increased noradrenergic activity in a dose-dependent manner (50 pg-5 ng), which was reversed by microinjection of an IL-1R antagonist (Borsody and Weiss, 2002). They also reported that at very low doses (5 pg), IL-1β had an inhibitory effect on LC activity, which was abolished by CRH-stimulated release of IL-1β, suggesting a specific intrinsic circuit.

Wood et al. (2015) studied inflammatory cytokines in the LC of socially defeated rats. They observed that passive coping rats, which assumed a subordinate behavioral response to a dominant rat, showed decreased sucrose preference (Short Latency group, SL). In contrast, active coping rats displayed longer latency (LL) to assume a defeat posture and did not exhibit anhedonia-like responses (Wood et al., 2015). Gene expression analyses in the LC revealed that stress had opposing effects on IL-1β, with increased expression in SL rats and decreased expression in LL rats. Supporting these findings, the administration of an IL-1 receptor antagonist into the lateral ventricle reversed

anhedonia in SL rats. The resilient-like phenotype in LL rats was also associated with reduced expression of TNF-α, Egr1, and Oprk1, which have pro-inflammatory roles. Therefore, resilience to social stress might be linked to reduced inflammatory factors within the LC.

### 5.4. Metabotropic glutamatergic receptor (mGluR5)

Another potential player in resilience mediation by the LC-NE system is the metabotropic type 5 glutamate receptor (mGluR5). This receptor has been studied in relation to stress resilience in the nucleus accumbens (NAc), medial PFC, and ventral HPC. Research has shown that mice lacking mGluR5-mediated signaling in the NAc exhibit more depression-like behaviors such as LH, social withdrawal and anhedonia (Shin et al., 2015). Similarly, it has been suggested that mGluR5 overexpression in the mPFC and vHPC enhances resilience following CSDS (Kim et al., 2022). A similar effect was observed in the BLA where increased expression of mGlu5 mRNA facilitated resilience to the long-term effect of SPS exposure.

The LC is known to be activated by stress through NMDA and mGluR-mediated glutamatergic input (Olpe et al., 1989; Page et al., 2005), and mGluR5 has been identified in noradrenergic varicosities (Poe et al., 2020). A LC transcriptomic analysis following single exposure to SPS stressor between rats with high vs low anxiety index in the EPM revealed mGluR5 gene as the most downregulated gene, showing it role in the LC for anxiety modulation (Nahvi et al., 2023).

Studies have shown that the expression level of the mGluR5 gene is higher in LC neurons of individuals with major depressive disorder (MDD) compared to controls (Chandley et al., 2014). Moreover, another study demonstrated that selective antagonism of the mGluR5 receptor reduces basal and acute tail pinch stress-induced extracellular norepinephrine (NE) levels in the PFC following acute systemic administration (Page et al., 2005).

### 5.5. Genetic modulation

Catechol-O-methyltransferase (COMT) is an enzyme that degrades dopamine and noradrenaline, thus regulating the levels of these neuromodulators in the brain. The COMT gene contains a functional single-nucleotide polymorphism at codon 158, where a substitution of the amino acid valine with methionine is associated with reduced COMT activity (Lachman et al., 1996). In humans, this polymorphism (Val158Met) has been found to be relevant to resilience. In the context of PTSD, the Met158 allele has been associated with diminished stress resilience, impaired fear memory extinction, increased susceptibility to developing PTSD, higher catecholamine levels, and increased anxiety and limbic reactivity to unpleasant stimuli (Heinz and Smolka, 2006; Lonsdorf et al., 2009; Met et al., 2010; Mier and Kirsch, 2009). Conversely, downregulation of COMT mRNA in peripheral blood has been associated with resilience to depressive symptoms, suggesting that reduced degradation of catecholamine contributes to resilience against depression in humans (Azadmarzabadi et al., 2018).

A recent study evaluated the LC and NAc transcriptome profile of rats exhibiting high versus low SPS-triggered anxiety in the EPM (Nahvi et al., 2023). They reported more than six times the number of differentially expressed genes (DEGs) in the LC compared to the NAc, indicating a more robust involvement of the NE system in mediating resilience versus susceptibility to SPS. Although specific resilience-related genes were not detailed, the authors found that LC DEGs in high versus low anxiety index groups were associated with morphological changes, including regulation of actin cytoskeleton, growth factor activity, regulation of cell size, brain development, and memory.

Additionally, Wood et al. (2015) reported that rats resistant to developing anhedonia following the resident-intruder paradigm exhibited downregulation of the Knch8 gene within the LC (Wood et al., 2015). Knch8 is a potassium voltage-gated channel (subfamily H
member 8) regulating action potential production and propagation. In the context of social stress, it remains to be verified whether down-regulated Knch8 expression is linked to the high NE transmission characteristic of resilience. In the same study, reduced gene expression of NPY2R (Neuropeptide Y Receptor Y2), DRD1 (Dopamine Receptor D1), and OPRK1 (Opioid Receptor Kappa 1) was observed selectively in the resilient group. This suggests altered dopamine, opioid, and Neuropeptide Y modulation of the LC-NE system in resilience following social defeat.

## 5.6. CRF modulation

Corticotropin-releasing factor (CRF) is a putative mediator of stress-related activation of LC neurons and subsequent NE release (Valentino et al., 1993). Increased CRF expression has been associated with stress-related disorders, including evidence of elevated levels in the LC of depressed individuals (Bissette et al., 2003). In rodents, CRF gene expression in the PVN has been linked to susceptibility to social stress (Elliott et al., 2010). This adaptation was necessary for the development of social avoidance, as knockdown of the CRF gene in the PVN prevented stress-related behaviors, and its DNA methylation status predicted stress resilience (Elliott et al., 2010). CRF-KO mice, specifically in GABAergic neurons (CRFcKO-GABA), were resilient to CSDS, with absence of social interaction deficit and exhibited impaired stress-induced expression of c-fos and zif268 in cortical and limbic brain regions (Dedic et al., 2019). Additionally, downregulation of LC CRF1 receptors was found in resilient rats in the LH model (Taneja et al., 2011). Similarly, systemic antagonism of CRF1 receptors prevented anxiety-like responses in the open field and zero maze induced by photostimulation of central amygdala (CeA)-CRF projecting neurons to the LC (McCall et al., 2015). Hence, reduced CRF modulation of LC NE neurons seems to be associated with resilience to non-social stress. Considering CRF activates NE cell activity, this finding aligns with PTSD and LH models where reduced NE release underlies resilience.

Regarding social stress, CRF modulation within the LC has been reported in rats with long (LL) versus short (SL) latency to assume a supine posture during social defeat for 5 days. In this paradigm, SL animals displayed increased vulnerability to develop a susceptible phenotype, while LL rodents were more prone to be resilient. Reduced CRF1 receptor (CRF1R) expression within the LC has been reported through western blot and electron microscopic studies in male and female LL rats (Chaijale et al., 2013; Reyes et al., 2019). Another study, based on c-fos expression, revealed that CeA-CRF inputs to the LC are more activated in SL rats and show a tendency toward enhanced activation in LL rats compared with controls (Reyes et al., 2015). This result seems inconsistent with increased LC-NE activity in resilient mice after 10 days of social defeat. The evidence described here is valuable for understanding coping strategies after repeated stress; however, whether reduced CRF modulation within the LC is linked to a resilient phenotype following chronic social stress needs further corroboration.

Considering that CRF inputs to the LC include both GABAergic and glutamatergic projecting neurons, and that CRF can also indirectly modulate NE cell activity by affecting LC glutamatergic inputs (Barcomb et al., 2022), it is essential to clarify how different CRF inputs modulate the LC-NE system to promote resilience to social versus non-social stress.

# 6. Perspective on development and sex differences

The role of the LC-NE system in sex differences in vulnerability to stress and its influence on neurodevelopment provides a new perspective on understanding psychological resilience.

## 6.1. Sex differences in vulnerability to stress and psychopathologies

It is well established that male and female brains respond differently to stressful events (Bangasser and Wicks, 2017; Mathers and Loncar,

2006). The prevalence of MDD is reported to be twice as high in females as in males across different nations (Bromet et al., 2011; Lim et al., 2018), with higher prevalence in high-income countries compared to low-income ones (14.6 % vs 5.5 % and 11.1 % vs 5.9 %, respectively) (Bromet et al., 2011). (Gili et al., 2019). It has been reported that woman are more likely to have suicidal thoughts and to attempt suicide (Richardson et al., 2023), however, men are more likely to die from suicide: death rate 4–5 times higher across European Union (Freeman et al., 2017).

According to last reports on PTSD sub-clusters scores (Charak et al., 2014), similar trends are observed, with prevalence rates around 10–12 % in females, which is also twice as high as in males (Dückers and Olff, 2017). Similarly, women are reported as being twice likely to suffer from anxiety disorder (7.1 % vs 4.2 %) and panic disorder (6.2 % vs 3.1 %). In general, females are more affected by affective disorders (24.4 % vs 17.5 %) and related issues as migraine and insomnia, while males are more likely to suffer from substance related disorders, such as alcohol (7.5 % vs 19.6 %) and drug abuse (4.8 % vs 11.6 %) (Bangasser and Valentino, 2014).

Men and women are exposed to different types of stress and likely utilize different mechanisms to cope with stress, influenced by varying concentrations of sex hormones (testosterone in males and estrogen in females). A recent meta-analysis of brain functional studies reported that women show increased activation of the LC during emotion-evoking tasks (Filkowski et al., 2017), suggesting that stressful events trigger different arousal responses in women compared to men.

Anatomical studies indicate that the LC is larger in adult female rats compared to males, with females having more NE neurons in the LC core, particularly during puberty (Luque et al., 1992; Pinos et al., 2001). This difference is potentially due to the influence of ovarian hormones, as LC neurogenesis continues during puberty in females (Pinos et al., 2001). This was suggested since LC is masculinized partly because of prenatal testosterone (Rodriguez-Zafra et al., 1993). In humans, comparative studies are limited, but some evidence suggests a higher number of NE neurons in females (18 000 LC-NE neurons in females vs. 15 000 in male) (Busch et al., 1997; Ohm et al., 1997).

Estrogen appears to play a significant role in NE metabolism, enhancing NE synthesis and reducing its degradation (for review: Bangasser et al., 2016b). Estrogen treatment in castrated male or ovariectomized female rats increases TH and DBH expression and NE levels in a dose-responsive way (Serova et al., 2002, 2004). NE levels increased in the HYP and in ventral HPC of ovariectomized female rats, following estradiol treatment (Alfinito et al., 2009; Lubbers et al., 2010). Estrogen also reduces adrenergic receptors expression and function in the cortex and striatum (Etgen et al., 2001; Meitzen et al., 2018). The COMT level, another enzyme responsible for the quantity of NE in the synaptic cleft, as it degrades the NE, is lower during the pro-estrus cycle in female rats (Parvez et al., 1978), suggesting an inverse relationship between COMT and blood level of estrogen. These studies suggest female hormones influence NE metabolism by acting on its synthesis, degradation, and receptor expression.

Sexual dimorphism in LC regulation by CRF has also been demonstrated. (see section “CRF modulation”, for review: Wellman et al., 2018). Females exhibit increased sensitization of the LC-NE system to CRF, with low doses of CRF increasing NE neuron firing activity in females but not in males (Bangasser et al., 2011; Curtis et al., 2006). This increased sensitivity is linked to differences in the cAMP/PKA pathway of CRF1 receptors (Bangasser et al., 2016a, 2011), and lower binding of CRF1 receptors with β-arrestin2 in females (2016) leading to decreased internalization of these receptors after stress (Bangasser et al., 2016a).

All this information reveals that mechanisms involved in males are not necessarily transferable in females, and highlight the importance of sex-specific studies in understanding the role of the LC-NE system in stress and resilience against psychopathologies.
## 6.2. Neurodevelopmental effect

Trauma during neurodevelopmental periods can significantly impact the development of neural systems and brain connectivity. The LC-NE system plays a crucial role in brain development (Saboory et al., 2020), with noradrenergic neurons appearing early in gestation, (GD 10–13 in rodent brain) (Coyle, 1977; Saboory et al., 2020) and influencing brain wiring during critical developmental periods. Changes in NE neurotransmission during these periods can result in abnormal behaviors later in life (Shishkina et al., 2004).

Early life adversity (ELA) has been shown to disrupt the LC-NE system both anatomically and functionally, with lasting impact on cognitive and emotional functions throughout the lifespan, possibly sustaining psychopathological development. Recent study shown long-term increased LC-NE neuronal activation following early maternal separation (Fóscolo et al., 2022), suggesting that early stress induce change in the brain stress response at adulthood.

However, the long-term consequences of ELA vary between individuals. While ELA can in some individuals precipitate the emergence of psychopathologies, other will escape this condition. Some children have the ability to adapt in response to adversity and avoid its long-term negative consequences. The search for protective factors in the context of adversity that predict positive psychiatric outcome has only recently emerged and still in its early stage (Moreno-López et al., 2020). Imaging studies suggest that resilience to the effects of child abuse (CA) may be mediated by larger hippocampal volume (Frodl et al., 2010; Gerritsen et al., 2015), increased fractional anisotropy in the posterior cingulum (Fani et al., 2012), and positive resting-state functional connectivity between prefrontal areas and the limbic regions (Kaiser et al., 2018; Philip et al., 2016). However, how the resilient network is controlled by stress-integrative structures and the upstream neuronal and molecular mechanisms responsible for the functional alteration of this network remains to be deeply investigated. No study to date has investigated how features of the LC-NE system may induce positive adaptations following ELA while evidences suggest it could play a pivotal role in determining the long-term effect of CA-induced psychopathology or resilience.

## 7. Conclusion

In conclusion, addressing the complexity of stress-induced psychopathologies, particularly within the context of the locus coeruleus-norepinephrine (LC-NE) system, requires a multifaceted approach that considers the diverse nature of traumatic experiences, the intricate functioning of the LC-NE system, and the inherent inter-individual variability in stress responses.

The recognition that different types of trauma can evoke opposing pathophysiological mechanisms while converging on a common depressive phenotype underscores the need for a paradigm shift in diagnostic strategies. Moving beyond symptom-based classifications, recent advances in identifying distinct neurobiological signatures offer promising avenues for personalized therapeutic interventions. The heterogeneity of depression itself, reflected in various functional impairments impacting affective information processing, necessitates a nuanced understanding of neurobiological substrates. The efforts to subtype patients based on brain dysfunction patterns rather than symptom clusters present a significant advancement. Studies such as those by Drysdale et al. (2017), revealing biotypes defined by dysfunctional connectivity in specific brain networks, provide a foundation for tailoring interventions to individualized neurobiological characteristics. Furthermore, animal model studies trend to demonstrate that classification of patients according to the type/nature of the stressor or trauma could point out the brain network dysfunction involved in the development of the pathology at the individual level.

Within this framework, the LC-NE system emerges as a pivotal player in stress-related disorders. Despite its well-established significance, it biological relevance to treat stress-related disorders has suffered from

the complexity of this neuromodulator. It action is widespread in the central nervous system, as it acts on multiple target regions and participate in several brain functions. Acknowledging the functional and anatomical heterogeneity of the NE system and its multiple sub-circuits is paramount in deciphering the effects of NE drugs on stress responses.

Moreover, taking into account inter-individual variability in the stress response adds another layer of complexity. Assessing protective mechanisms, particularly through longitudinal studies utilizing advanced imaging techniques, allows for a deeper understanding of both stress-induced neuronal plasticity and intrinsic factors contributing to susceptibility or resilience. Techniques like calcium imaging through miniscope and fiber photometry, in animal model, enable real-time monitoring of network activity, providing valuable insights into the dynamics of brain function before, during, and after exposure to stress. This approach allows for a real-time exploration of changes in brain activity, offering insights into baseline network properties that may predict an individual's response to stress.

Advancing our comprehension of stress-induced psychopathologies demands a holistic perspective that considers the diverse nature of traumatic experiences, the intricacies of the LC-NE system, and the individual variations in stress responses. By integrating these insights into therapeutic approaches, we may pave the way for more effective and personalized interventions in the treatment and prevention of stress-related disorders.

## Acknowledgement

The authors acknowledge, for financial supports, the ANR - FRANCE (French National Research Agency, ANR-21-CE16-004), the FRM (Fondation pour la recherche médicale, EQU202203014667), the Sissley Foundation, the IDEX Emergence grant and the doctoral school MCTI (ED 563, Médicament, Toxicologie, Chimie, Imageries) from the University Paris Cité.

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