Norepinephrine Structure, Function, Physiology, and Dysfunction
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Norepinephrine (NE) or noradrenaline as it is also referred to, is a dynamic catecholamine neurotransmitter with extensive distribution in the brain and spinal cord, It is principally derived from the locus coeruleus (LC), a small brainstem nuclei in mammals. NE is evolutionarily conserved in vertebrates, and is proposed to be integral for species survival as a neuromodulator and hormone. It is the chief neurotransmitter of central noradrenergic and peripheral sympathetic post-ganglionic neurons, and the ganglia of chest, abdomen, and other visceral organs. As it is an extremely influential neurotransmitter throughout the nervous system, dysfunction in the noradrenergic system encompasses a vast repertoire of clinical conditions, including psychiatric, neurologic, and cardiopulmonary disorders, making it a compelling target for treatment.
Norepinephrine functions in expansive behavioral and physiological processes, and it’s release at target sites in the nervous system plays a pivotal role in arousal, vigilance, cognitive flexibility, sleep-wake cycle, appetite, nociception, and ‘fight-or-flight’ response, all essential for maintaining homeostasis. The boost in NE release upon encountering noxious conditions is experienced as the ‘adrenaline surge’ in everyday parlance.
Noradrenaline also participates in higher-order cognitive functions such as, attention, memory, decision making, mood, sensory perception, and motor function. Along with dopamine, NE is intimately associated with the function of the prefrontal cortex (PFC) and working memory, with both neurotransmitters exhibiting an inverted U-shaped influence on cognition, with low and high levels being detrimental and moderate levels being beneficial for optimal function. Because the PFC is highly sensitive to levels of neurochemicals, dysregulation is implicated in many neuropsychiatric disorders and neurologic dysfunction, such as Attention Deficit Hyperactivity Disorder (ADHD), Post-Traumatic Stress Disorder (PTSD), Parkinson’s (PD) and Alzheimer’s disease (AD), age-related dementia, traumatic brain injury (TBI), and other mental illnesses, including depression, and pain. In this regard, agents that target the noradrenergic system have been deployed in treating and alleviating the symptoms of these and other disorders. The α-2A adrenergic receptor (AR) agonists, clonidine and guanfacine, have been shown to improve deficits in working memory, and atomoxetine is effective for ADHD.
At the physiological level, discharge of adrenergic neurons is tied to behavior as the neurons exhibit tonic firing during moderate arousal and robust phasic firing when experiencing salient and significant sensory events. In short, tonic LC-NE activity is observed to be non-existent during REM sleep, and increasing arousal galvanizes the system and ramps up NE levels in stressful conditions - meaningful for stress-related disorders. Phasic firing in contrast is associated with interest in the task or experience. Thus, these temporal transitions in firing patterns are relevantly and physiologically linked to behavior, more advertently for adaptive behavior.
As previously mentioned, the LC-NE system is persistently and potently activated under stressful conditions and is integral to the ‘stress circuit’. Indeed, owing to its substantial regional connections to areas crucial for survival and executive function, and its divergent roles as a neuro-transmitter, -modulator, and hormone, NE is leveraged to bridge cognitive function with the activities of the sympathetic nervous system. The swift and global modulation of brain function in response to changing environmental conditions, its capacity in modulating arousal states, vigilance, and cognitive flexibility, makes norepinephrine essential in mounting quintessential, intuitive, and adaptive responses. In addition to its well established role in stress, NE is a key actor in other aversive states like anxiety and depression, and as a result discord in the LC-NE system is consequential for the development of neuropsychiatric illnesses.
NE is also synthesized peripherally, in the adrenal chromaffin cells (CC) of the sympathetic nervous system, and is deployed in the classic ‘fight-or-flight’ response under stressful, threatening conditions. Acetylcholine from preganglionic splanchnic fibers figures into this scenario by binding to nicotinic receptors on adrenal chromaffin cells that via Ca2+-dependent mechanisms, trigger the release of NE and epinephrine into the bloodstream - a scenario of ‘stimulus-secretion coupling’. The resultant increase in these catecholamines serves to regulate vasoconstriction and vasodilation, whereby - increased blood is diverted to the skeletal muscles and heart, boosting their ability and potential for action in challenging situations; restricting blood supply to the ‘rest and digest’ systems in the periphery and internal gastrointestinal organs; mobilizing glucose from the liver to supplement energy demands; dilating pupils and pulmonary bronchioles to enhance visual acuity and respiration, respectively - all in service of ‘fight-or-flight’, underscoring the significant advantage the noradrenergic system confers to survival.
The LC-NE neurons, with their massively ramified axonal arborizations were historically thought to be homogenous. The prevailing view was that they were structurally similar and released norepinephrine simultaneously and indiscriminately, inevitably globally, in all regions of the brain and spinal cord. Accordingly, the LC-NE was considered to act uniformly and simultaneously on cells and circuits in order to influence brain function and general arousal. Convergence of anatomical, mechanistic, molecular, pharmacological, structural evidence over recent past decades, and robust ongoing work is making it abundantly clear that these divergent projections also retain a more functionally segregated, modular organization, with independent and selective targeting of discrete regions, and discriminate and differential neurotransmitter release and activity. Evidence strongly points to individual subsets of LC-NE neurons receiving similar inputs from the autonomic nervous system (ANS) specifying the arousal state of the organism, additionally, they receive selective and specific cortical inputs that command influence on their individual cognitive processing. In these ways - with different spatiotemporal innervation patterns, heterogeneity of receptors, molecular expression patterns - complex modes of NE-LC global reach is specialized to determine adaptive responses.
Synthesis and Metabolism
Norepinephrine (NE), like dopamine, from which it is derived, is released centrally and peripherally, and is synthesized from the aromatic amino acid precursor tyrosine. It consists of a catechol group, i.e., a benzene ring with 2 hydroxyl sidechains and an amine group linked by an ethyl chain (Figure 1). The rate-limiting step in catecholamine synthesis is the addition of an hydroxyl group to tyrosine by the enzyme tyrosine hydroxylase (TH) to generate l-3,4-dihydroxyphenylalanine (L-DOPA), which is rapidly decarboxylated by aromatic L-amino acid decarboxylase to form dopamine. Further on in noradrenergic neurons, dopamine is transported from the cytosol to secretory vesicles by vesicular monoamine transporter (VMAT) for conversion to norepinephrine by the actions of the enzyme dopamine ß-hydroxylase. Norepinephrine can be further converted to epinephrine in cells that carry the enzyme phenylethanolamine-N-methyl transferase (PNMT).
The termination of NE activity occurs both intraneuronally, within the same cell, or extraneuronally. Within the cell, NE leaks into the axoplasm from vesicular stores and is inactivated by oxidative deamination, a reaction catalyzed by the enzyme monoamine oxidase-A (MAO-A) and produces the metabolite 3,4-dihydrophenylglycolaldehyde (DOPEGAL). Accumulation of DOPEGAL is neurotoxic as it covalently modifies tau, instigating its aggregation and implicates the noradrenergic LC neurons in the cognitive decline and pathophysiology of Alzheimer’s disease (AD). Upon NE release into the synaptic cleft, the cessation of its physiological action occurs via enzymatic inactivation and reuptake into the terminals. The extraneuronal enzymatic inactivation of NE represents a minor mode of deactivation and involves O’methylation by catechol-O-methyltransferase (COMT) that transfers a methyl group from S-adenosyl-L-methionine (SAMe) to generate normetanephrine. Norepinephrine transporters (NET, discussed below) in an ion gradient-dependent manner, channel NE back into the presynaptic terminal, clearing it from the synaptic cleft and halting its action.
Norepinephrine acts on 3 families of G-protein coupled adrenergic receptors (ARs), two types of alpha and a beta family of -α-1, α-2, and β - ARs, in the central and peripheral nervous system of humans and other species. These receptors have 7 transmembrane domains and are characterized as belonging to the rhodopsin family/Class A group of G-protein coupled receptors, The β ARs were the first characterized and serve as a representative G-protein coupled receptor. Pharmacological and molecular cloning studies have contributed immensely to our knowledge of the distinction between these receptor subtypes the physiological and cellular actions they execute. Actions of norepinephrine and epinephrine are mediated by 9 subtypes of ARs within the broader group of the 3 families, and are classified as, α-1A, α-1B, α-1D; α-2A, α-2B, α-2C; and β-1, β-2, β-3. Coupling with different G-proteins and transduction pathways in different areas of the nervous system, on different time-scales, confers distinct signaling properties to these receptors. In addition to coupling with G-Proteins and being labeled as GPCRs, the regulation and signaling via these receptors is more diverse and complicated, as it is well acknowledged that they transduce signals via pathways independent of G-proteins and are now are widely referred to instead as 7 transmembrane - 7TM - receptors. Below are characterizations of a few ARs, relevant to the focus of this article.
Norepinephrine binding to α-1 and β adrenergic receptors is stimulatory, whereas binding to α2 ARs is generally inhibitory. Regional differences in receptor distribution may alter the signaling of ARs, for instance, activation of α-1ARs is excitatory in sensory cortices, while its activity remarkably suppresses firing of neurons in the prefrontal cortex (PFC) that regulate cognitive function, including working memory. NE binds with higher affinity to the inhibitory α-2 ARs, (56nM), that are consequently recruited at lower concentrations of NE, and the preferential engagement of α-2A ARs in the PFC strengthen synaptic connectivity underlying working memory. Higher concentrations recruit the stimulatory, lower affinity α-1 (330 nM), and β ARs that function to consolidate long term memory in the amygdala and hippocampus, and are also engaged in sensory cortices. Thus moderate levels of norepinephrine that engage α-2 ARs are beneficial for cognitive function, and higher levels released during, for example stress, interact with α-1 and β ARs, with the activation of α-1 in the PFC being detrimental to cognitive function.
Characteristics of α-1 ARs
Norepinephrine binding to α-1 ARs (α-1A, α-1B, α-1D) is stimulatory via its coupling to the heterotrimeric Gq/11 (Gαq) G-protein family to activate phospholipase Cβ1 (PLCβ1). PLCβ1 hydrolyzes the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) to release inositol trisphosphate (IP3) and diacylglycerol (DAG) into the cytoplasm. These proteins accomplish different things, with IP3 regulating calcium levels, by binding to the IP3 receptor on the endoplasmic reticulum, causing calcium channels to open and surging intracellularly stored calcium into the cytosol. DAG activates protein kinase C (PKC) that phosphorylates scores of proteins in the undulating signal cascade. The α-1 ARs also operate by G-protein independent mechanisms, continuing to signal upon internalization into endosomes through mechanisms involving the scaffold protein, β-arrestin, that enlists second messengers such as extracellular signal-regulated protein kinase (ERK 1/2), p38, and Src.
The presence of α-1A ARs throughout the brain and spinal cord influences the functioning of different neurons they colocalize with, including those that contain GABA, NMDA glutamate receptors, and interneurons. α-1A ARs are highly enriched in human hippocampus and PFC, both areas involved in cognition and memory, and their levels are significantly reduced in Alzheimer’s disease (AD). In the hippocampus, the widespread expression of the a-1A ARs in neurons and glia has an impact on long-term potentiation (LTP) and enhances memory formation. Expression of α-1A ARs in human hippocampus is observed in the granule cell layer, dentate gyrus (DG), and the pyramidal cell layer in cornu ammonis (CA) CA1, CA2, and CA3 regions.
In the PFC, stress triggered elevation of NE engage the low-affinity α-1A ARs and impair working memory, this stands in contrast to its role in hippocampal memory consolidation and furthermore to the role that high-affinity α-2A ARs play under stressful conditions to enhance memory.
Additionally, pre- and post-synaptic α-1 ARs at cortical sites acting via PKC-dependent mechanisms, facilitate synaptic transmission of excitatory glutamatergic and cholinergic neurons and regulate GABA-mediated inhibition in different regions. α-1A ARs are very effective in modulating the strength of connections between neurons underlying both short- and long-term synaptic plasticity via there effects on spatiotemporal pre- and post-synaptic events. These mechanisms influence short term plasticity occurring over milliseconds, and is important for switching attention and adjusting behavior to new enviornmental cues. Over the longer term, they have an impact on the more durable plasticity involving long-term potentiation (LTP), which is a significant mechanism underpinning learning and memory in the hippocampus and PFC.
α-A ARs modulation of cognitive function - such as learning and memory, including spatial memory, fear conditioning, olfaction, and their modulation of synaptic efficacy in concert with other neurotransmitters, neurons and interneurons - lends credence to investigate and evaluate drugs that selectively target these receptors for therapeutic potential in treating neurodegenerative diseases, such as AD, and other age-related cognitive deficits and dementia.
Characteristics of α-2 ARs
The α-2 AR subtypes are encoded by separate genes and are structurally and functionally similar, exhibiting a high degree of amino acid sequence homology. NE binds with high affinity to the α-2 ARs, and activates these receptors at lower norepinephrine concentrations. All three types of α-2 ARs are found post-synaptically in the nervous system, with some α-2A and α-2C autoreceptors observed at pre-synaptic sites on NE cell bodies and terminals. All α-2 ARs are Gi/o coupled (Gαi), and signaling via these receptors inhibits adenylyl cyclase (AC) activity and 3’,5’-cyclic adenosine monophosphate cAMP production from adenosine triphosphate (ATP), suppresses calcium mobilization through voltage-gated calcium channels and opens K+ channels, culminating in hyperpolarization of the neuron. The α-2A ARs couple to Gi at lower concentrations of NE, and in addition, have been shown to couple to Gs, stimulating adenylyl cyclase activity at higher NE concentrations and receptor levels. This could represent functional differences that may have emerged in the evolution of the receptor.
In the PFC α-2A ARs benefit cognitive function by promoting the strengthening of synaptic connections. In contrast to the classical post-synaptic actions, like in the hippocampus, where cAMP bolsters synaptic plasticity, the inhibition of cAMP via α2A ARs in the PFC serves to strengthen synaptic connections by opening K+ channels and closing the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that halts the flux of mixed Na+/K+ currents into the cells, a mechanism that could also be invoked by phospholipase C-phosphokinase C (PLC-PKC)-linked signaling pathway. The ensuing hyperpolarization in recurrently connected circuits of pyramidal cells with shared properties that underlie working memory, in this case enhances the efficacy of synaptic inputs and the functional connectivity of cells.  In this way, α-2A AR agonists, e.g., guanfacine, clonidine, ameliorate many of the cognitive impairments of neuropsychiatric conditions related to PFC dysfunction, such as chronic stress and ADHD.
Besides its role as a neurotransmitter, NE produce anti-inflammatory effects as it is released extra-synaptically and binds to α-2 ARs on microglial cells. This neuromodulatory influence of NE on microglial activity, decreases their phagocytosis of neuronal spines that are crucial for cognitive function. Thus, abnormal NE levels could compromise this anti-inflammatory neuromodulation of microglial activity and has important implications for the ensuing neuronal and tissue damage, and for therapeutic applications for neurodegenerative diseases, such as Alzheimer’s disease. In light of their anti-inflammatory actions, cognitive effects, and suppression of neuronal firing, selective α2 ARs agonists, dexmedetomidine and clonidine are used clinically as sedatives and to augment pre-surgical anesthesia to reduce post-operative delirium.
Characteristics of β ARs
Beta-ARs are widely distributed throughout the nervous system and other tissue and underlie adaptive behavior, memory consolidation, cardiac function, vasorelaxation, and bronchodilation. NE and epinephrine exert their physiologic effects during ‘fight-or-fight’ situations by activating β-1 ARs peripherally in the sympathetic nervous system, to increase heart rate, respiration, visual acuity, in response to stressful or challenging and dangerous conditions.
β-ARs couple to Gs, (Gαs), mediating stimulatory actions of NE. Binding of NE to β-ARs unravels this pathway that stimulates adenylate cyclase and raises the levels of cAMP, activating phosphokinase A (PKA) that in turn phosphorylates calcium channels and elevates intracellular calcium levels due to the increased influx of the ion . These receptors also function independently of this G-protein cascade, and via the adaptor protein β-arrestin, recruit ERK, which along with PKA plays important roles in memory enhancement by β-ARs.
β-1 ARs expressed in heart tissue and are critical for the cardiac response to norepinephrine and epinephrine. In the brain they are distributed in the basolateral amygdala (BLA), hippocampus, and cerebral cortex. Additionally, β-2 ARs are ubiquitously expressed with higher levels in airway smooth muscles and are also expressed in the brain. β-3 ARs are localized to adipose tissue and the nervous system. All 3 β ARs are implicated in stress-related behaviors, anxiety and depression. Notwithstanding their high sequence homology, epinephrine binds both receptors, β-1 than β-2, with equal affinity, whereas reportedly, norepinephrine is greatly, ~ 10-fold, more selective for β-1 than β-2 ARs. This could most likely be due to the rate at which the catecholamines associates with the receptors and the structural bias of β-1 ARs, facilitating ease of access by NE, whereby it can interact with the β-1 AR faster and more easily than with β-2 ARs. This has implications for the biological accuracy of drug design to treat the catecholamine-associated disorders targeted at these receptors that subserve different functions. In this respect certain β-2 AR agonists specially designed to treat asthma, display a 1000-fold higher selectivity over β-1 ARs.
β-ARs in the amygdala and hippocampus mediate long-term memory consolidation, conversely activation of β-1 ARs in the PFC, such as during stress, is detrimental to cognitive function, and engagement of β-2 AR in the PFC and amygdala has a beneficial effect on memory and cognitive function. Emotional and arousal states enhance the formation of memories and β-ARs are vital to the synaptic plasticity underlying this process. These receptors are relevant to these processes both in the amygdala for acquisition and encoding of memories, and the hippocampus, via their powerful impact on the induction of LTP, for the retrieval of emotionally charged memories. In humans, agents that impede β-ARs, like propranolol, diminish the remembrance of emotional versus benign stories, a testament to the substantial role these receptors have on affect. In the hippocampus, β-ARs enhance LTP and influence the formation of enduring memories via PKA phosphorylation and activation of glutamatergic NMDA receptors, the latter being pivotal to the process.
β-2 ARs, as mentioned above, are essential for certain types of synaptic plasticity (like LTP) in the hippocampus and PFC, and remarkably form complexes with other proteins, serving as nanodomains of cellular signal processing. The discovery of these ensembles formed with β-ARs represents a milestone finding that provided incredible insight into the specific, and spatially restricted mode of cAMP signaling mediated by β-2 ARs. These complexes incorporate the manifold of all the requisite molecular elements required for precision signaling and consist of β-2 AR- Gs along with cellular machinery, adenylyl cyclase, PKA, multiplexed with its prominent targets L-type Ca2+ channels (LTCC) Cav1.2, glutamatergic GluR1 containing AMPA receptors. By linking the NE and glutamate systems, these super assemblies could be responsible for a significant mode of NE’s actions in the brain related to arousal, memory and learning, and could prove to be effective targets for disorders of the noradrenergic system, such as PTSD and ADHD.
Norepinephrine Transporters (NET)
Norepinephrine transporters (NET) judiciously regulate synaptic transmission and spatiotemporally modulate adequate levels of NE for ideal signaling. NETs belong to the solute carrier 6 (SLC6), neurotransmitter sodium symporter family that utilizes Na+-derived energy to transport the substrates against their concentration gradient. These SLC6 symporters transfer neurotransmitters, monoamines NE, DA, 5-HT, and GABA into presynaptic terminals from the extracellular space, and also flux amino acids (glycine, proline) and osmolytes (creatine, taurine, betaine) into the cells, and in this regard they function to maintain metabolic and fluid homeostasis. NET (SLC6A2) are chloride and sodium dependent transmembrane proteins that facilitate the transfer of NE into presynaptic terminals, to critically maintain optimal, biochemically relevant intra- and extra-cellular NE levels for signaling between neurons.
NE transporters are distributed in the central and peripheral nervous system, and dysregulation of NET structure, function, or expression is associated with various behavioral and psychiatric conditions, such as ADHD, PTSD, depression, suicide, and conditions such as chronic pain. Since aberrant levels of NE in the synaptic cleft contribute to these dysfunctional states, much research has shown that NE reuptake inhibitors (NRIs), agents that block the recycling of NE by NETs into the presynaptic terminals, increase the availability of NE for neural transmission and are being employed in clinical settings to alleviate symptoms related to a decline in NE neurotransmission. Selective NET blockers, such as the NRI atomoxetine are used to treat ADHD. Additionally, dual targeting drugs that block both NE and 5-HT systems, serotonin and NE reuptake inhibitors (SNRIs), in contrast to selective reuptake inhibitors, work synergistically, and with differing selectivity on the serotonin and NE transporters to increase the bioavailability of NE and 5-HT. SNRIs are deployed to safely and effectively treat major depressive disorder (MDD) and other conditions, such as chronic pain that are related to these two neurotransmitter systems. Structure-based studies and clinical trials for NE related disorders, are continuing to discover more efficacious molecules and drugs to distinctively target these transporters.
Anatomy and Pathways
Locus Coeruleus (LC) nucleus and its afferents and efferents
The Locus Coeruleus (LC), is a bilateral pontine nucleus, lying in the brainstem just lateral to the fourth ventricle. It was identified over 200 years ago, and referred to as locus coeruleus, Latin for ‘blue spots’, alluding to its pigmented appearance in unstained tissue. Humans have roughly a total of 50,000 densely packed noradrenergic neurons encompassing the LC of both hemispheres. Irrespective of its small size, the LC-NE has considerable reach, and consequently a tremendous influence on the nervous system with trajectories consisting of dorsal and ventral bundle streams. The dorsal path ascends to the forebrain and midbrain regions, projecting to the cortex, amygdala, hippocampus, thalamus, hypothalamus, basal ganglia with key roles in arousal, vigilance, memory, behavioral flexibility, stress and fear response, pain detection, and neuroendocrine functions; a cerebellar pathway which is involved with modulating local circuits concerning motor activities; and a ventral route with axon collaterals in the brainstem nuclei, and projections that descend to the spinal cord that process sensory information and analgesia/hyperalgesia. The LC also receives reciprocal afferents from areas that it innervates, and this makes it a crucial player in diverse functions mentioned above in the central and peripheral arms of the nervous system.
Much research has centered on detailing the broad projection and collateralization patterns of the LC-NE axons and their specific and targeted local effects. One crucial issue relating to LC-NE organization pertains to how its global distribution could have a specific impact without impacting all functions at once. Studies like a recent human imaging study noted increased LC activity during simultaneous attentional tasks and pain, demonstrating the specificity of LC-NE function in concurrently processing signals for two very disparate functions.
Dissecting the physiological effects and impact on behavior has been challenging, as its small size and location deep in the brainstem has made the LC intractable for in-depth study. Anatomical studies using light and electron microscopic methods have revealed that the cell bodies of the noradrenergic neurons are packed in the core of the nucleus, with dendrites populating the surrounding pericoerulear shell, a region rife with non-NE afferents. The LC-NE neurons are targeted by over a 100 brain regions, and the nucleus maintains its reciprocal connections with a regional bias, i.e., dorsal regions projecting to the forebrain and ventral ones to the hindbrain. Consistent with this bias, the LC maintains a functionally topographic organization, with the dorsal aspect, subserving more higher-order cognitive functions, and ventral routes asserting influence over affect, motivation.
LC neurons although exclusively adrenergic, display a distinctly heterogenous phenotype. They exhibit diversity in size between dorsal and ventral regions of the nuclei, with smaller fusiform cells predominating in the dorsal region, and more multiform neurons populating the ventral portion. Noradrenergic neurons also differ in their co-expression of neuropeptides, especially galanin, and to a lesser extent Neuropeptide Y (NPY), that could presumably modulate NE release at target sites. Differences in LC-NE neurons run to distinct gene and protein expression, electrophysiological properties, efferent and afferent connections, and correspondingly they could represent coherent functional subsets of adrenergic neurons specialized for specific functions in modes, both independent and coordinate.
The LC-NE network harnesses the distinct functional properties of its numerous receptors to finely tune information processing regarding specific conditions. The forebrain receives massive LC input and NE exercises excitatory influence on cognition and states of arousal by deploying the stimulatory α-1 and β adrenergic receptors (ARs) on excitatory glutamatergic cortical neurons, and inhibitory α-2 ARs on GABAergic interneurons. In this way these NE neurons are assigned to implement functionally heterogenous phenotypes.
Afferents from and efferents to a multitude of brain regions plays to the integrative role of LC-NE nucleus, and these innervation pattens also underlie specificity - internally in the subcircuits of the nucleus and externally through its axonal trajectories. Cognitive and arousal states representing external and internal states are reconciled by top-down and bottom-up information processing. It engages in top-down, goal-directed processes as it receives afferents from the PFC and central amygdala, facilitating the goal-directed, purposeful, and stress-related behavioral responses e.g., anxiety in response to the external environment. LC activation upon encountering salient stimuli related to different sensory modalities - tactile, visual, olfactory, and vestibular - via inputs from the brainstem, particularly from gigantocelluar reticular nucleus, represent bottom-up processing related to the internal states. Both efferent and afferent projections of the LC-NE system are considered important for deciphering the emergent, functionally relevant properties of its modular organization.
Projections & Modularity
To decipher the global and discrete influence of LC-NE on the nervous system, the crafting of new techniques and exploiting novel ways of utilizing older ones, has ushered in an era of methodological advances that are being deployed to study the once intractable nucleus. Newer tools in the neuroscience toolkit – include use of different viral vectors for retrograde neuron labeling (viral tract tracing), viral-genetic tracing of LC organization, which includes delineating the projection patterns of its highly ramified axon collaterals, highly refined imaging and reconstruction, including calcium imaging, electrophysiological, large-scale recordings and manipulation of cells, optogenetics, chemogenetics, and identifying unique genetic patterns expressed in individual or neuronal ensembles, i.e., using molecular reporters, functional MRI (fMRI), computational models, and approaches utilizing different behavioral paradigms – have revolutionized the conduct of research that continues to reveal insights into the intricacy and complexity of the LC-NE system.
Architecturally, the projections reconstructed by viral vector retrograde labeling and serial 2-photon tomography of the mouse brain mesoscale connectome (Allen Mouse Brain Connectivity Atlas), reveal LC-NE global trajectories, each with unique distribution patterns reminiscent of a modular organization. Novel input-output tracing implemented by viral-genetic tools show that LC-NE efferents project broadly and further receive inputs from multitude of brain regions, with some specificity in neuronal subcircuits. This is consistent with their role of integrating inputs from diverse areas of the brain, and ‘broadcasting’ to multiple regions in order to influence brain states. Single LC neurons that connect to a specific brain region are observed to be stronger and are distinguishable from weaker projections of single neurons that innervate a multitude of brain regions. Furthermore, discrete subsets of LC-NE neurons display modularity in their projections to functionally related areas of the cortex, with minimal overlap. The density of axonal varicosities in these projections is nonuniform, with higher levels in superficial versus deeper cortical layers and regional differences with higher levels in the prefrontal cortex (PFC) compared to other cortices, implying the targeted and functional regulation of norepinephrine at different projection sites.
As previously mentioned, the LC-NE projections to the PFC are important in regulating and maintaining proper function related to higher cognitive operations and behavior, including working memory and attentional states. The LC-NE targets to PFC could induce dynamic shifts in target neural networks that underlie the cognitive ability to interrupt ongoing behavior in response to salient and surprising stimuli, facilitating appropriate and adaptive behavioral modifications suited to the new demands.
The LC terminals provide local, demarcated neuromodulation to neurons confined to the afferent sites in the forebrain and discrete cellular ensembles in the LC display differentiated spatiotemporal properties, which can sustain synchronous firing, and target specific cortical areas. In contrast to previous single-cell or multi-cell recordings, the advent of high-density electrode arrays has accelerated our understanding of neuronal firing patterns. Single-cell population activity in over 3000 LC cell pairs in rats, using silicone probes with high channel density allow for large-scale ensemble recordings. Synchronously firing cells, over different time scales, were observed from multi-cell recordings to project to functionally related cortical areas, however no en masse ensemble firing was detected in the LC as a whole. These cells assemble into functionally synchronous clusters, and regulate cortical and subcortical activity related to higher cognitive functions, and sensory and motor processing. The LC-PFC are reciprocally connected, implying top-down control of LC by PFC. In this regard, the quality of PFC synchronous activity and response of LC neurons has been elucidated, with circuit-specific transients increasing in the PFC preceding neuronal oscillations in LC-NE, evidence of the top-down control of LC by cortical areas. Utilizing whole brain mapping of transynaptic circuits reveals that LC-NE subpopulations that project to the amgdala and medial PFC receive, on a gross level, mostly similar afferents from brain regions. However, they receive partially-segregated inputs at a finer level, suggesting context dependent activation of different subsets of NE neurons and noradrenergic input to these separate targets that subserve emotion and higher-order executive function. Furthermore, the amygdala-projecting LC-NE subpopulations revealed sex related differences in inputs they receive.
A recent study on learned behavior demonstrated the spatiotemporal differences in the way LC-NE processed two concurrently encoded functions, i.e., executing a task and enhancing subsequent performance an example of functional modularity of its projections. LC-NE projections to distinct cortical areas were differentially active during the two functions, in that the release of NE specifically in the motor areas preceded the execution of behavior related to the task, whereas NE release followed a negative reinforcement (punishment) received to optimize performance, which registered more broadly in the brain. This showcases that the modularity of NE projections, and their discrete and global signals are optimized to facilitate behavior and adaptive responses.
Cortical areas with similar levels of NE, ascertained by amounts of dopamine ß-hydroxylase transcripts (NE biomarker), are differentially modulated. For instance, LC-NE projections to the orbitofrontal cortex (OFC) and PFC that undergird higher-order cognitive function are more excitable than those targeting the primary motor cortex (M1). The latter is involved in movement generation, processes that are different and downstream to higher-order PFC processes. Using multiple investigative techniques, these projections to the PFC are characterized to have different anatomical, molecular phenotypes, and electrophysiological properties that make them more excitable and responsive to glutamate compared to M1, reflecting a greater demand and engagement of NE in cortical circuitry related to executive function. This discrete organization could have functional implications for noradrenergic modulation of the different cortical regions and behavior and psychiatric diseases, and is leveraged by drugs specifically targeting the PFC, like a low dose of the psychostimulant, methylphenidate (Ritalin) used in treating ADHD, that improves cognitive function without any impact on locomotor activity.
It is the convergence of methodological tools and decades of research that continues to shed light on the complexity of the noradrenergic system, unveiling global and modular influences on brain function and behavior. Exciting work continues to energize the field, with more exciting findings coming out each day.
Attention Deficit Hyperactivity Disorder (ADHD)
Attention Deficit Hyperactivity disorder (ADHD) is characterized by attention deficits, an inability to inhibit inappropriate responses, impulsive behaviors, and excessive motor activity. Volumetric and structural changes have been indicated in cortical and subcortical regions compromised in ADHD, especially dysfunction of the right inferior prefrontal cortex (PFC) in children. Recurrent excitatory interactions of pyramidal cells recruited for the same purpose and lateral inhibition of unrelated pyramidal neurons by GABAergic interneurons located in deep layer III PFC, represent processes that underlie working memory. The PFC subserves our ability to make mental representations that are comprised of inputs from external and internal sources. This includes working memory that guides appropriate behavior and affords one the ability to plan a future course of action, and further entails the appropriate cortical, top-down management of attention, emotion, and action.
Catecholamines, NE and dopamine (DA) in the PFC are critical for cognitive and emotional functions, and treatments employing drugs that selectively target high-affinity α-2A ARs, and D1 DA receptors are used in alleviating the dysfunctional symptoms of ADHD. Under optimal conditions, NE engages post-synaptic, cortical α-2A ARs located on the spines of deep layer III pyramidal cells, and inhibits intracellular cAMP-PKA signaling associated with hyperpolarization – via cAMP-PKA activation of K+ and closure of hyperpolarization-activated cyclic nucleotide-gated HCN channels - and in this way rapidly fine tunes and strengthens synaptic connectivity that undergirds cognitive operations, including working memory.
Dysfunctional psychological and physiological states, such as chronic stress, ADHD, reduced oxygen, bring about architectural alterations in cortical pyramidal cells, causing dendrite and spine loss correlated with cognitive impairment. Specific α-2A AR agonists, like the FDA approved non-stimulant drug, guanfacine (Intuniv) that mimic NE activity in the PFC , rescue the neurons from these detrimental structural changes and are used to treat ADHD. Conversely, antagonists of α-2A ARs, like yohimbine promote an ‘ADHD phenotype’ by diminishing working memory, impulse control, and hyperactivity, supporting the central role of this adrenergic receptor in this disorder. Taken together, these studies provide evidence for the therapeutic deployment of α-2A AR agonist, guanfacine, in treating ADHD and stress related conditions. Agents that increase the availability of NE and confer cognitive improvements, like selective NE uptake inhibitors, atomoxetine and viloxazine, are also used therapeutically for ADHD.
Psychostimulants, such as low-dose methylphenidate (Ritalin), are effective in elevating levels of NE and DA, specifically in the PFC compared to other cortical areas. Psychostimulants differentially target α-1 and α-2 ARs to enhance sustained attention and working memory, respectively. Low dose psychostimulants effectively alleviate symptoms of ADHD, calming behavior and enhancing cognition to reduce inattention and impulsivity. The dosing follows an inverted U-shape to facilitate these effects, with the lower dose acting to enhance PFC neural activity for processing relevant information and higher doses being detrimental to neuronal activity, with negative impact for behavior and cognition. Thus, dosing of psychostimulants need to be carefully administered to ameliorate symptoms of ADHD.
Stress is conceptually defined as any threat, either real or perceived to one’s homeostasis or well-being, and the stress response involves the physiological and behavioral efforts to regain the internal balance. A threat to oneself elicits internal, systemic changes, which are physical in nature, including and not limited to hypoglycemia, decreased blood volume, in response to a physically alarming challenges. The perceived threat of impending danger elicits anticipation and an attendant emotional response, akin to anxiety. Acute stressors elicit adrenaline release that promote memory consolidation of the event as a result of heightened attention and enhanced sensory processing.
Noradrenergic neurons are activated under various stressful conditions, by the internal, psychogenic, or external, physical environment. LC-NE system is essential for mounting an adaptive response in stressful circumstances. These neurons powerfully drive the hypothalamic-pituitary-adrenal (HPA) axis response evoked by stress. The hypothalamic paraventricular nucleus (PVN) neuro-secretory parvocellular cells express corticotrophin-releasing hormone (CRH) that is integral to the stress response. These neurons function in the HPA axis, ‘the final common pathway’ for mediating and mitigating the stress response. Noradrenergic terminals innervate CRH neurons, orchestrating the behavioral and physiological adaptations resulting from encountering stress. CRH neurons themselves have a broad distribution in the nervous system, and innervate the LC-NE. This input most likely results in the activation of adrenergic neurons by stressors and facilitates behavioral and cognitive response to the challenge.
In stressful conditions the dorsal LC - an area that is responsive to stress - projections to the central amygdala (CeA), elevate activity and induce anxiety-like behavior whereas the projections to mPFC promote exploration. The LC-NE terminal fields in these distinct regions appear to adapt to stress in opposing ways that are consequential for behavior.
LC-NE neurons recruited by CRH in the stress response, are biased to transition to a tonic mode of firing during anxiety and acute stress. This activity and anxiety is also observed with optogenetic stimulation of NE-LC cells bodies. The CRH afferents to the LC-NE from the CeA are thought to be responsible for driving this change in firing pattern and behavior and the consequent anxiety under conditions mimicking stress. LC-NE neurons project to cortical areas and impact cognitive functions, like working memory and focused and flexible attention. Under normal conditions, moderate levels of noradrenergic input to PFC would recruit high-affinity post-synaptic α-2 ARs and would have a positive impact on working memory. With higher levels of NE release, such as during stress, that engages lower-affinity α-1 ARs, working memory is compromised whereas focus and flexibility is enhanced. The LC-NE tonic activity elicited by stressors promotes scanning and flexibility, exploratory modes of behavior that are suited to an adaptive response and more likely benefit survival, highlighting the essential role of norepinephrine in mounting an appropriate response to stress. These kinds of findings strengthen the viewpoint that the LC is a complex nucleus with a uniquely modular organization, with nuanced and diverse physiological and behavioral effects.
Global LC activity like that evoked by stressful situations, heighten anxiety and increase exploration that is aimed at selecting behaviors that would prove adaptive. The swift transformation of the functional connectivity in specific large-scale networks in response to LC activation and elevated NE correlate with higher, low-affinity α-1 adrenergic receptor expression. These changes however are obstructed by pre-synaptic, auto-inhibitory β-2 adrenergic receptor activation. All these behavioral, physiological, and network responses to stress induced LC-NE activity, serve to bolster vigilance and threat detection.
The LC-NE modular projections to basolateral amygdala (BLA) and medial PFC (mPFC) have differential effects in fear learning and extinction, respectively. The projection to the lateral amygdala is crucial for fear acquisition with β-ARs being essential for the process. LC projections to certain mPFC areas are associated with cognitive functions and facilitate learned flexible behavior, indispensable for adapting to changing environmental conditions. Specific LC-NE connections to the amygdala underlie emotional and associative learning, whereas distinct, non-overlapping segments targets the infralimbic mPFC to enable cognitive flexibility and mount an adaptive response. These discrete cell groups lying in the LC constitute populations of noradrenergic neurons that operate in opposition and are selectively enlisted to mediate divergent behaviors. Selective photostimulation of noradrenergic projections to the BLA elicits NE release and evokes anxiety-like states via β-AR receptors. The BLA projecting neurons are engaged in mediating the fear response, with different sets of neurons activated during highly fearful and low fear conditions. There is observed to be an overwhelmingly global activation of these disparate LC-NE neurons under exceedingly harmful situations versus a more contained and dynamic response by individual neuronal populations in response to less aversive conditions that require a more considered response. This sets up the LC-NE system to remain flexible and commensurate in furnishing an adaptive response to the environmental demands. Specifically, the mPFC projecting LC-NE cell group is vital for the inverted-U shaped response underlying behavioral flexibility.
The LC-NE system in involved in neuropathic pain and has disparate connections to the spinal cord and PFC, representing distinct and discernible responses to pain. This level of distinction is attributable to the anatomical and functional modularity of the LC. The ascending LC-NE projections to the PFC are observed throughout the LC. They are present more dorsally in the nuclei and represent functionally and anatomically separate group of cells compared to the descending projections destined for the spinal cord dorsal horn, which are located more ventrally in the nuclei.
Retrograde labeling techniques have delineated the axonal trajectories of LC neurons and have uncovered that LC neurons predominantly connect to PFC in the cortex, and that LC-spinal connections appear to project ipsilaterally. Selective activation of the LC-spinal cord neurons, acting via α2-adrenergic receptors mediate anti-nociception- an analgesic effect in models of neuropathic pain- an effect that seems to be lateralized to the ipsilaterally projecting neurons. In contrast, the PFC projecting neurons that themselves induce anxiety without any alterations in pain sensitivity exhibit heightened spontaneous pain after nerve injury. The LC-NE connections with the PFC are important for cognitive function, and higher levels of NE have been observed in the PFC in conditions of pain that contribute to impaired attention. Thus in the context of chronic and neuropathic pain, the noradrenergic LC-PFC projections are associated with negative symptoms of increased anxiety and impaired attention. This response to neuropathic pain is consistent with the modularity of the system, with separate independent branches subserving different functions, and being recruited in the context of pain, such as associated with nerve injury. Reconciling these functionally distinct branches could attenuate pain outcomes and prevent it from becoming chronic. Specific targeting of the noradrenergic afferents to the spinal cord involved in suppressing pain could be leveraged for therapeutic purposes.
Alzheimer’s Disease (AD)
Our understanding of Alzheimer’s disease (AD) pathology is based on a lot of work done on examining post-mortem brains from diseased individuals with varying degrees of severity and cognitive decline that also include detailed comparisons to non-diseased brains.
The hallmarks of neurodegenerative AD are decline in cognitive function, and the pathological aggregation of extracellular Aβ in amyloid plaques and hyper-phosphorylated tau protein in neurofibrillary tangles (NFTs) within cells. Tau is a microtubule-associated protein (MAP), essential for structural stability and function of axons, and as a result abnormal tau found in the core of NFT is functionally debilitating.
The 6 Braak stages of progressive development of tau lesions essentially characterized the LC as the initial area of the brain to accumulate tau lesions. This is followed by pathological tau in the transentorhinal cortex, spreading to the hippocampus, temporal lobe, and polymodal association areas.
The LC decreases in size due to the substantial reductions in volume, estimated at 8.4% loss in LC volume per unit increase from Braak stage 1. This early shrinkage in volume and accumulation of NFTs is followed by substantial LC-NE neuron loss starting midway in AD. This same study also showed a gradient of vulnerability in the LC, with the caudal aspect suffering less AD-related changes. Dorsal LC has reciprocal connections with cortex, diencephalon and forebrain structures and since tau pathology spreads between connected regions, this has significant functional consequences for cognitive function. The mostly unaltered caudal portion of the LC shares connections with the cerebellum and spinal cord that are relatively unaffected. The loss of LC-NE neurons is correlated with increasing cognitive deficits, such that in early amnestic mild cognitive impairment (aMCI) there is a 30% decline in LC-NE neurons, with progressive degeneration that eventually results in a loss of over 50% of the neurons upon conversion to AD. The loss of integrity of the LC-NE neurons is associated with pathological cognitive decline in episodic, semantic, working memory, and deficits in perceptual speed and visuospatial ability. This loss and impairment of LC function in AD is manifested early in the disease process, and includes anxiety, depression, agitation, problems with sleep, followed by cognitive dysfunction as the disease advances.
The LC-NE projections to the hippocampus contribute to all aspects of memory, including encoding, consolidation, retrieval and reversal. NE input also contributes to structural changes to the post-synaptic dendrites of pyramidal cells, a plasticity related to expansion of spines with LTP and their contraction as a result of LTD. Thus, the magnitude of LC-NE degeneration in AD is clinically consequential for its detrimental impact on memory and attentional states.
DOPEGAL ia a highly neurotoxic aldehyde metabolite resulting from the oxidation of NE by the enzyme MAO-A. Similar to other aldehyde metabolites it generates free radicals, and its unhealthy accumulation is considered to be destructive for adrenergic neurons. DOPEGAL and MAO-A levels are found to be approximately 3-fold higher in AD compared to non-AD individuals, with normal DOPEGAL levels being ~ 1.4mM. Additionally, DOPEGAL disrupts the function of tau by covalently modifying its primary amine at Lys353, resulting in tau aggregation. The understanding as mentioned above, is that the pathological accumulation of tau is propagated via interconnected cells, and the cell-to-cell transmission of proteinaceous tau seeds, recruit and modify endogenous tau that ultimately seed the entire brain and impairs cognitive and other functions. DOPEGAL also activates an asparagine endopeptidase (AEP) that cleaves tau at Asn368 and promotes NFT aggregation, and furthermore it also cleaves amyloid precursor protein (APP) to assist in the generation of Aβ, the stereotypical, extracellular marker of AD. Thus high levels of DOPEGAL are neurotoxic and wreak havoc on adrenergic neurons, making them selectively vulnerable to damage and deterioration observed in AD.
Inflammation is highly prevalent in AD and is linked to the anti-inflammatory activity of microglia whose job is to continuously scan the environment and swiftly respond to any changes via phagocytosis of deleterious or misfolded proteins and cellular debris, and excess pro-inflammatory neuromelanin with minimal impact on neuronal function. However, when chronically activated, microglia promote inflammation by releasing pro-inflammatory cytokine and chemokines, along with enhanced phagocytosis that is damaging to neurons. NE is a potent regulator offering protection from neuroinflammation via β ARs and reduces microglial phagocytosis of neurons. LC-NE loss in AD and the associated loss of protection from inflammation afforded by NE, leaves it and its projection areas such as the cortex and hippocampus, vulnerable to inflammation and phagocytosis by microglial cells, impairing cognitive functions.
The close association of LC to capillaries, its proximity to the cerebrospinal fluid (CSF) of the 4th ventricle, and its poorly myelinated neurons could make it selectively vulnerable to circulating toxins leading to tau accumulation, and loss of integrity and function. Additionally, the electron dense pigment, neuromelanin (NM) found in LC-NE neurons has a high affinity for metals, and stores catalyzed iron in an inactive form, protecting the neurons from oxidative stress. Normally activated microglia are highly effective in clearing away NM from the extracellular space, but their efficacy reduces with aging. The levels of both NE and neuromelanin decline with age, and the degenerating neuron spill NM into the extracellular space, where they are pro-inflammatory and further the degenerative changes in the LC associated with AD. This neuromelanin signal can be resolved by MRI and could serve as a marker for distinguishing cognitive function related to healthy aging and AD-related dementia.
Thus, substantial deterioration of LC-NE and its actions in AD is consequential for the deficits in memory, and attentional and perceptual impairments, and should be considered a relevant target for developing therapeutic interventions and tools for clinical assessment.
Parkinson’s Disease (PD)
Parkinson’s disease (PD) is a protracted neurodegenerative disease characterized by both neuropsychiatric and motor symptoms. In addition to the loss of DA neurons in the substantia nigra pars compacta (SNc) there is significant, ranging from 20% to a catastrophic 90% LC-NE cell loss in PD at advanced stages. LC-NE cell loss and the accompanying impairments in motor and non-motor symptoms are now propounded to be major events in establishing PD, as these changes are not detected in normal aging. For a long time, LC-NE was conceptualized to play a supporting role in PD genesis, but of late it is increasingly being recognized as a central character in PD. Moreover, the conspicuous pathological protein aggregates, Lewy bodies and α-synuclein that are hallmarks of the disease, are observed to be present in the LC early on in PD pathology, prior to their appearance in the SNc. Additionally, the DA and NE metabolite, neuromelanin, which is a marker for neurodegeneration in PD is detected both in the SNc and LC of patients suffering from PD. The degeneration of LC-NE neurons occurs throughout the nucleus and peri-coerulear regions, while the remaining neurons shrink in size and display an altered phenotype.
In PD, the pathology of LC-NE precedes the emergence of motor deficits that are linked to detriments in the nigral dopaminergic neurons. The changes in LC-NE are responsible for the early cognitive deficits, including attentional states, depression, and other non-motor comorbidities. As noted previously from the wealth of work and literature on the subject, NE targets many regions of the brain and its activity has an immense neuromodulatory impact on the function of target circuits, affecting the functional connectivity and communication between different areas of the brain. The dwindling of the normally dense NE inputs to the hippocampal memory circuits and other cortical areas responsible for myriad cognitive functions, expectedly and progressively ravages mental states. The LC-NE input optimizes cognitive faculties involved with continuing tasks and is also involved with adaptive behaviors by regulating the communication in specific and wide-ranging neural circuitry. Different modes of LC activity influence behavior differently, for instance upon encountering stressful, menacing, or significant events, LC activity interrupts ongoing behavior and enhances brain wide connectivity, with a strong bias for the salience and amygdala networks. This is accompanied by discrete changes in α- and β-ARs, and specific changes in NE turnover, illustrating mechanisms by with NE reconfigures the functional connections in the brain and resulting behavioral adaptations. A recent study with a large sample size of individuals with PD, has confirmed previous reports that the degeneration of the LC in these patients is accompanied by cognitive decline and the functional disorganization of brain regions subserving these abilities. Another study stressing the importance of LC-NE, demonstrated reduced cognitive capacity in PD individuals with blockage of NE neurotransmission. PD patients also suffer early on from other non-motor comorbidities related to dysregulation of the LC-NE, such as, anxiety, sleep disturbances, sleep with labored breathing, apathy, fatigue, and rapid eye movement sleep behavior disorder (RBD).
LC-NE ascending and descending pathways also contribute to the motor symptoms of PD that most likely intersect with dopaminergic transmission. It is well established that motor deficits in PD emerge only after significant, ~80%, destruction of dopaminergic terminals, suggesting the involvement of multiple neuronal systems that compensate for the progressive damage incurred by the dopaminergic system, including the nigrostriatal projections. In animal models, the neurotoxin, MPTP (1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced select lesioning of nigral DA neurons alone do not give rise to pronounced motor deficits, which are observed only when coupled with LC-NE lesions, suggesting LC neurons shield SNc dopamine neurons from MPTP damage. LC-NE afferents are proposed to be neuroprotective to the dopaminergic system, and indeed with progressive loss of adrenergic neurons the protection is lost. The compensatory role played by NE-LC with respect to motor deficits, is most likely exerted by the α-2 (α-2C) ARs, that serve to modulate the activity of dopaminergic neurons in the early stages of PD. The fortification of dopaminergic neurons by LC-NE could also be offered by co-transmitters, galanin and brain-derived neurotrophic factor (BDNF). Additionally, NE functions as an antioxidant to scavenge superoxide, and also restrains the expression of proinflammatory agents. Chronic use of L-DOPA to alleviate PD symptoms comes at a cost of developing L-DOPA-induced dyskinesis (LID), which can be rescued by α-2 AR antagonists, such as idazoxan, without affecting other L-DOPA mediated benefits, again invoking the influence of the LC-NE neurotransmission on dopaminergic function.
NE is crucial for limiting neuroinflammation and additionally has neurotrophic properties along with providing protection from oxidative stress. LC-NE confers neuroprotection in PD, and therefore interventions that arrest the degeneration of the LC or enhance NE release, serve as evidence that could inform treatments that exploit these mechanisms and would be beneficial in treating PD and other neurodegenerative diseases.
These findings advocate the LC-NE as being a major contributor to the initiation and progression of PD, including contributing to the severity of neuronal damage and symptoms, rather than incidental collateral damage of the diseased brain.
- ↑ 1.0 1.1 1.2 1.3 Foote, S. L.; Bloom, F. E.; Aston-Jones, G. (1983). "Nucleus locus ceruleus: new evidence of anatomical and physiological specificity". Physiological Reviews. 63 (3): 844–914. doi:10.1152/physrev.1922.214.171.1244. ISSN 0031-9333.
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- ↑ Arnsten, Amy F.T.; Li, Bao-Ming (2005). "Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions". Biological Psychiatry. 57 (11): 1377–1384. doi:10.1016/j.biopsych.2004.08.019. ISSN 0006-3223.
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- ↑ Breton-Provencher, Vincent; Drummond, Gabrielle T.; Sur, Mriganka (2021). "Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets". Frontiers in Neural Circuits. 15. doi:10.3389/fncir.2021.638007. ISSN 1662-5110. PMC 8215268 Check
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- ↑ Marzo, Aude; Totah, Nelson K.; Neves, Ricardo M.; Logothetis, Nikos K.; Eschenko, Oxana (2014). "Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex". Journal of Neurophysiology. 111 (12): 2570–2588. doi:10.1152/jn.00920.2013. ISSN 0022-3077.
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- ↑ 202.0 202.1 Mercan, Dilek; Heneka, Michael Thomas (2022). "The Contribution of the Locus Coeruleus–Noradrenaline System Degeneration during the Progression of Alzheimer's Disease". Biology. 11 (12): 1822. doi:10.3390/biology11121822. ISSN 2079-7737. PMC 9775634 Check
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- ↑ Matchett, Billie J.; Grinberg, Lea T.; Theofilas, Panos; Murray, Melissa E. (2021). "The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer's disease". Acta Neuropathologica. 141 (5): 631–650. doi:10.1007/s00401-020-02248-1. ISSN 1432-0533. PMC PMC8043919 Check
|pmc=value (help). PMID 33427939 Check
|pmid=value (help).CS1 maint: PMC format (link)
- ↑ 204.0 204.1 Oertel, Wolfgang H.; Henrich, Martin T.; Janzen, Annette; Geibl, Fanni F. (2019). "The locus coeruleus: Another vulnerability target in Parkinson's disease". Movement Disorders. 34 (10): 1423–1429. doi:10.1002/mds.27785. ISSN 0885-3185.
- ↑ Giguère, Nicolas; Burke Nanni, Samuel; Trudeau, Louis-Eric (2018). "On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease". Frontiers in Neurology. 9: 455. doi:10.3389/fneur.2018.00455. ISSN 1664-2295. PMC 6018545. PMID 29971039.CS1 maint: PMC format (link)
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- ↑ Cash, R.; Dennis, T.; L'Heureux, R.; Raisman, R.; Javoy-Agid, F.; Scatton, B. (1987). "Parkinson's disease and dementia: Norepinephrine and dopamine in locus ceruleus". Neurology. 37 (1): 42–42. doi:10.1212/WNL.37.1.42. ISSN 0028-3878.
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