No abstract

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.T he brainstem nucleus locus coeruleus (LC), the primary source of the catecholamine neurotransmitter norepinephrine (NE) to the forebrain, cerebellum, and spinal cord, is conserved across several taxa, including fish, birds, and mammals (1). In mammals, it is the largest noradrenergic nucleus in the brain and the main source of NE to the neocortex. This projection system modulates sensory processing, motor behavior, arousal, and executive functions (2-10) and is implicated in a number of neuropsychiatric disorders (4). The LC has long been considered a homogeneous assembly of NE-containing cells, each with highly divergent axons that innervate broad regions of the CNS. There is only limited evidence of functional or topographic order within the nucleus (11-16), leading to the generally accepted notion that activation of the LC leads to simultaneous release and uniform physiologic action of NE throughout the brain. However, using the rat as a model, we have recently demonstrated the existence of three minimally overlapping populations of LC neurons that project to orbitofrontal (OFC), medial prefrontal (mPFC), and anterior cingulate (ACC) cortices (17,18). This projection pattern suggests a more segregated mode of operation for this projection system.The goals of the present study were to determine whether this trend of minimal axonal collateralization extended to LC neurons innervating primary motor cortex (M1) and to identify the molecular and electrophysiological characteristics that distinguish the target-specific cell populations within the rat LC. Because these prefrontal subregions regulate higher-order executive operations (19,20) whereas M1 regulates the generation of motor behaviors downstream of prefrontal cortical processes, we hypothesized that M1 and each prefrontal cortical subregion receives input from functionally distinct populations of LC neurons. ...

The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive functions and is composed of several distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These regions serve dissociable cognitive functions, and are heavily innervated by acetylcholine, dopamine, serotonin and norepinephrine systems. In this study, fluorescently labeled retrograde tracers were injected into the ACC, mPFC, and OFC, and labeled cells were identified in the nucleus basalis (NB), ventral tegmental area (VTA), dorsal raphe nucleus (DRN) and locus coeruleus (LC). DRN and LC showed similar distributions of retrogradely labeled neurons such that most were single labeled and the largest population projected to mPFC. VTA showed a slightly greater proportion of double and triple labeled neurons, with the largest population projecting to OFC. NB, on the other hand, showed mostly double and triple labeled neurons projecting to multiple subregions. Therefore, subsets of VTA, DRN and LC neurons may be capable of modulating individual prefrontal subregions independently, whereas NB cells may exert a more unified influence on the three areas simultaneously. These findings emphasize the unique aspects of the cholinergic and monoaminergic projections to functionally and anatomically distinct subregions of PFC.

The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. As a diffuse neuromodulatory system, noradrenaline affects learning and decision making, control of sleep and wakefulness, sensory salience including pain, and the physiology of correlated forebrain activity (ensembles and networks) and brain hemodynamic responses. However, our understanding of the LC is undergoing a dramatic shift due to the application of state-of-the-art methods that reveal a nucleus of many modules that provide targeted neuromodulation. Here, we review the evidence supporting a modular LC based on multiple levels of observation (developmental, genetic, molecular, anatomical, and neurophysiological). We suggest that the concept of the LC as a singular nucleus and, alongside it, the role of the LC in diverse theories of brain function must be reconsidered.

Norepinephrine released by the locus coeruleus modulates cellular processes and synaptic transmission in the central nervous system through its actions at a number of pre- and postsynaptic receptors. This transmitter system facilitates sensory signal detection and promotes waking and arousal, processes which are necessary for navigating a complex and dynamic sensory environment. In addition to its effects on sensory processing and waking behavior, norepinephrine is now recognized as a contributor to various aspects of cognition, including attention, behavioral flexibility, working memory, and long-term mnemonic processes. Two areas of dense noradrenergic innervation, the prefrontal cortex and the hippocampus, are particularly important with regard to these functions. Due to its role in mediating normal cognitive function, it is reasonable to expect that noradrenergic transmission becomes dysfunctional in a number of neuropsychiatric and neurodegenerative diseases characterized by cognitive deficits. In this review, we summarize the unique role that norepinephrine plays in prefrontal cortical and hippocampal function and how its interaction with its various receptors contribute to cognitive behaviors. We further assess the changes that occur in the noradrenergic system in Alzheimer's disease, Parkinson's disease, attention-deficit/hyperactivity disorder, and schizophrenia and how these changes contribute to cognitive decline in these pathologies.

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.

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.

Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder.