Noradrenergic alterations associated with early life stress

Significant stress in childhood or adolescence is linked to both structural and functional changes in the brain in human and analogous animal models. In addition, neuromodulators, such as noradrenaline (NA), show life-long alterations in response to these early life stressors, which may impact upon the sensitivity and time course of key adrenergic activities, such as rapid autonomic stress responses (the ‘fight or flight response ’ ). The locus-coeruleus noradrenergic (LC-NA) network, a key stress-responsive network in the brain, displays numerous changes in response to significant early-life stress. Here, we review the relationship between NA and the neurobiological changes associated with early life stress and set out future lines of research that can illuminate how brain circuits and circulating neurotransmitters adapt in response to childhood stressors


The health, social and neurobiological effects of early life stress
Early life stress (ELS) comprises a variety of stressors that individuals can encounter during childhood or adolescence including physical, sexual, and emotional abuse; physical and emotional neglect; divorce and domestic violence (Hughes et al., 2020).ELS (also termed adverse childhood experiences or ACEs) can refer to both human and analogous animal models of significant stress (Schmidt, 2010).ELS can significantly impact mental and physical health and increase impulsivity, therefore, incidences of substance abuse and alcoholism increase (Carr et al., 2013;Finlay et al., 2022) resulting in a heightened risk of early mortality (Carr et al., 2013).
ELS may impact upon how individuals process and react to stressful situations throughout their lives.For instance, they may show increased fearfulness, or alterations in memory when faced with stressful situations (Weltz et al., 2016;Vogel and Schwabe, 2016).Despite the pervasiveness of these issues, there is a relatively poor understanding of how alterations in brain structure and function following stress result in these behavioural changes.In rodents, we see similar behaviours as ELS induced by maternal separation and restraint paradigms is associated with increased depressive and anxiogenic behaviours in adulthood (Seewoo et al., 2020).
The brain shows considerable adaptation in response to ELS.Individuals who have experienced ELS display loss of volume in the amygdala and hippocampus (Godoy et al., 2018;Hanson et al., 2015) altered white matter integrity (Ho et al., 2017) and changes in functional connectivity (the synchronised activity of brain networks) (Zerbi et al., 2019).Yet the underlying mechanisms driving these structural and functional brain changes are as yet unclear.Increasingly, evidence points towards a critical role for altered neurotransmitter release and function.
One key neurotransmitter that is involved in stress responses and broader brain changes is noradrenaline (NA).NA is released as part of the rapid sympathetic response when individuals encounter a fearful or stressful situation.In this review, we examine links between ELS and altered structure and function of NA systems in the brain.We consider how NA shifts in response to ELS.We specifically consider alterations in the locus coeruleus-noradrenergic (LC-NA) network, which may drive structural and functional brain alterations, as well as behavioural and physiological changes following ELS.We propose several converging investigations in both human and animal models to map out the patterns of NA alterations associated with ELS.

Stress response systems
Upon encountering a physical or psychological stressor, an immediate reflexive response occurs promoting alertness and vigilance (Joëls and Baram, 2009).Two key routes are involved.
The first route is the activation of the rapid sympathetic adrenomedullary system (SAM).During periods of acute stress, the hypothalamus is activated, which signals the sympathetic branch of the autonomic nervous system (ANS) to activate the adrenal medulla to release NA throughout the central nervous system and adrenaline (AD) throughout the periphery (Bangasser et al., 2012;Bangasser and Valentino, 2014;Duman, 2004;Godoy et al., 2018;Makris et al., 2023;Pitzer, 2019;Smith, 2007;Song et al., 2017;Hackney, 2018).Upon removal of the stressor, the parasympathetic branch of the ANS engages via acetylcholine release, to return the body to baseline homeostatic state (Fengolio et al., 2006).This is the 'rest and digest' response with the sole aim to conserve energy and resume bodily functions which were halted during the acute stress response (McCorry, 2007).
The second route is activating the relatively slow hypothalamicpituitary-adrenal (HPA) axis.The LC-NA network and HPA-axis are thought to act synchronously in response to a stressor as corticotrophin releasing hormone (CRH) governs both responses (Valentino and Van Bockstaele 2008;Valentino and Van Bockstaele 2008).Neurons in the paraventricular nucleus (PVN) of the hypothalamus are activated after a stressor, releasing CRH (Stephens et al., 2014) which shifts the locus coeruleus-noradrenergic network to high tonic firing, further increasing NA discharge and transiently activating the HPA axis, creating a feedforward system (Fan et al., 2009;Levy and Tasker, 2012), see Fig. 1.This co-ordination of stress systems is considered to be due to the ADRA1 receptors in the PVN as when stimulated, the HPA-axis is activated, however, when these receptors are pharmaceutically blocked, the HPA-axis does not respond to stressors (Toufexis et al., 1998).
PVN neurons also release arginine vasopressin (AVP) alongside this CRH into the hypophysial blood portalblood vessels connecting the hypothalamus to the anterior pituitary gland (Tsigos and Chrousos, 1994).This stimulates the production of proopiomelanocortin, a prohormone that serves as the basis of ACTH, which stimulates the zona fasciculata of the adrenal glands (Tsigos and Chrousos, 1994).Consequently, glucocorticoids are released into the bloodstream, namely cortisol in humans and corticosterone in rodents (Stephens et al.,2014).
To prevent sustained activation, the HPA axis is modulated through a negative feedback loop via cortisol in the bloodstream, inhibiting further hypothalamic activation to return the body to a baseline state.
There are two types of glucocorticoid receptors: mineralocorticoid (MR) or glucocorticoid (GR) receptors, with cortisol having higher affinity to the former (Goncharova et al., 2019).Only when cortisol levels significantly increase (for example, during stress) does cortisol begin to bind to GRsthis then terminates the stress response (Stephens et al., 2014) preventing the negative impacts of too much or too little cortisol in the bloodstream.

Defining early life stress
ELS is defined as either one significant or several cumulative major stressful encounters that occur during childhood or adolescence (Lester et al., 2020).While no childhood is without stress, there are thought to be nine key ACEs that constitute evidence for ELS (Hughes et al., 2020).These include physical, sexual, and verbal abuse; parental separation; exposure to domestic violence; mental illness; familial incarceration and substance abuse (Hughes et al., 2020).Encountering these significant ELS repeatedly activates the stress response systems, detrimentally impacting neural, social, and emotional development and neuroendocrine regulation (Teicher et al., 2016;Berens et al.,. 2017).

Fig. 1.
After encountering a stressor, neurons in the paraventricular nucleus (PVN) in the hypothalamus begin firing and release corticotrophin-releasing hormone (CRH), shifting the LC-NA network to release more NA activating both the acute (sympathomedullary or SAM pathway) and chronic (hypothalamic-pituitary adrenal or HPA axis,) stress response.Arginine vasopressin (AVP) is also released from the PVN into the anterior pituitary gland, which then releases proopiomelanocortin (POMC) which is the basis for adrenocorticotrophic hormone (ACTH) which stimulates the zona fasciculata of the adrenal glands in the kidneys, releasing cortisol into the bloodstream.Created with BioRender.com.
M. Sheppard et al.

Prevalence and long-term effects of early life stress
The original CDC-Kaiser Permanente ACE study, conducted on 17,000 participants in the USA between 1995 and 1997, identified that 64 % of participants experienced one key stressor and 12.5 % experienced four or more (Boullier and Blair, 2018).A more recent general population survey of ~15,000 adults in England found that 15.4 % of respondents experienced two or three key childhood stressors and 8.4 % experienced four or more (Hughes et al., 2020).
ELS is associated with a number of adverse outcomes throughout the lifespan, including an increased incidence of mental and physical health problems along with an increased likelihood of engaging in dangerous behaviours (Ridout et al., 2018).This leads to a larger use of resources, increasing economic burden (Ridout et al., 2018).For example, the estimated annual societal and health cost associated with ELS in England in 2020 was £42.8 billion (Hughes et al., 2020).These effects are compounded by societal factors: those most at risk to trauma tend to be in marginalised low socioeconomic status areas, with lower household income and educational attainment (Ridout et al., 2018).Nevertheless, not everyone who experiences ELS will develop the same negative outcomes, and so there must be biological factors that confer resilience to these early adverse experiences.
Early life stress is frequently associated with deficits in social, cognitive, and emotional development (DeBellis and Zisk, 2014).For example, a graded relationship has been identified between the number of stressors encountered and the use of psychotropic drugs (Finlay et al., 2022).In this case, ELS may predispose individuals towards engaging in risky behaviours, such as substance abuse (Carr et al., 2013).Over the life course, these effects of ELS may accumulate (see Fig. 2), with an increased risk of developing chronic illnesses, including heart disease and diabetes, prior to the age of 69 (Finlay et al., 2022) and subsequent early mortality, with a significantly greater likelihood of death up to 20 years earlier than their non-stressed counterparts (Finlay et al., 2022).One explanation for this is that ELS is a risk factor for hypertension (Su et al., 2015), obesity (Wiss and Brewerton, 2020) and smoking (Ford et al., 2011) which are proven to significantly contribute to the development of cardiovascular disease and diabetes (Smith et al., 2007).Furthermore, ELS is a robust predictor of developing ischemic heart disease, cardiovascular disease, stroke, respiratory disease and cancer (Poplawski et al., 2020).Rodent models outlined specific metabolic markers associated with ELS including abnormal energy metabolism, branched chain amino acid biosynthesis and degradation, methylhistidine metabolism, arginine and proline metabolism, glycine and serine metabolism and aminoacyl-tRNA biosynthesis (Poplawski et al., 2020).These makers were all related to anxiogenic behaviours (Poplawski et al., 2020).This could provide a biological mechanism explaining the link between ELS and physical illnesses such as CVD and metabolic syndrome.
Those who have experienced ELS have an increased risk of multiple mental health problems, including depression, bipolar disorder, anxiety, personality disorders, schizophrenia, and PTSD (Juruena et al., 2020).There is a linear relationship between the frequency, severity and chronicity of the ELS and the subsequent degree of mental illness (DeBellis and Zisk, 2014).Furthermore, the risk of body dysmorphia and eating disorders increases with ELS frequency, which further leads to disease and social problems (Carr et al., 2013), indicating multiple pathways by which ELS can influence morbidity and mortality.

Future stress responses after early life stress
Exposure to ELS can impact stress-response processes throughout life, with changes in initial autonomic and HPA responses, including changes in cardiovascular responsivity, inflammatory response and abnormal glucose and cortisol responses (van Bodegom et al., 2017;Brindle et al., 2022).This dysfunction intensifies as life stressors accumulate, resulting in more significant and long-term health consequences (McEwen, 2004) and subsequent allostatic overload (Ridout et al., 2018) with overproduction of numerous stress response mediators (Finlay et al., 2022).Consequently, the neuroendocrine systems associated with the autonomic stress response are thought to be permanently altered by the cumulative toxic stress of ELS (Silberman et al., 2016).These alterations are long-lasting pervasive changes that occur via the epigenetic modification of the genome (Brindle et al., 2022).For example, altered methylation of cytosine (5mC) at specific sites and throughout the entire genome was identified in those who have experienced ELS (Bearer and Mulligan, 2018), which was associated with a number of negative mental and physical health outcomes.

Noradrenaline
Stress disrupts homeostasis within the nervous system, leading to a cascade of physiological and psychological consequences.Two key candidates in this response are glucocorticoids (GCs) and NA.GCs, produced by the adrenal glands, act throughout the body to regulate various functions, while NA operates within the central nervous system (CNS) and sympathetic nervous system (SNS) to orchestrate the fight-orflight response via amygdala complex activation, which induces the secretion of catecholamines (see box 1) (Sugama and Kakinuma, 2021;Hakamata et al., 2022).
As ELS has been associated with an overproduction of NA (Finlay et al., 2022), it is important to understand what this neuromodulator is and its role in the stress response.A series of seminal studies conducted by Dahlström and Fuxe (1964) originally identified monoamine nerve terminals throughout the brain, including NA. Catecholamines (NA, dopamine, and AD) act as both neurotransmitters and hormones and maintain homeostatic equilibrium in the ANS (Paravati et al., 2022).In the brain, NA is synthesised in the locus coeruleus, where concentration is highest, and richly concentrated in the ventral tegmental area (Fuxe et al., 1970) and central nucleus of the amygdala (CeA) (Valentino et al., 1991).NA activation is a required pre-requisite for the fight-or-flight response, imperative for survival (Hussain et al., 2023).
It is important to note that during sympathetic activation, AD is released alongside NA in the periphery as well as centrally (Chu et al., 2024).Although these catecholamines are often released synchronously and used as biomarkers of the stress response, the ratio of these monoamines in urine differs dependent upon the type of stressor.For example, when measuring catecholamines in urine, both NA and AD were significantly increased after a psychosocial stressor, however, after a physical stressor only NA significantly increased (Konzett et al., 1971).When inducing a painful stressor, AD significantly increased in the urine whereas NA increased but not significantly (Konzett et al., 1971).In terms of chronic stressors, when comparing the effect of shift work, AD was significantly raised in the urine, however, NA only represented ambulatory changes during work hours (Boettcher et al., 2020).Therefore, despite these monoamines being closely related, they seem to be differentially affected by the type of stress experienced, as well as the duration of the stressor.
Each receptor varies in its affinity for NA, with ADRA2 having the highest, followed by ADRA1 and ADRB, with ADRB2 having the lowest potency (Bylund and Bylund, 2014;Orlando et al., 2023).ADRA1 modulates phospholipase C via G q proteins, whereas ADRA2 and ADRB are coupled to adenylyl cyclase via G-proteins.It is, though, important to note that ADRA2 proteins are coupled negatively by inhibitory G-proteins (G i proteins) however, ARDRB proteins are coupled positively by stimulatory G-proteins (G s ,) (Ciccarelli et al., 2013).Each of these subtypes has three subunits, which display functional and structural variances, see Fig. 3 and Table 1 (Strosberg, 1993;Toufexis et al., 1998;Ciccarelli et al., 2013;Hackney et al., 2018).
The level of NA release governs which receptors are stimulated.Under a moderate release of NA, the receptors with the highest affinity, post-synaptic ADRA2a receptors are responsible for uptake (Orlando et al., 2023).However, high levels of NA release stimulate ADRA1a receptors on post-synaptic dendritic spines (Orlando et al., 2023).

The locus-coeruleus noradrenergic network
The LC-NA network is the key NA system innervating the brain, see Fig. 4 (Orlando et al., 2023).This network consists of the densely populated locus coeruleus (LC) in the dorsal pons (Orlando et al., 2023), as well as sites in the PFC, cerebellum, temporal and parietal cortices, and subcortical structures (thalamus, amygdala and hippocampus) (Benarroch, 2018).The LC nucleus projects widely throughout the brain, suggesting a widespread influence on physiological and cognitive functions (Berntson et al., 2003).As there are numerous diffuse projections and associated behaviours, the specific outcome is dependent upon where the projection that emanates from the LC terminates and, consequently, which region of the brain is activated (Schultz, 2007).
NA neurons within the LC-NA network exhibit three distinct activation profiles (McCall et al., 2015).In resting state, rodents display low-tonic activity (~1-2 Hz), whereas, when awake but given specific Fig. 3. ADRA2 receptors are the most easily stimulated after only a moderate NA release and allow for task related activation and allowing for an adaptive response.These are found in the synaptic clefts of sensory neurons.These are also the receptors which signal to inhibit further NA release to prevent an overproduction of NA.There are three subtypes: ADRA2a, ADRA2b and ADRA2c.ADRA1 receptors have the second highest affinity, and these are located in the hypothalamus with extensive distribution within the paraventricular nucleus of the hypothalamus.These have three subtypes: ADRA1a, ADRA1b and ADRA1d.These are required to be activated for a stress response to occur.ADRB receptors have a lower potency and have more distinct subcategories with ADRB1 being found on cardiac tissue to increase heart rate and contractility in times of stress; ADRB2 being extensively distributed throughout the body to allow for bronchodilation and vasodilation; and ADRAB3 being found on white and brown adipose tissue to allow for metabolisation in times of extreme stress.(ADR = adrenoceptor).Created with www.biorender .com.stimulation, such as light flashes or touch, phasic activity occurs (McCall et al., 2015).Stress induced CRH release shifts to high-tonic NA firing simultaneously reducing phasic firing (Curtis et al., 1997).The shift to high-tonic firing increases NA throughout the brain, reaching the threshold to stimulate ADRA1 and ADRB adrenoceptors (Cools and Arnsten, 2022).This shift is thought to act as a "circuit-breaker", interrupting ongoing functional networks brain-wide and reconfiguring how these systems communicate to meet changing demands (McCall et al., 2015;Valentino and Van Bockstaele, 2008).Specifically, the amygdala and salience networks (a set of brain regions including the insula, amygdala anterior cingulate cortex that co-activate in response to salient internal and external stimuli) display increased synchronised activity (Zerbi et al., 2019).This response is thought to be evolutionarily advantageous as it promotes potentially adaptive changes in stress-responsive behaviours.NA projections to other brain regions are thought to facilitate alterations in a variety of behavioural responses.For example, CRHR1 receptors within the CeA are activated upon CRH release post-stress induction, stimulating NA release and promoting anxiogenic behavioural responses (McCall et al., 2015).NA signalling in the CeA and thalamic reticular nucleus is thought to direct attention towards processing salient information (Zikopoulos and Barbas, 2007;Campese et al., 2017).Furthermore, NA regions throughout the medial septum and hippocampus may facilitate alterations in stress-related learning and memory (Ehlers and Todd, 2017).For example, the LC-NA projection to the dentate gyrus is associated with aversive contextual learning (Seo et al., 2021).Each NA projection may therefore play specific roles within the autonomic stress response.
NA projections are likely responsible for specific behaviours, each with distinct functional roles (Morris et al., 2020).Sometimes these projections can have opposing roles, for example, CeA projections allow for aversion learning, whereas medial forebrain projections facilitate extinction learning (Uematsu et al., 2017).Each projection displays discrete asynchronous spiking activity, which govern various levels of NA discharge (Chandler et al., 2014) supporting the idea of distinct functional roles.However, strong aversive stimuli elicit whole-network responses (Uematsu et al., 2017) allowing this system to provide specific modulation of discrete stress-related behaviours and global changes required for arousal states (Morris et al., 2020).

The LC-NA network, noradrenaline, and stress
As previously highlighted, NA release initiates both the autonomic and chronic stress systems.Despite the importance of NA modulation in the stress response, there is an inverted U-shaped relationship here (Morris et al., 2020).Clearly, without any NA response, the required fight-or-flight response would not occur, which would be maladaptive in the face of threat.The typical shift to high-tonic firing during stress induces anxiogenic responses (Zerbi et al., 2019), with moderate NA release stimulating ADRA2 receptors, enhancing task-related network activation and producing an adaptive behavioural response (Wang et al., 2007).However, large NA release engages ADRA1 receptors, suppressing task-related firing and impairing behavioural responses (Arnsten et al., 2012).Thus, either too much or too little NA results in a maladaptive stress response (Aston-Jones and Cohen, 2005).
Changes in LC firing during stress responses can help explain cognitive adaptations to stress.When the LC-NA network is triggered by a stressor-induced CRH release, high-tonic NA discharge prevents the LC from being able to respond to salient stimuli with phasic bursts as it usually would in a stress-free environment (Borodovitsyna et al., 2018).Consequently, the result is an inability to discriminate sensory signals, specific cognitive impairments (such as altered memory encoding and retrieval, see McManus et al., 2022a) and an overall anxiogenic state (Bangasser et al., 2014).
The cognitive consequences of high-tonic NA firing in response to stressors may appear maladaptive, yet this shift promotes adaptive behaviour and increases chances of survival in potentially dangerous situations (Henderson et al., 2012).For example, increasing LC firing increases NA in the prefrontal cortex (PFC) promoting vigilance and scanning behaviour (Patki et al., 2015;Vazey et al., 2018), which may help facilitate escape from life-threatening situations (Henderson et al., 2012).Importantly, responses are considered to habituate over time if the trigger is not aversive, and so greatest responses will be triggered by aversive stimuli or by novel or unpredicted stimuli.This provides a specialised function for how the LC-NA network responds to threatening or stressful stimuli to improve chances of survival (Morris et al., 2020).

Dysregulation of the LC-NA Network
As CRH release helps initiate the initial cascade of both the autonomic and adrenal cortisol responses, it is important to understand the impact of dysfunctional CRH release.An overproduction of CRH after an initial stressor produces a series of morphological changes in LC neurons including longer and more complex dendritic arbours and neurite outgrowth in rodent models (Borodovitsyna et al., 2018;Swinny et al., 2009).Rodent models also display increased expression of neurotrophin 3 (a protein coding gene that promotes neuronal survival, differentiation, and outgrowth) after encountering a stressor (Borodovitsyna et al., 2018).This implies that dysregulated CRH induces morphological changes in LC neurons and alters genetic expression in rodents.This would explain why these changes are long-lasting adaptations that persist after the termination of the stress response (Borodovitsyna et al., 2018).
LC neurons go through additional adaptations including receptor trafficking after chronic stress (Bangasser, 2013) which may increase the uptake of NA and alter LC reactivity to future stressors (Verbitsky et al., 2020).Furthermore, a reduction in the ability of the LC to autoinhibit itself after a physical stressor was identified in rodent models (Jedema and Grace, 2003), with control animals having greater ability to intrinsically self-regulate NA production.This demonstrates a mechanism through which chronic stress dysregulates the LC-NA network.
Cardiovascular responses are an important part of the sympathetic response to stressors.However, long-term toxic psychosocial stressors, such as cumulative ELS, can have negative impacts on cardiovascular health leading to atherosclerosis (Black and Garbutt, 2002) and cardiovascular disease (Satyjeet et al., 2020).Dysregulation in the LC-NA network has been posited to explain the link between chronic stressors and CVD (Wood and Valentino, 2017).The LC processes cardiovascular information to transiently increase heart rate and blood pressure in a fight-or-flight response, however, this relationship has been demonstrated to be mediated by inflammation (Heidt et al., 2014).Therefore, when there is repeated sympathetic activation, such as during ELS throughout childhood, proinflammatory cytokines including interleukin-1β and interleukin-2 are overproduced (Lacosta et al., 2000;Sirivelu et al., 2012), this then produces dysfunctional NA and cardiovascular responses (Wood et al., 2017).This could provide an explanation for the increased risk of CVD and other inflammatory diseases associated with ELS.Although, the relationship between LC-NA dysfunction and cardiovascular disease is important clinically, the specifics of this relationship is outside of the scope of this review, for further information on this relationship see reviews by Wood and Valentino (2017) or Wood et al. (2017).

Volumetric and associated noradrenergic changes associated with ELS
An individual's early life experiences play a key role in the structural development of the brain (Teicher et al., 2016).Early deprivation has been associated with significantly altered hippocampal volume in murine models during adolescence (Biedermann et al., 2012).Further animal models suggests that ELS remodels brain circuitry in the amygdala as well as the hippocampus (Hanson et al., 2015;Howell et al., 2014).In humans, ELS is associated with morphometric alterations in the amygdala, albeit with both increases (Mehta et al., 2009) and decreases in volume (Hanson et al., 2015).The directionality could relate to changes in specific amygdala nuclei (Oshri et al., 2019).For example, ELS in rodents and humans has been linked to decreased volume in the right CeA (Mehta et al., 2009;Oshri et al., 2019), whereas prenatal stress is linked to increased BLA volume (Guadagno et al., 2021).Overall, we see a series of morphological changes associated with ELS that are particularly pronounced in both the hippocampus and the amygdala.
Stress-related structural changes in the brain are associated with alterations in behaviour, such as increases in trait anxiety (Hanson et al., 2015).The hippocampus specifically prevents the coupling of a stress response to a non-stressful stimuli in an adaptive response, yet, in a maladaptive response (e.g., after ELS) this dysfunctional coupling can occur (Sherin and Nemeroff, 2011).Furthermore, the CeA mediates the behavioural and psychological response to stressors, such as whether we fight, flee, or freeze in the face of danger (Kalin et al., 2004).As highlighted, both the amygdala and hippocampus have significant NA input from the LC and high adrenoceptor density in these regions.These stress-related changes in volume, alongside the associated behavioural changes, could arguably result from changes in adrenoceptor distribution in these regions after significant stress, such as ELS.Adrenoceptors are key for the uptake of noradrenaline in the autonomic stress response, therefore, changes in their expression provides a plausible mechanism for later behavioural alterations.
Morphological changes after ELS are also observed in other limbic regions and wider LC-NA networks in both human and rodent models (Cohen et al., 2006).The prefrontal cortex (PFC) has substantial structural and functional connections with the locus coeruleus and is a key part of the LC-NA network (Patki et al., 2015).As the PFC is one of the last regions to mature (Gee and Casey, 2015), there is a large window of neuroplasticity that ELS could influence.For children who were institutionalised at an early age, the cortical thickness of the PFC was significantly smaller than their non-institutionalised counterparts (McLaughlin et al., 2015).More specifically, the orbitofrontal cortex within the PFC demonstrates cortical thickness reductions associated with physically abused children, poverty, and parental neglect due to mental illness (Hanson et al., 2010;Sandman et al., 2015;Busso et al., 2017).As these regions have dense NA innervation, this could provide a potential explanation for these findings (Henderson et al., 2012).
In humans, more than two substantial stressors in childhood are associated with a 2-5 % reduction in the volume of the caudate nucleus and anterior cingulate cortex compared to controls (Cohen et al., 2006).Children who were institutionalised at an early age showed significantly thinner orbitofrontal cortex, which has high NA expression (Henderson et al., 2012), compared to controls (Busso et al., 2017).In rodents, after a maternal separation paradigm, grey matter reductions were identified throughout the limbic system, specifically in the dorsal striatum and in the PFC (Sarabdjitsingh et al., 2017).Interestingly, these alterations were not diminished by pharmacologically blocking glucocorticoid receptors during the neurodevelopmental period.Dysfunction in the autonomic stress system may therefore underpin these volume changes in rodent models.By mapping the relationship between adrenoceptors and ELS-induced volumetric changes in both human and analogous rat models we may gain greater insight into the brain mechanisms linking ELS to behaviour change.
ELS-related volumetric changes may differ depending upon the specific stressor encountered.For example, witnessing domestic violence is associated with significant grey matter alterations in facial recognition areas including the fusiform gyrus (Tomoda et al., 2009).Pharmacologically blocking ADRB-receptors in this region impacts the ability to accurately recognise faces (Terbeck et al., 2015).In contrast, adult women with a history of sexual abuse prior to puberty display cortical thinning of the medial somatosensory cortex linked to the genitalia (Heim et al., 2013).The somatosensory cortex is innervated by the LC via NA input (Simpson et al., 1997;McBurney-Lin et al., 2020).In addition, women who also experience emotional abuse display thinning in the bilateral precuneus (Heim et al., 2013), and blockade of ADRA2-receptors of LC neurons leads to reduced activation in the precuneus following LC stimulation (Song et al., 2017).These examples provide plausible links through which stressful events can influence brain structure via NA pathways.

Structural LC-NA network changes associated with ELS
In addition to grey matter changes, the microstructure of white matter tracts is altered in those who have experienced ELS.Measures from diffusion MRI, such as fractional anisotropy (FA, which reflects the directionality of water diffusion), can be used to assess the integrity of these tracts.In white matter tracts, water is constrained to move along the axon, however, damage to the axonal membrane or surrounding myelin causes the water to diffuse more freely in a more isotropic (i.e., less directional) manner (González-Reimers et al., 2019).Using these measures, it has been shown that a history of ELS is associated with altered FA in the posterior thalamic radiation (McManus et al., 2022b).Furthermore, those with a history of parental verbal abuse show lower FA in the language processing pathwaythe arcuate fasciculus (Hanson et al., 2013), whereas those who have witnessed interparental violence show reduced FA in the left inferior longitudinal fasciculus (Choi et al., 2012).
White matter integrity changes following ELS are also apparent within the LC-NA network.For example, those who experienced childhood neglect have diminished FA in tracts that connect the PFC to the temporal lobe (e.g., uncinate) (Ho et al., 2018;Hanson et al., 2013).These changes following ELS are associated with behavioural changes, such as altered socio-emotional processing (Choi et al., 2012).Furthermore, ELS is associated with microstructural alterations in limbic tracts including the cingulum, the fimbria and fornix of the hippocampus (Villarreal et al., 2002;Gur et al., 2019).It has been proposed that white matter tracts within the LC-NA network are particularly sensitive to ELS during the early maturation period (Duman et al., 2004) in part explaining these findings.As white matter continues to develop into adulthood, severe ELS may alter maturation of the white matter tracts throughout the brain leading to higher fibre density and cross-section of the inferior-frontal occipital fasciculus, the anterior thalamic radiation, and the superior and inferior longitudinal fasciculi (Chahal et al., 2021).There is however a paucity of experimental studies on whether ELS affects white matter tracts within the LC-NA network as a whole (or indeed other neuromodulators), which could be fertile grounds for understanding the mechanisms underpinning these changes.

Functional connectivity changes and ELS
As ELS occurs during a critical period associated with development, this renders the brain particularly susceptible to environmental influences (Herman et al., 2003).Substantial stress in childhood may therefore influence both the structural, but also the functional connectivity of the brain.Indeed, the acute stress reconfigures functional connectivity within the LC-NA network almost immediately (Hermans et al., 2017) but the long-term effects of substantial stress within this neuroplastic window have not been characterised.
In animal models, activation of the LC disturbs current functioning and increases levels of synchronised activity between the salience and amygdala networks (Zerbi et al., 2019).These changes were argued to promote the vigilance and threat-detective behaviours required when presented with a stressor.Furthermore, in rodent models, experiencing maternal deprivation from birth is associated with strengthened prefrontal connectivity (Gee et al., 2013).Maladaptive behavioural stress responses associated with ELS could therefore lead to a reconfiguration of brain-wide networks, altering functional connectivity of the LC-NA network.
In humans, acute stressors have been shown to affect LC-NA networks, although with conflicting results.For example, acute stress has been found to increase functional coupling between an area corresponding to the LC with the amygdala, the anterior insula, and dorsal anterior cingulate (dACC) (van Marle et al., 2010), and to alter connectivity between the default mode network and key nodes of the salience network, namely the anterior insula, dACC, sensorimotor regions and visual cortices (Clemens et al., 2017).In contrast, administration of corticosteroids reduces functional connectivity between the amygdala and a region corresponding to the LC (Hermans et al., 2017).These findings confirm that ELS impacts on activity between structures with dense NA receptors, which may facilitate altered basal states of vigilance and other anxiogenic behaviours (Clemens et al., 2017).

Concluding remarks and future perspectives
ELS is a well-established risk factor for the development of various mental health disorders later in life (e.g., MDD, ADHD and PTSD).As such, exposure to ELS is associated with increased likelihood of medication prescription, with those who have experienced 4 ACEs being 1.5x more likely to be on psychotropic medication than those with 0 ACEs (Manzari et al., 2019;Makris, 2023).Therefore, medicated individuals may develop a novel 'adaptive homeostatic state' and without this intervention these individuals may have otherwise developed abnormally.Therefore, understanding how these medications influence development after ELS is an area of interest which requires further study.Additionally, these mental health disorders exhibit distinct prevalence patterns and underlying neurobiological mechanisms (Swaab and Bao, 2020).This observation suggests potential moderating factors, such as sex differences, that may influence how ELS impacts mental health trajectories (Hakamata et al., 2022).This review suggests two promising lines of future research.
First, it will be useful to investigate sex-based variations in the locus coeruleus (LC)-noradrenaline (NA) system (Hakamata et al., 2022).Estrogen is linked to increased NA release (Bangasser et al., 2016), and females exhibit structural and functional differences within the LC, such as hypersecretion of the stress receptor CRF1 and heightened sensitivity of LC neurons (Bangasser et al., 2016;Perry et al., 2020).Elucidating how these sex differences in LC-NA dynamics interact with ELS is crucial for understanding how sex modulates the overall neurobiological consequences of early life stress (Hakamata et al., 2022).
Second, it would help to understand how altered expression of NA predicts brain volume changes following ELS.Regions that are part of the LC-NA network, such as the amygdala and hippocampus, show structural changes following ELS, but it needs to be demonstrated whether the whole of this LC-NA network is particularly sensitive to these formative experiences.Further structural changes in this network, in remote grey matter regions and in white matter integrity, could also explain the behavioural and physiological changes associated with ELS.Similarly, by mapping ELS-related changes in functional coupling within the LC-NA network we can develop greater understanding of how, and why, brain communication responds to early adverse experiences.
Thirdly, It is of note that different monoaminergic neurotransmitters likely vary in their developmental trajectory (for more information on this see review by Pitzer (2019).For example, it is known that dopamine and serotonin have clearer developmental changes in early life compared to NA.Although the consideration of other neurotransmitters is beyond the scope of this review, these trajectories could highlight greater sensitivity of other monoaminergic neurotransmitters to stressful events in childhood.The reasons behind these sensitivities are not yet clear and deserve greater study in future work.
Finally, this review highlights converging findings across analogous human and rodent models of ELS.By carrying out such cross-species work, we can gain insight into common principles underpinning how early stressors impact on brain structure and function.We can also further branch out into understanding the complex interplay of how other neurotransmitters interact with NA systems, influencing rapid non-genomic and slower genomic responses.

Fig. 2 .
Fig. 2. The Pyramid Model outlining the progression from ACE to early death based on the original CDC-Kaiser Permanente ACE study.

Fig. 4 .
Fig. 4. The LC-NA network adapted from Matchet et al. (2021).The rostral LC projections are blue, middle LC are yellow and caudal LC are red.Created with www.biorender.com.

Table 1
Adrenoceptor function and location.