Norepinephrine, neurodevelopment and behavior

Journal Pre-proof Norepinephrine, neurodevelopment and behavior Saboory Ehsan, Maedeh Ghasemi, Mehranfard Nasrin PII:

S0197-0186(20)30097-8

DOI:

https://doi.org/10.1016/j.neuint.2020.104706

Reference:

NCI 104706

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Neurochemistry International

Received Date: 24 January 2020 Revised Date:

14 February 2020

Accepted Date: 16 February 2020

Please cite this article as: Ehsan, S., Ghasemi, M., Nasrin, M., Norepinephrine, neurodevelopment and behavior, Neurochemistry International, https://doi.org/10.1016/j.neuint.2020.104706. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Ltd. All rights reserved.

Norepinephrine, neurodevelopment and behavior

Saboory Ehsan1, Maedeh Ghasemi2, Mehranfard Nasrin3* 1

Metabolic Diseases Research Center, Zanjan University of medical sciences, Zanjan, Iran.

2

Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3

Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran *Author for correspondence: Nasrin Mehranfard, Neurophysiolog Research Center, Urmia University of Medical Sciences, Urmia, Iran. E-mail: [email protected]

Abstract Neurotransmitters play critical roles in the developing nervous system. Among the neurotransmitters, norepinephrine (NE) is in particular postulated to be an important regulator of brain development. NE is expressed during early stages of development and is known to regulate both the development of noradrenergic neurons and the development of target areas. NE participates in the shaping and the wiring of the nervous system during the critical periods of development, and perturbations in this process can alter the brain’s developmental trajectory, which in turn can cause long-lasting and even permanent changes in the brain function and behavior later in life. Here we will briefly review evidence for the role of noradrenergic system in neurodevelopmental processes and will discuss about the potential disruptors of noradrenergic system during development and their behavioral consequences. Keywords: Neurodevelopment; Norepinephrine; Adrenergic receptors; Behavior; Locus coeruleus

1. Introduction Brain development is a highly organized and dynamic multistep process that occurs in precisely timed stages including neurogenesis, neuronal migration and differentiation (i.e. process of neuronal maturation, dendrite formation and synaptogenesis). These events occur during distinct time windows that span from the early embryonic stages to adulthood. Of the many factors involved in brain development, neurotransmitters have been shown to be principle players in the developing nervous system, and norepinephrine (NE) is in particular postulated to be an important regulator in this process (Felten et al., 1982; Gustafson and Moore, 1987; Lovell, 1982). In the brain, NE is produced primarily by noradrenergic neurons in the locus coeruleus (LC) (Loughlin et al., 1986; Robertson et al., 2013) and is released in almost throughout the brain areas. NE participates in a variety of behavioral and physiological processes such as arousal, learning and memory, attention, mood,

appetite, and stress reactivity (Levine et al., 1990; Berridge and Waterhouse, 2003; Rinaman, 2011; Sara and Bouret, 2012). Robust evidence shows an involvement of the LC adrenergic neurons in the regulation of brain development (Maeda et al., 1974; Coyle, 1977; Wendlandt et aL, 1977; Sievers et aL, 1981; Blue and Parnavelas, 1982; Felten et aL, 1982; Parnavelas and Blue, 1982; Lovell, 1982; Gustafson and Moore, 1987), supported by the studies that indicate noradrenergic fibers in the cerebral and cerebellar cortices are emerged before the development of cortical neurons (Lauder and Bloom, 1974; Yamamoto et al., 1977; Sievers et aL, 1981). NE is known to participate in the shaping and the wiring of the nervous system during the critical periods of development, but it opens a window where early life experiences could affect neuronal circuits and alter performance permanently. This developmental timeline is a critical period when noradrenergic activity can shape the development of the brain and, therefore, behavior. Hence, changes in NE transmission early in life have essential implications for behavior, cognitive and mental health throughout the lifespan. For example, a change in expression of key genes for regulation of noradrenergic transmission in rats during vulnerable periods of its development can cause an array of abnormal behaviors later in life (Shishkina et al., 2004a,b). Here, we will briefly review evidence for the role of noradrenergic system in neurodevelopmental processes and its implications for impaired brain development, and then will discuss about the critical periods during which developmental disruptions of NE may have an important role in the pathology of behavioral abnormalities.

2. Ontogeny of adrenergic innervation and the patterns of adrenoreceptor expression In rodent brain, noradrenergic neurons appear to be present between gestational day (GD) 10 and 13 (Coyle, 1977). Noradrenergic fibers project to the diencephalon (future thalamus and hypothalamus) at about GD 14 (Olson and Seiger, 1972), and the first noradrenergic innervation of the cortical and subcortical areas occurs between GD16 and 17 (Berger and Verney, 1984). Robust synaptogenesis of noradrenergic pathways appears to be between PNDs10-15 and 20-30 (Murrin et al., 2007) and the density of noradrenergic innervation reaches adult value in the third to fourth postnatal weeks (Coyle, 1977; Berger and Verney, 1984; Murrin et al., 2007). The enzymes involved in catecholamine synthesis are present in the rat brain at GD15 (Coyle and Axelrod, 1972a,b; Lamprecht and coyle, 1972). At this time, the level of NE is 2% of the adult level (Coyle and Henry, 1973), and reaches its adult level within 5-10 weeks of age (Kohno et al., 1982), thus, although LC noradrenergic neurons appear early in fetal brain development, the majority of noradrenergic maturity is acquired during 5-10 weeks of age. This developmental timeline of the noradrenergic system provides a vulnerable period during which increases or decreases in noradrenergic transmission may alter the development of neuronal circuitry and cause alterations in brain function and behavior. Different stages of noradrenergic system development in the rat brain are summarized in diagram 1.

3. Adrenergic receptors

NE signals through G-protein–coupled receptors α1, α2 and β, which in turn have three subtypes (α1A, α1B, α1D; α2A, α2B, α2C; β-1, -2, -3) (Ramos and Arnsten, 2007). In the central nervous system (CNS), adrenergic receptors (ARs) placed presynaptically on adrenergic neurons and postsynaptically on target cells. 3.1. α-ARs: In the developing rat brain, α-ARs are present at birth (Deskin et al., 1981). The number of αARs increases in most areas after birth and reaches a peak at about postnatal day (PND) 15 for α2-ARs (Happe et al., 2004) and between PNDs 15 and 20 for α1-ARs (Morris et al., 1980) (For review see Murrin et al., 2007). α-AR development in certain brain regions in rats has been shown to be before the appearance of NE nerve terminals (e.g. globus pallidus), while α-AR development in other brain regions such as olfactory bulb has been reported to be dependent on maturation of their noradrenergic presynaptic nerve terminals (Deskin et al., 1981; Jones et al., 1985). This suggests that other factors may also be responsible for the development of noradrenergic receptors. NE promotes cell replication via α-ARs during the first week of life (Duncan et al., 1990). α2A- and α2B-ARs have also been reported to be extensively expressed during neuronal migration and differentiation in the neocortex as well as in the caudate-putamen and cerebellum in embryonic rat brain which may mediate a neurotrophic effect on fetal brain development (Winzer-Serhan and Leslie, 1997, 1999). Furthermore, the timing of noradrenergic innervation of the cortex and hippocampus coincides with the developmental expression of α2-AR, suggesting α2-ARs play a role in synaptogenesis (Sanders et al., 2008). It has been reported that the functional maturity of cortical presynaptic α2-ARs, which inhibit NE release, is acquired between PNDs 1 and 7 in rat (Mirmiran, 1988), hence stimulation or blocking of these receptors during this period may alter the development of neural circuits in the cerebral cortex. In mice, the stimulation of α2-ARs at PND 20 has been shown to block short-term memory in young animals (Calvino-Núñez and Domínguez-delToro, 2014), possibly in part via inhibiting the LC firing activity. Effects of α2-ARs stimulation on brain development appear to be partly via activating extracellular signal–regulated kinase (ERK) and immediate early genes (IEGs) signaling pathways. For example, the α2-ARs stimulation leads to activation of ERK in developing but not in adult CA1 hippocampus (Vanhoose et al., 2002). ERK activation during critical periods has been suggested to be important for proper development of brain functioning and its transient suppression at PND 6 has been shown to result in autistic phenotypes such as social deficits, cognitive impairment and decreased long-term potentiation in mice (Yufune et al., 2015). Furthermore, increased activation of the ERK pathway in the hippocampus of neonatal BTBR mice (a mouse model of autism) has been shown to be associated with altered development of dendrites, which in turn could potentially lead to aberrant hippocampal function and behavior observed in the animals (Cheng et al., 2017). Thus, perturbed α2-adrenergic neurotransmission during the critical period may be linked to defects in ERK signaling and its relevant neurodevelopmental disorders. Results from neonatal NE lesions also indicate that α2-ARs differentially regulate the expression of IEGs of Arc, zif268 and c-fos in developing and adult rat brain and suggest that α2-AR activation increases the expression of IEGs of Arc, zif268 and c-fos in developing rat brain, while declines their expression in adult brain (Sanders et al., 2008). These transcripts have been suggested to be involved in brain development (Sanders et al., 2008; Velazquez et al., 2015) and also play an essential role in learning and memory (Minatohara et al., 2016). Thus, changes in α2-ARs signaling during development may cause abnormally postnatal IEGs expression, which in turn could have significant outcomes on the normal brain development and learning and memory. Regarding α1-AR, direct excitatory projections from ventral hippocampus to prefrontal cortex (PFC) seem to be essential for the normal development of α1-AR, since neonatal ventral hippocampus lesion in rats

has been shown to lead to dysregulation of PFC α1-AR signaling with an aberrant protein kinase C and ERK1/2 activation, which in turn significantly diminished the plasticity of glutamatergic transmission and impaired long term depression in this area in adult rats and may contribute to cognitive deficits (Kamath et al., 2008; Al-Khairi et al., 2009; Bhardwaj et al., 2014). 3.2. β-ARs: β-ARs are present early in development. In the rat cerebral cortex, β-AR density increases after birth and reaches greater than adult values within two to three weeks of age, and then attains adult levels during several months, while in the cerebellum, β-AR density gradually enhances at PND 5 and reaches adult levels around 6 weeks of life (For review see Murrin et al., 2007). Forebrain β-ARs were first detected at about GD15 (Bruinink and Lichtensteiger, 1984; Schlumpf et al., 1987). The density of βARs in forebrain is higher than cerebellum/medulla pons regions, suggesting an important developmental role for the receptors in forebrain (Erdtsieck-Ernste et al., 1991). Thyroid hormone has been proposed to be essential for normal development of β-AR and its signaling transduction components including adenylate cyclase, ornithine decarboxylase (ODC) and c-fos expression (Wagner et al., 1994b). In addition, thyroid hormone could affect differentiation and maturation of astrocytes via an increase in βAR activity (Ghosh and Das, 2007). Hence, thyroid hormone deficiency during fetal and postnatal development may disrupt normal development of β-AR signaling and likely astrocytes. Functional development of β-ARs occurs when their stimulation results in the activation of β-adrenergic signal transduction pathway. Cyclic AMP (cAMP) is the second component of β-adrenergic signal transduction pathway and has been shown to increase markedly during prenatal and in the first two weeks postnatally (Harden et al., 1977; Walton et al., 1979). The cAMP, in turn activates the cAMP-dependent protein kinase (PKA) that phosphorylates numerous intracellular substrates to affect so many various aspects of neuronal function. β-ARs exert their trophic function in part via an increase in intracellular levels of cAMP and c-fos as well as activation of signaling molecule of ODC (Morris et al., 1983; Morris and Slotkin; 1985; Wagner et al., 1994a; Wagner et al., 1995), an enzyme obligatory for cell replication and differentiation (Morris and Slotkin; 1985). The β2-ARs are prenatally and early postnatally coupled to ODC, but NE-induced ODC activity appears to terminate during the period of robust synaptogenesis (Morris et al., 1983). The percentage of the β2-adrenoceptor binding in forebrain areas reduces from prenatal to adult life (Pittman et al., 1980; Erdtsieck-Ernste et al., 1991), while the density of the forebrain postnatally β1-ARs is increased in forebrain (Pittman et al., 1980; Erdtsieck-Ernste et al., 1991). The higher density of the forebrain β1-ARs postnatally coincides with, two postnatal events, synaptogenesis (Coyle, 1977; Berger and Verney, 1984) and increase in glia/neuron ratio (Parnavelas et al., 1983), consistent with the idea that states synaptogenesis is regulated by glial cells (Pfrieger, 2009), although a possible role of β2-AR in maturation of glia cell has also been indicated in culture (Ghosh and Das, 2007). This suggests that both β1- and β2-ARs postnatally contribute to synaptogenesis of adrenergic pathways partly via an effect on glia cells, with a predominant effect of β1-ARs. β-ARs were found to inhibit cell division during robust synaptogenesis and intense increase in synaptic activity in developing rat brain regions (Slotkin et al., 1988; Duncan et al., 1990). This negative trophic effect of β-ARs is specific region and seems to involve β2-AR subtype. This may be related to maturational profiles of β2-ARs as well as a selective loss of ODC (that plays an important role in cell replication) response to β2-ARs in specific brain regions. For example, β2-adrenergic stimulation of ODC activity in the cerebral cortex reduces in the first week of age correspond with a reduction in the percentage of β2-ARs in forebrain areas during this time, while β2 stimulation of ODC activity in the

cerebellum still continues into 2 weeks of age consistent with a high percentage of the receptor binding in the region (Morris and Slotkin; 1985). NE via β1 and β2-AR activation causes anti-inflammatory and neuroprotective effects in organotypic hippocampal CA1 slices from developing mice brain (Markus et al., 2010), possibly in part via an increase in cAMP (Slotkin et al., 2003). A study performed by Toshimitsu et al also supports a possible neuroprotective role of NE in neonates in part via an increase in the phosphorylation of cAMP response element-binding protein (pCREB) in the brain (Toshimitsu et 2018). β-ARs may also stimulate apoptosis in neuronal cells in part via an increase in cAMP. Protein kinase A (PKA) is proposed to mediate proapoptotic responses to cAMP, but more transient PKA activation due to receptor desensitization generally prevents pro-apoptotic effects of cAMP (Insel et al., 2012). In contrast to mature brain, fetal and newborn tissues are resistant to β-AR desensitization (Slotkin et al., 2001; Slotkin et al., 2003), a critical homeostatic mechanism that protects cell from prolonged overstimulation of the receptors. Hence, long term overstimulation of β-AR during pregnancy or in newborn (PND 0-7) may have adverse effects on function of specific brain regions as well as on behavior (Witter et al., 2009). For example, prenatal exposure to terbutaline, a β2-adrenoceptor agonist which fails to evoke β2-AR desensitization, has been shown to have adverse effects on cellular differentiation and synaptogenesis in developing brain rat (Slotkin et al., 1989), possibly in part via an increase in cAMP (Slotkin et al., 2003). Thus, although the inability to desensitize β-AR signaling in developing brain may contribute to the preservation of noradrenergic trophic input to immature targets, it may also induce neurochemical and functional disruptions that enhance risk of cognitive and psychiatric disorders (Pitzer et al., 2001; Witter et al., 2009).

4. Locus coeruleus-norepinephrine (LC-NE) system in developing brain Studies indicate that several electrophysiological events occur in LC neurons during different stages of development to acquire adult functional and physiological characteristics. Some examples are as follows (Also see Diagram 2). During the first 9 PND, infants are very dependent on their mother and learn to identify their mother’s odor and receive care, a type of learning which known as infant attachment learning, and is critical for pups’ survival. During this time, infants readily learn the attachment, while aversion and fear learning are attenuated (Moriceau et al., 2010). After PND10, offspring can learn aversions. This ability of infants to learn the attachment and to decrease their ability to attain aversions during the first 9 PND seems to be partly due to hyper-functioning LC. The infant attachment learning is supported by the hyper-functioning LC that is required for a substantially increase in NE release into the olfactory bulb (Sullivan, 2001; Landers and Sullivan, 2012). Previous studies have indicated an important role of the infant attachment learning in shaping behavior in adult (Sevelinges et al., 2007; Raineki et al., 2010; Sevelinges et al., 2011). For example, rat pups exposure to novel odor-0.5 mA shock conditioning (an animal model of abusive attachment) from PND 8 to 12 has been shown to attenuate adult fear conditioning, increase depression-like behavior and is associated with a deficit in amygdala and olfactory cortex functions in adulthood (Sevelinges et al., 2007; Sevelinges et al., 2011). Hence, LC activity disruptors such as early life stress during the sensitive period (during the first 9 days after birth) for the attachment learning have adverse impacts on subsequent behaviors in adult (Moriceau et al., 2009b). The hyper-functioning LC has

been suggested to be due to a lack of α2-ARs on LC neurons, which suppress LC firing and subsequent NE release into the olfactory bulb (Nakamura et al., 1987; Nakamura and Sakaguchi, 1990; Marshall et al., 1991; Winzer-Serhan et al., 1997). Both α1- and α2-ARs are present on the somadendritic membranes of LC neurons in developing brain (Nakamura and Sakaguchi, 1990) which are activated by NE released from the terminals of recurrent axon collaterals and play an important role in the regulation of LC neurons activity. While NE has an inhibitory effect on LC neurons firing in mature brain, it produces a dual impact on LC firing in developing brain in a dose-dependent manner; high concentrations of NE via α2ARs inhibit and low levels of NE via α1-ARs stimulate LC neurons (Nakamura and Sakaguchi, 1990). The LC α2- receptors are present on LC at birth, but they appear to be functional about at PND 10 (Winzer-Serhan et al., 1997; Rankin, 2002), which in turn is associated with a reduced ability of rats to learn odors (Landers and Sullivan, 2012). Under normal conditions, stress exposure leads to LC activation which in turn results in NE release in certain structures responsible for reactions to stress including the amygdala, the hippocampus, the prefrontal cortex and the paraventricular nucleus of the hypothalamus (PVN) to activate the HPA axis and alter cognitive function and arousal state in the response to stress. However, there is an attenuation of the hypothalamic PVN response to NE during the first PND 9, which in turn results in reduced HPA axis activity. This decreases synthesis and secretion of corticosteroids in the amygdala and reduces its activity, which in turn has been suggested to be one mechanism for an inability of infants to learn aversions and respond to the stressors during early stages of development (Shionoya et al., 2007). Fear learning appears to be hippocampal dependent and certain hippocampal adrenergic signaling components needed for fear learning are non-functional during the first PND 9 (Kabitzke et al., 2011), and this may be another possible mechanism for an inability in aversion learning. For example, in the hippocampus, NE via activation of β-AR has been shown to lead to contextual fear learning in juveniles but not in infant (PND 14) rats. At the molecular level, the fear learning is associated with β-AR increase in pCREB via cAMP stimulation in the hippocampus of the juveniles but not infant rats that possibly underlies transcription of immediate-early and late-response genes involved in learning (Kabitzke et al., 2011). Together, these data suggest that an interaction between the LC activity and NE signaling in the hypothalamus and the hippocampus as well as an appropriate activity of amygdala are important for fear learning during early development. Possible mechanisms for an ability of infants to easily learn the attachment and to decrease the ability to learn aversion during early postnatal life have been shown in diagrams 3 and 4. The LC neurons indicate spontaneous firing rate (SFR) that maintains basal noradrenergic tone in target brain areas, and in fetal and neonatal periods differs from that in adults. In fetal and neonatal rats, the majority of LC neurons have no spontaneous activity, while LC neurons indicating spontaneous activity discharge sporadically that is synchronous about among all neurons. These discharge patterns become periodic with age and in rats older than PND 20 switch from periodic to a tonic pattern of firing with increasing age (Kimura and Nakamura, 1985; Sakaguchi and Nakamura, 1987; Nakamura and Sakaguchi, 1990). Stress and its hormones have been shown to influence development of the noradrenergic system of the brain (Dygalo et al., 1991; Dygalo and Kalinina, 1993, 1994, 1996; Kreider et al., 2005; Green et al., 2011; Kalinina et al., 2013), in part via an effect on SFR of LC neurons. Under normal conditions, stress exposure leads to the release of corticotropin-releasing factor (CRF) into LC, which in turn shifts LC neurons discharge to a high tonic mode (Valentino and Van Bockstaele, 2008). At the same time, opioid drive is also increased to the LC neurons to restrain excitatory effect of CRF and restore the LC neurons discharge to the basal level after stressor termination (Curtis et al, 2001, 2012). This is an adaptive

response to stress that is thought to facilitate behavioral flexibility. However, a 180 min/day maternal separation (an animal model of early life stress) at PNDs 2–14 leads to a sustained high tonic LC activity in offspring rats at age 22–35 d (Swinny et al., 2010). This is a maladaptive response, resulting in a hyperarousal state and disruption of focused attention and is similar to that found in anxiety and posttraumatic stress disorder (Borodovitsyna et al., 2018). In addition, chronic social stress exposure during adolescence was found to cause a sustained activation of LC neurons in rats even after stress termination, while repeated social stress in adult rats relatively suppressed LC activity in the absence of the stressor (Zitnik et al., 2016), indicating an immaturity in mechanisms controlling LC neuronal activity during development. Abnormalities in SFR of LC neurons in developing brain following chronic exposure to stressors may be in part due to an imbalance between excitatory CRF and inhibitory endogenous opioid effects on the LC adrenergic neurons (Curtis et al, 2001, 2012), changes in α2-autoreceptors binding levels in the noradrenergic cell body of the LC (Liu et al., 2000), changes in γ-aminobutyric acid type B (GABAB) tonic inhibition through GABAB receptors on LC neurons (Wang et al., 2015) and likely in LC ion channels (Pachenari et al., 2019). The spontaneous activity of LC neurons in developing rats is tightly controlled by GABAB tonic inhibition through GABAB receptors which are found on LC neurons. There is a developmental increase in GABAB receptor-mediated tonic inhibition that maintains the SFR of LC neurons at a proper level and might be important for ensuring appropriate NE levels for the maturation of normal brain function (Wang et al., 2015). Effective antidepressant treatments have been shown to affect the GABAB receptor activity in developing and mature brain (West et al., 2010; Darling et al., 2011), but a precise role of GABAB tonic inhibition in immature brain remains unclear. A significant electrical coupling among LC neurons has been shown in brain slices from neonatal rats (Christie et al., 1989). Prior to PND 8, the electrical coupling is extensive with synchronized oscillations which is decreased at PND 8-21 and disappear beyond PND 21 (Patel and Joshi, 2015). Prior to PND 8, the coupling is excitatory mediated by α1-ARs, but thereafter α1-ARs vanish and the coupling is inhibitory (via α2-ARs) (Patel and Joshi, 2015). The coupling synchronizes membrane potential oscillations between LC neuron pairs and in neonates could promote synchronous increases in the NE release and cause a more effective excitation (Ishimatsu and Williams, 1996). This in turn may be important for the extensive positive trophic function of the noradrenergic neurons during development, and possibly for inducing and facilitating synaptic plasticity in brain regions associated with infant attachment learning including olfactory bulb. LC is known to play an important role in switching between the sleeping and waking states (Aston-Jones and Bloom, 1981; Takahashi et al., 2010). A concordance between shifting sleep– wake state and developmental reductions in the synchronized oscillations of LC neurons has been shown using a rat LC modeling and has been suggested to underlie the ability of the LC to modify and affect the development of sleep–wake cycling from infancy into adulthood (Patel and Joshi, 2015). Hence manipulations influencing the activity of LC-NE neurons during the sensitive period for shifting sleep– wake behavior (i.e. PND 8-21) could alter sleep/wake cycle. For example, treating rats with α2-AR agonist clonidine from 8 to 21 days of life causes a significant reduction in time spent in rapid eye movement (REM) sleep in the developing rats (Mirmiran et al., 1990). REM sleep deprivation in neonatal rats has been shown to increase apoptosis, decrease brain mass in developing brain (Morrissey et al., 2004) and lead to depression-like behaviors in adulthood (Feng and Ma, 2003). The electrical coupling between LC neurons is attributed to the existence of gap junctions between dendrites of LC neurons, in the peri-LC region (Ishimatsu and Williams, 1996), and manipulations influencing LC dendritic characteristics during early postnatal development particularly during the first 3 weeks of life may also

influence synchronized oscillations and sleep/arousal states. Maternal separation from PNDs 2–14 was found to lead to a decrease in LC dendritic length and branching in offspring rats at age 22–35 d (Swinny et al., 2010). Since dendrites of LC neurons extend preferentially into peri-LC region (Shipley et al., 1996), hence a reduction in LC dendritic length may lead to decreased synaptic coupling between LC neurons, which in turn may influence behavior. Sex differences in LC dendritic characteristics have been suggested to underlie a greater incidence of stress-related psychiatric disorders including depression and anxiety in women compared to men (Bangasser et al., 2011). Bangasser et al. (2011) compared LC dendritic characteristics between male and female rats and observed an increase in dendritic density in the peri-LC in female compared to male rats. LC dendrites of females were also longer and had a more complex pattern of branching. This in turn could increase synaptic contacts with various afferents terminating in the peri-LC and result in a hyperarousal state that has been suggested to be a symptom of stress-related psychiatric disorders. The presence of coupling between LC neurons in adult animals is difficult to be demonstrated directly (Travagli et al., 1995), but under certain conditions, synchronous activity is produced in adult animals (Travagli et al., 1995; Ishimatsu and Williams, 1996; Zhu and Zhou, 2005). For example, morphine induces synchronous oscillatory activity in the LC of adult rats, this in turn could alter NE release in LC target areas and induce synaptic plasticity leading to opioid abuse (Zhu and Zhou, 2005). The present findings suggest that a reduced coupling among LC neurons with age may be one mechanism by which the LC promotes an appropriate response to stressors and decrease stress vulnerability. Other forms of early life stress have been shown to affect morphology and survival of LC adrenergic neurons. For example, neonatal hypoxic/ischemic injury in human and neonatal handling in rats were found to induce a reduction in size of LC neurons of the human neonate (Pagida et al., 2016) as well as in volume of LC nucleus of neonatal rats (Lucion et al., 2003). A significant association was also found between maternal smoking and fetal/neonatal defects in human LC complex. These developmental defects include hypoplasia and a high rate of LC neuronal death likely induced by a reduction in neuromelanin accompanied by fetal/neonatal sudden unexplained death (Lavezzi et al., 2013). Neuromelanin is a dark pigment which is largely found in catecholaminergic neurons of the LC and substantia nigra pars compacta in the human brain and its reduction increases vulnerability of neuromelanin-containing neurons to cell death (Fedorow et al., 2005; Sasaki et al., 2006). Loss of the LC noradrenergic neurons is thought to play a principal role in the pathogenesis of Parkinson's disease and pharmacological treatment increasing NE bioavailability have been suggested to cause neuroprotective effects (O'Neill and Harkin, 2018). Since some studies have suggested a developmental component for Parkinson disease (Riederer, 2003; Oliveira et al., 2017; Schwamborn, 2018), hence the degeneration of LC adrenergic neurons targeting substantia nigra during early postnatal development may contribute to increased susceptibility to this disorder later in life. In addition to main noradrenergic neurons originating from LC, early life stress has been shown to affect adrenergic system in nucleus tractus solitaries via an effect on α2-ARs. Some neuronal subpopulations in the nucleus tractus solitaries are noradrenergic cell group A2 that provide the bulk of noradrenergic innervation to the central amygdala (CeA) and implicate the amygdala as a principal integrator of physiologic and behavioral responses to stress (Kravets et al., 2015). Early stress was found to increase α2-autoreceptors binding levels in nucleus tractus solitaries in adult rats (Liu et al., 2000). This could affect NE release in the CeA, which in turn may contribute to dysregulated responses of the amygdala to stress (Williams et al., 2000; Clayton and Williams, 2000).

5. Developmental influences of noradrenergic modulation Previous studies have shown that negative early-life events and stress episodes can affect neurodevelopment in part via early disruptions of NE receptor signaling. For example, exposure to prenatal or early postnatal malnutrition leads to a reprogramming of the brain noradrenergic signaling, altering cognitive function and performance in attentional tasks (McGaughy et al., 2014; Mokler et al., 2019), possibly in part via a long term attenuation of NE turnover in cerebral cortex and cerebellum, a reduced α2- and β-adrenergic binging sites in cerebral cortex (Seidler et al., 1990) and a transient overexpression of α2C-AR in the frontal and the occipital cortices during early postnatal life (Walter et al., 2006). In addition, prenatal stress in rats resulted in a delayed development of α1-ARs in cerebral cortex of 16 day-old offspring and decreased α2-receptor binding in most brain regions in adult offspring (Peters, 1984a). Exposure to abuse substances has also been shown to induce behavioral and brain neurochemical changes in the offspring, at least in part, via an involvement of NE system. For example, in utero exposure to cocaine results in increased plasma NE concentrations in infants with neurobehavioral perturbations at 1 to 3 days of life (Mirochnick et al., 1997). Chronic neonatal nicotine exposure from PND 1 to PND 7 has also been shown to enhance responsiveness to stress and anxiety later in life, in part via a significant reduction in the LC IEGs of c-Fos, Egr-1 and Npas4 (Halawa et al., 2018). In addition, prenatal nicotine exposure is associated with an increase in NE levels in cortex and hypothalamus in infancy as well as with a significant increase in AR-binding in cerebral cortex in adult offspring (Peters, 1984b). This increase in NE transmission of offspring may enhance the risk of substance abuse later in life, consistent with idea that states the elevated noradrenergic signaling can be an etiological factor in the abuse of a variety of substances (Fitzgerald, 2013). This idea originates from a set of studies that indicate both acute and chronic use of a wide range of commonly abused drugs affect noradrenergic signaling. Acute withdrawal after long term use of several abused drugs boosts noradrenergic signaling and NE transmission decreasing drugs including clonidine and guanfacine have been shown to reduce withdrawal symptoms. Noradrenergic signaling is also increased during psychological stress, a condition that has been shown to promote relapse of drug seeking in susceptible individuals. Considering these data and results from several genetic studies, it was suggested that an increase or dysregulated endogenous NE signaling, which may be prior to drug abuse, likely contribute to etiology of the abuse of a variety of substances (Fitzgerald, 2013). Genetic and pharmacologic models of perturbed NE neurotransmission during sensitive periods of brain development also indicate changes in certain neural circuitry that produce (mal)adaptations in these areas and increase risk for psychiatric disorders. For example, the ability of the cerebral cortex to respond to environmental enrichment is decreased following early postnatal disruption of NE signaling with α2-AR agonist clonidine (Mirmiran and Uylings, 1983; Mirmiran et al., 1983). Furthermore, a short term decrease, by RNA interference or antisense oligonucleotide, in expression of the gene of the α2A-AR in neonatal rat brainstem on the days 2-4 of life reduced anxiety-related behavior (Shishkina et al., 2004a) and acoustic startle response in adult rats (Shishkina et al., 2004b). Disruptions in sensorimotor gating including acoustic startle response are reported to specific neuropsychiatric disorders including schizophrenia, attention deficit hyperactivity disorder and autism (Braff et al., 1992; Cadenhead, Geyer, & Braff, 1993; Castellanos et al., 1996; Ornitz et al., 1999; Swerdlow et al., 1995; Perry et al., 2007). Polymorphisms of α2A- and α2C-AR genes have also been suggested to cause developmental

dysregulations of central noradrenergic and have been linked with childhood attention deficit hyperactivity disorder (Park et al., 2005; Cho et al., 2008). In addition, knock down of growth arrest and DNA-damage-inducible beta (Gadd45b) in the neonatal rat amygdala resulted in a programmed decrease in the expression of α2-ARs in juvenile rats, which in turn may in part be responsible for altered social behavior observed in the animals (Kigar et al., 2015). Gadd45b gene is involved in modulating the cellular response to stress and has been suggested to play a role in the etiology of several psychiatric disorders and alcohol-drinking (Gavin et al., 2012; Kigar et al., 2015; Gavin et al., 2016; Labonté et al., 2019), likely in part via an altered NE signaling. Moreover, deletion of Engrailed-2 (En2) gene in mice in PNDs 7-21 has been reported to cause a disruption in NE signaling (Genestine et al., 2015). This suggests that neonatal period of 7-21 is a critical time for normal development of NE system in mice. The En2 gene is known to play a role in pathogenesis of neurodevelopmental disorders, particularly autism spectrum disorder (Choi et al., 2014), and may contribute to some neurodevelopmental disorders involving noradrenergic dysregulation. Genetic models of perturbed NE neurotransmission have produced evidence that indicate interference with β-AR activation during early postnatal development results in an abnormal hippocampal neurogenesis (Genestine et al., 2015). Disrupted β-neurotransmission during sensitive periods of development could also cause behavior deficits later in life, since, β-ARs are involved in certain types of early learning including olfactory-based attachment learning which is critical to subsequent behavior in adulthood (Wilson et al., 1994; Landers and Sullivan, 1999; Sullivan et al., 2000; Sevelinges et al., 2007; Moriceau et al., 2009a; Raineki et al., 2010; Sevelinges et al., 2011). Prenatal exposure to β2-adrenergic agonists has been shown to increase the risk of cerebral palsy in female offspring (Li et al., 2018). Cerebral palsy is a common neurodevelopmental disorder in childhood and is reported to be associated with a high prevalence of mental health problems (Foster et al., 2010; Bjorgaas et al., 2013). Several studies have also revealed an increased risk for autism spectrum disorders in juvenile rats (Slotkin et al., 2003; Rhodes et al., 2004; Meyer et al., 2005; Zerrate et al., 2007) as well as among children (Croen et al., 2011) following early developmental exposure to some β2-adrenoceptor agonists such as terbutaline, depending on β2-AR agonist dose, duration of the exposure, and developmental period of β2-AR agonist used (Witter et al., 2009). Chronic prenatal β-antagonist propranolol exposure leads to a reversible upregulation of fetal β1-ARs in the rat brain with brain NE activity in later life (Erdtsieck-Ernste et al., 1993) as well as an increase in the number of β-adrenergic binding sites in the cerebral cortex of offspring rats at postnatal age 21 days (Miller and Friedhoff, 1988), this in turn may lead to overstimulation of the β-ARs and cause adverse effects on brain development in immature brain as well as on behavior later in life. Early postnatal treatment of rats with propranolol during PNDs 7-20 resulted in an increased NE levels in the limbic forebrain and cerebellum and was associated with a reduction in the percentage of active sleep as well as an increase in waking and in voluntary alcohol consumption in adult rats (Hilakivi et al., 1988). PND 7 to PND 20 is a critical time that overlap with a time period when the noradrenergic neurons play an important role in switching between the sleeping and waking states (i.e. PND 8-21). Therefore, a disturbance in wake/sleep state by use of propranolol during the critical time suggests a role of β-ARs in the regulation of wake/sleep cycling during development. Together, these data suggest that increases in β-AR activity during sensitive periods of brain development can affect the organization and functioning of noradrenergic system later in life. Nevertheless, rat neonatal experience involving reward also increases NE levels in the PFC of neonatal and adulthood as well as enhances expression of mRNA and protein levels of β1-ARs and its downstream

effector pCREB in the PFC in adulthood accompanied by an increase in cognitive performance of the animals (Kalpachidou et al., 2016). This suggests that an increase in noradrenergic transmission in stressassociated circuits and reward-associated ones during critical periods of development acts in an opposite manner to program the function of the noradrenergic system both at the neurochemical and behavioral level in adulthood.

6. NE depletion studies Multiple studies have investigated brain development and behavior in the absence of the noradrenergic system. Most studies relied on LC lesions with electrolytic lesions or with the injection of neurotoxins of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or 6-hydroxydopamine (6-OHDA) (Maeda et al., 1974; Wendlandt et al., 1977; Schmidt and Bhatnagar, 1979; Jaim-Etcheverry and Zieher 1980; Blue and Parnavelas, 1982; Lovell, 1982; Medina and Novas 1983), while few studies relied on genetic or pharmacological disruption of NE synthesis (Mirmiran et al., 1988; Mirmiran et al., 1990; Gorter et al., 1990; Jin et al., 2004). These studies may provide essential insights into the mechanisms by which developmental noradrenergic changes and the timing of those changes affect behavioral outcomes later in life. The LC provides the only source of NE to the cerebral cortex and its lesions during neonatal produces a marked and long-lasting depletion of NE concentrations (Jaim-Etcheverry and Zieher 1980; Medina and Novas 1983; Schmidt and Bhatnagar, 1979), which in turn could influence the normal development of the cerebral cortex. For example, LC lesions during early postnatal life were associated with abnormality in cortical differentiation in rat (Maeda et al., 1974; Wendlandt et al., 1977). In addition to NE, this abnormality in cortical development in part may be due to a lack of trophic effect of brain-derived neurotrophic factor (BDNF) following LC lesion, since in addition to NE, LC adrenergic neurons appear to release BDNF during development which has been shown to promote cortical neuron survival and differentiation (Fawcett et al., 1998). In addition, LC lesion during the first 4 days of postnatal life significantly increased synaptogenesis in the cortex of lesioned rats during the first week, but the density of synapses had not significant changes during the second postnatal week, and at day 90 (Blue and Parnavelas, 1982). This in turn led to behavioral abnormalities particularly deficits in behaviors-related to attention (Berger-Sweeney and Hohmann, 1997). These data indicate that the NE exerts an inhibitory effect on synapse formation in the cortex during the first week of life, possibly via an effect on β-ARs. In fact, NE appears to have a dual effect on brain development and there is evidence suggesting that NE promotes brain development via α-ARs during the first week of life, while exerts an inhibitory effect via β-ARs during this time (Duncan et al., 1990). NE depletion with 6-OHDA has been shown to result in arrest of the cerebellar development (Lovell, 1982). Nevertheless, genetic approach of disrupting the dopamine beta-hydroxylase gene to produce mice lacking NE shows that NE is not essential for the appearance, proliferation, or survival of both adrenergic neurons and cerebellum (Jin et al., 2004). In contrast to cerebral cortex, neonatal LC lesion leads to a progressive rise in the NE levels in the cerebellum (Jaim-Etcheverry and Zieher 1980; Medina and Novas 1983). This may be, at least in part, because LC lesions are associated with a compensatory axonal sprouting of LC neurons in the cerebellum (Schmidt and Bhatnagar, 1979), possibly in an effort for preserving extracellular levels of NE that may decrease the extent and severity of alterations in this

region. Also, some observed phenotypes with 6-OHDA may be due to toxic effects of 6-OHDA on dopaminergic terminals and co-transmitters released with NE such as ATP, neuropeptide Y, and galanin (Sievers et al., 1980; Lundberg et al., 1990; Hokfelt et al., 1998; Mulryan et al., 2000). For example, neuropeptide Y was found to strongly promote survival of cerebellar granule cells in the presence of other neuromediators such as NMDA or GABA during development (Neveu et al., 2002). Even though NE is not essential for the acquisition of the cerebellar phenotype, it has been shown to exert a facilitatory effect on maturation of the cerebellar function during early postnatal days. For example, NE increases inhibitory responses of cerebellar Purkinje cells to GABA during early postnatal days, before periods of extensive morphological differentiation (Yeh and Woodward, 1983a). It also exerts a profound modulatory effect on responses of immature Purkinje cells to activation of newly-established inputs by PND 5 (Yeh and Woodward, 1983b). NE may thereby contribute to the wiring of neuronal circuit in the cerebellum during early development. Results from neonatal NE depletion in rats suggest that NE during early development plays an important role in programming responsiveness of its own receptors and other neurotransmitter systems in the brain. NE appears to play an important role in trophic control of differentiation as well as in preventing supersensitivity of β-ARs and thus teratogenesis related to β-AR hyperactivity, via an effect on reactivity of c-fos to cAMP stimulation (Wagner et al., 1995). NE neonatal depletion with α2-AR agonist clonidine also been shown to result in supersensitivity of hippocampal CA1 cells to NE in adult rats via inducing a markedly stronger depression of glutamate-evoked activity of CA1 pyramidal neurons by NE compared to control group (Gorter et al., 1989), thereby retarding epileptic activity in the animals (Gorter et al., 1990). Noradrenergic neurons are found to have a great effect on the development of dopamine receptor sensitivity. A D2 dopamine receptor supersensitivity during perinatal period has been shown to cause cognitive deficits and increase susceptibility to schizophrenia in rats (Kostrzewa et al., 2016), and neonatal NE depletion in rats has been shown to decrease D2 dopamine receptor supersensitivity (Nowak et al., 2006). A role of NE in development of dopaminergic system is also supported by a study that indicated prenatal nicotine exposure leads to an increase in dopamine level and a decrease in Catechol-Omethyl transferase (COMT)-dependent dopamine turnover (Dwyer et al., 2019) in PFC of adolescent rats due to a reduction in the levels of PFC norepinephrine transporter (Dwyer et al., 2019), a transporter that is thought to provide primary reuptake mechanism of dopamine in the PFC (Moron et al., 2002). NE-denervated PFC with DSP-4 at PNDs 1-3 was found to increase GABA level in PFC of adult rats compared to control group (Bortel et al., 2008) and NE depletion with α2-AR agonist clonidine at PNDs 8-21 was reported to induce more potent inhibition of GABA in adult PFC (Mirmiran et al., 1990). An altered GABAergic activity in the prefrontal cortex during development has been suggested to be a potential important component of the pathophysiology of psychosis (Benes et al., 1996), and GABA receptor activation in the medial PFC has been shown to induce an anxiolytic-like response in rat (Solati et al., 2013). Neonatal LC lesion also leads to desensitization of 5-HT1A autoreceptor (which regulates 5-HT release and is involved in the pathogenesis of depression) accompanied by an increase in 5-HT release in the brain and an antidepressant-like effect in adult rats (Dabrowska et al., 2004; Dabrowska et al., 2008). β‐ ARs were found to control the activity of dorsal raphe serotonergic neurons during the first 2 weeks of

age in rats, while exert a weak influence in adults (Waldmeier; 1981; Lanfumey and Adrien, 1988a; Bortolozzi and Artigas, 2003; Haj-Dahmane and Shen, 2014). A neonatal noradrenergic lesion, however, leads to a sustained β-regulation of dorsal raphe neuronal firing in adult rats (Lanfumey and Adrien, 1988b), suggesting that transient regulation of raphe neurons firing by β-ARs during early postnatal development may be important for correct development of the raphe neurons function. These developmental alterations in the raphe neuronal activity may influence emotional behavior in later life, consistent with the hypothesis that a change in the activity of dorsal raphe serotonergic neurons results in altered affection state (Challis et al., 2013; Teissier et al., 2015; Asaoka et al., 2017; Nishitani et al., 2019).

Conclusions Present evidence demonstrates the crucial significance of an intact noradrenergic system for the proper development of brain structure and function. NE acts as a trophic factor specifically during fetal and early postnatal development, and AR activity forms an essential part of a signaling cascade leading to developmental events such as proliferation, neuronal migration and differentiation all of which can participate in the shaping and the wiring of the nervous system. NE also interacts to other neurotransmitters to yield a net effect on neuronal maturation. Perturbations of these processes could alter developmental trajectory and contribute to CNS disorders. There are important developmental differences in noradrenergic receptor function between developing and mature brain. Although, the underlying mechanisms for these differences remain mostly unknown, it could be partly due to different regulation of transcription factors by ARs as well as to the existence of differences in the time of appearance and differentiation rate of neuronal pathways in developing and mature brain. This ontogenetic heterogeneity may describe, partly, the anomalous responses of developing animals to pharmacological treatments compared to mature animals. Environmental and social challenges during vulnerable periods of brain development produce disrupted NE signaling in several brain regions with (mal)adaptations in these areas and phenocopy some features of brain disorders. Further experiments are required to establish potential mechanisms by which different challenges may affect noradrenergic signaling during development and to determine their behavioral outcomes. Understanding the effect of early alterations in noradrenergic signaling offers profound insights that might describe patterns of individual differences in susceptibility to brain disorders later in life.

Abbreviations ARs- adrenergic receptors cAMP- cyclic AMP CNS- central nervous system CREB- cAMP response element-binding protein DSP-4- N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

ERK- extracellular signal–regulated kinases GABA- γ-aminobutyric acid GD- gestational day HPA- hypothalamic-pituitary-adrenal IEGs- immediate early genes LC- locus coeruleus NE- norepinephrine ODC- ornithine decarboxylase 6-OHDA- 6-hydroxydopamine PFC- prefrontal cortex PKA- Protein kinase A PND- postnatal day REM- rapid eye movement SFR- spontaneous firing rate

Conflict of interest The authors have declared no conflict of interest.

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Highlights -

NE acts as a neurotrophic factor and interacts with other neurotransmitter systems including GABA, glutatmate, dopamine and serotonin systems to yield correct development of brain.

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NE signaling is important for experience-dependent plasticity in developing brain, and its disruptions during early postnatal development can alter responses of organism to novel situations.

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Interactions between the LC, the amygdala, the hypothalamus and the hippocampus are important for fear learning during early development and α- and β-ARs signaling play an essential role for this type of learning.

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The timing of α2- and β-AR expression in the brain during early postnatal development is important for acquisition of some types of early learning including attachment and associative learning, which in turn are critical for subsequent behavior in adulthood.