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The brainstem nucleus locus coeruleus (LC) is the primary source of norepinephrine (NE) to the mammalian neocortex. It is believed to operate as a homogeneous syncytium of transmitter-specific cells that regulate brain function and behavior via an extensive network of axonal projections and global transmitter-mediated modulatory influences on a diverse assembly of neural targets within the CNS. The data presented here challenge this longstanding notion and argue instead for segregated operation of the LC–NE system with respect to the functions of the circuits within its efferent domain. Anatomical, molecular, and electrophysiological approaches were used in conjunction with a rat model to show that LC cells innervating discrete cortical regions are biochemically and electrophysiologically distinct from one another so as to elicit greater release of norepinephrine in prefrontal versus motor cortex. These findings challenge the consensus view of LC as a relatively homogeneous modulator of forebrain activity and have important implications for understanding the impact of the system on the generation and maintenance of adaptive and maladaptive behaviors.

The brainstem nucleus locus coeruleus (LC) sends projections to the forebrain, brainstem, cerebellum and spinal cord and is the source of the neurotransmitter norepinephrine (NE) in these areas. For more than 50 years, LC was considered to be homogeneous in structure and function such that NE would be released uniformly and act simultaneously on the cells and circuits that receive LC projections. However, recent studies have provided evidence that LC is modular in design, with segregated output channels and the potential for differential release and action of NE in its projection fields. These new findings have prompted a radical shift in our thinking about LC operations and demand revision of theoretical constructs regarding impact of the LC-NE system on behavioral outcomes in health and disease. Within this context, a major gap in our knowledge is the relationship between the LC-NE system and CNS motor control centers. While we know much about the organization of the LC-NE system with respect to sensory and cognitive circuitries and the impact of LC output on sensory guided behaviors and executive function, much less is known about the role of the LC-NE pathway in motor network operations and movement control. As a starting point for closing this gap in understanding, we propose using a novel intersectional recombinase-based viral-genetic strategy TrAC (Tracing Axon Collaterals) as well as established ex vivo electrophysiological assays to characterize efferent connectivity and physiological attributes of mouse LC-motor network projection neurons. The novel hypothesis to be tested is that LC cells with projections to CNS motor centers are scattered throughout the rostral-caudal extent of the nucleus but collectively display a common set of electrophysiological properties. Additionally, we expect to find these LC projection neurons maintain an organized network of axon collaterals capable of supporting selective, synchronous release of NE in motor circuitries for the purpose of coordinately regulating operations across networks that are responsible for balance and movement dynamics. Investigation of this hypothesis will advance our knowledge of the role of the LC-NE system in motor control and provide a basis for treating movement disorders resulting from disease, injury, or normal aging.

The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive operations. However, this region is not a single functional unit; rather, it is composed of several functionally and anatomically distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These prefrontal subregions serve dissociable behavioral functions, and are unique in their afferent and efferent connections. Each of these subregions is innervated by ascending cholinergic and noradrenergic systems, each of which likewise has a distinct role in cognitive function; yet the distribution and projection patterns of cells in the source nuclei for these pathways have not been examined in great detail. In this study, fluorescent retrograde tracers were injected into ACC, mPFC, and OFC, and labeled cells were identified in the cholinergic nucleus basalis of Meynert (NBM) and noradrenergic nucleus locus coeruleus (LC). Injections into all three cortical regions consistently labeled cells primarily ipsilateral to the injection site with a minimal contralateral component. In NBM, retrogradely labeled neurons were scattered throughout the rostral half of the nucleus, whereas those in LC tended to cluster in the core of the nucleus, and were rarely localized within the rostral or caudal poles. In NBM, more than half of all retrogradely labeled cells possessed axon collaterals projecting two or more PFC subregions. In LC, however, only 4.3% of retrogradely labeled neurons possessed collaterals targeting any two prefrontal subregions simultaneously, and no cells were identified that projected to all three regions. Of all labeled LC neurons, 49.3% projected only to mPFC, 28.5% projected only to OFC, and 18.0% projected only to ACC. These findings suggest that subsets of LC neurons may be capable of modulating neuronal activity in individual prefrontal subregions independently, whereas assemblies of NBM cells may exert a more unified influence on the three areas, simultaneously. This work emphasizes unique aspects of the cholinergic and noradrenergic projections to functionally and anatomically distinct subregions of PFC and provides insights regarding global versus segregated regulation of prefrontal operations by these neuromodulatory pathways.

Methylphenidate (MPH) is used clinically to treat attention-deficit/hyperactivity disorder (ADHD) and off-label as a performance-enhancing agent in healthy individuals. MPH enhances catecholamine transmission via blockade of norepinephrine (NE) and dopamine (DA) reuptake transporters. However, it is not clear how this action affects neural circuits performing cognitive and sensorimotor functions driving performance enhancement. The dorsal lateral geniculate nucleus (dLGN) is the primary thalamic relay for visual information from the retina to the cortex and is densely innervated by NE-containing fibers from the locus coeruleus (LC), a pathway known to modulate state-dependent sensory processing. Here, MPH was evaluated for its potential to alter stimulus-driven sensory responses and behavioral outcomes during performance of a visual signal detection task. MPH enhanced activity within individual neurons, ensembles of neurons, and visually-evoked potentials (VEPs) in response to task light cues, while increasing coherence within theta and beta oscillatory frequency bands. MPH also improved reaction times to make correct responses, indicating more efficient behavioral performance. Improvements in reaction speed were highly correlated with faster VEP latencies. Finally, immunostaining revealed that catecholamine innervation of the dLGN is solely noradrenergic. This work suggests that MPH, acting via noradrenergic mechanisms, can substantially affect early-stage sensory signal processing and subsequent behavioral outcomes.

Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.

Stress and stress-related psychiatric disorders, including post-traumatic stress disorder, are associated with disruptions in sensory information processing. The neuropeptide, corticotropin-releasing factor (CRF), coordinates the physiological and behavioral responses to stress, in part, by activating the locus coeruleus-norepinephrine (LC-NE) projection system. Although the LC-NE system is an important modulator of sensory information processing, to date, the consequences of CRF activation of this system on sensory signal processing are poorly understood. The current study examined the dose-dependent actions of CRF at the LC on spontaneous and sensory-evoked discharge of neurons within the thalamus and cortex of the vibrissa somatosensory system in the awake, freely moving rat. Peri-LC infusions of CRF resulted in a dose-dependent suppression of sensory-evoked discharge in ventral posterior medial thalamic and barrel field cortical neurons. A concurrent increase in spontaneous activity was observed. This latter action is generally not found with iontophoretic application of NE to target neurons or stimulation of the LC-NE pathway. Net decreases in signal-to-noise of sensory-evoked responses within both regions suggest that under conditions associated with CRF release at the LC, including stress, the transfer of afferent information within sensory systems is impaired. Acutely, a suppression of certain types of sensory information may represent an adaptive response to an immediate unexpected stressor. Persistence of such effects could contribute to abnormalities of information processing seen in sensorimotor gating associated with stress and stress-related psychopathology.

Irregular catecholamine transmitter activity is theorized to underly impaired prefrontal cortex (PFC)-mediated executive functions following repetitive mild traumatic brain injury (rmTBI). The psychostimulant, methylphenidate (MPH), enhances catecholamine neurotransmission by blocking reuptake transporters and is used off-label to treat post-TBI executive dysfunction. Although rmTBI and MPH have been shown to independently alter catecholamine transporter levels, the present report evaluated the interactive effects of rmTBI and a sub-chronic therapeutic dose of MPH on expression levels of vesicular monoamine transporter-2 (VMAT2) and norepinephrine reuptake transporter (NET) within subregions of the PFC in both male and female rats. Treatment with MPH restored rmTBI-induced reductions in transporter expression in females. However, in males subjected to rmTBI, MPH exacerbated reductions in transporter expression within the PFC. These results suggest MPH treatment produces beneficial effects in females but exaggerates pathological outcomes in males when used to treat post-rmTBI symptoms.Competing Interest StatementThe authors have declared no competing interest.

Mild traumatic brain injury (mTBI) can disrupt cognitive processes that influence risk taking behavior. Athletes, military personnel, and domestic violence victims often experience multiple mTBIs; however, little is known regarding the effects of repetitive injury (rmTBI) on risk/reward decision making or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is composed of several sub-regions including the medial PFC (mPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). These regions are densely innervated by catecholaminergic fibers, which modulate PFC-mediated cognitive processes. Aberrant catecholamine activity within the PFC has been documented following TBI, which may underlie TBI-induced risky behavior. Tyrosine hydroxylase (TH) and norepinephrine transporter (NET) regulate catecholamine homeostasis within the PFC; however, it has not been determined how rmTBI affects these proteins. The present study aimed to characterize the effects of rmTBI on risk/reward decision making behavior and catecholamine transmitter regulatory proteins within the PFC. Risk/reward decision making was evaluated using a probabilistic discounting task (PDT) which required rats to choose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with decreasing probabilities over a session. Rats were first trained on the PDT and then exposed to sham, single (smTBI), or a series of three closed-head control cortical impact (CH-CCI) injuries over the course of one week, followed by four weeks of PDT testing. In week 1 post-final surgery, mTBI generally enhanced preference for the larger/riskier option with these effects seemingly more prominent in females. These effects resolved by week 2 post-final surgery indicating that the effects of mTBI on choice behavior are transient. By week 4, males, but not females, exhibited increased latencies to make riskier choices following rmTBI, demonstrating a delayed effect of injury on information processing speed. A separate group of rats was used to measure changes in levels of TH and NET within the mPFC, ACC, and OFC forty-eight hours after mTBI. No injury-induced differences were observed within the mPFC or ACC. In the OFC, females exhibited dramatic increases in TH levels following smTBI, but only small increases following rmTBI. Both males and females; however, experienced reduced levels of NET following rmTBI, which may function as a compensatory response to increased extracellular levels of catecholamines. Together, these results suggest that OFC is more susceptible to catecholamine instability after rmTBI, a finding indicating that not all areas of the PFC contribute equally to the observed TBI-induced catecholamine imbalances. Overall, combining the CH-CCI model of rmTBI with the PDT proved effective in revealing time-dependent and sex-specific changes in risk/reward decision making and catecholamine regulation following repetitive mild head injuries.Competing Interest StatementThe authors have declared no competing interest.

Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability. We compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference. Rats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100-6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg). AMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices. These data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices or under different anesthetics or during wakefulness . LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes (\"tonic\" or \"phasic\"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.