Locus Ceruleus Norepinephrine Research Articles

Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT1 Receptors Located in the Locus Ceruleus Norepinephrine Neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

Locus Ceruleus Dynamics Are Suppressed during Licking and Enhanced Postlicking Independent of Taste Novelty.

Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning. Exposure to new tastes is known to increase norepinephrine (NE) release in taste processing forebrain areas, yet the central source for this release is unknown. Locus ceruleus norepinephrine neurons (LC-NE) emerge as a candidate in signaling salient information about taste, as other salient sensory stimuli (e.g., visual, auditory, somatosensation) are known to activate LC neurons. To determine if LC neurons are sensitive to features of taste novelty, we used fiber photometry to record LC-NE activity in water-restricted mice that voluntarily licked either novel or familiar substances of differential palatability (saccharine, citric acid). We observed that LC-NE activity was suppressed during lick bursts and transiently activated upon the termination of licking and that these dynamics were independent of the familiarity of the substance consumed. We next recorded LC dynamics during brief and unexpected consumption of tastants and found no increase in LC-NE activity, despite their responsiveness to visual and auditory stimuli, revealing selectivity in LC's responses to salient sensory information. Our findings suggest that LC activity during licking is not influenced by taste novelty, implicating a possible role for non-LC noradrenergic nuclei in signaling critical information about taste.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Pupil-Linked Arousal Response Reveals Aberrant Attention Regulation among Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus-norepinephrine (LC-NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC-NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurrent stimuli as well as a diminished phasic response to deviants, particularly those containing social information. Their tonic habituation impairment predicts their phasic orienting impairment, and both impairments correlated with the severity of ASD symptom. Because of the fact that these pupil-linked responses are observed when individuals passively listen without any task engagement, our findings imply that the intricate and dynamic attention allocation mechanism, mediated by the subcortical LC-NE system, is impaired in ASD.SIGNIFICANCE STATEMENT Autistic individuals show attentional abnormalities to even simple sensory inputs, which emerge even before formal diagnosis. One possible mechanism behind these abnormalities is a malfunctioning pacemaker of their attention system, the locus ceruleus-norepinephrine pathway. Here we found, according to the pupillary response (a noradrenergic activity proxy), autistic children are hypersensitive to repeated sounds but hyposensitive to surprising deviant sounds when compared with age-matched controls. Importantly, hypersensitivity to repetitions predicts hyposensitivity to deviant sounds, and both abnormalities positively correlate to the severity of autistic symptoms. This provides strong evidence that autistic children have faulty noradrenergic regulation, which might underly the attentional atypicalities previously evidenced in various cortical responses in autistic individuals.

A Neuroeconomic Framework for Creative Cognition

Neuroeconomics is the study of the neurobiological bases of subjective preferences and choices. We present a novel framework that synthesizes findings from the literatures on neuroeconomics and creativity to provide a neurobiological description of creative cognition. We propose that value-based decision-making processes and activity in the locus ceruleus-norepinephrine (LC-NE) neuromodulatory system underlie creative cognition, as well as the large-scale brain network dynamics shown to be associated with creativity. This reconceptualization leads to several falsifiable hypotheses that can further understanding of creativity, decision making, and brain network dynamics.

Sex hormones modulate neurophysiological correlates of visual temporal attention

The functional cerebral asymmetry (FCA) in processing targets within rapid serial visual presentation (RSVP) streams has been reported to fluctuate across the menstrual cycle, with identification of the second of two closely spaced targets being impaired when both targets occur in the left or the right hemifield stream during the luteal phase, while during the menstrual phase identification of the second target is only impaired for target pairs presented in the right hemifield stream. This fluctuation has been proposed to result from variations in estradiol levels. The current study used EEG to investigated whether the cycle-related fluctuation in RSVP target identification FCA relates to changes in early, stimulus-driven, bottom-up or in later, top down-driven aspects of FCA. While the former would be expected to become evident in the early visual evoked potentials (VEPs) P1 or N1, the latter would be evident in later event-related potentials (ERPs) such as N2pc or P3. Women performed a dual-stream RSVP task once during the menstrual phase and once during the follicular phase. Estradiol levels were determined from saliva samples. In contrast to previous findings, FCA in RSVP target identification was not affected by cycle phase. However, the impairment in second-target identification when targets where closely spaced was generally smaller during the menstrual phase than during the follicular phase. This effect was matched by shorter peak latencies of P1 VEPs for the menstrual phase, and by a reduction in the latency of the second-target P3 ERP for closely spaced relative to widely spaced target pairs, again for the menstrual phase. Results suggest that in a dual-stream RSVP setup, target identification, early stage stimulus processing, and target consolidation are affected by cycle phase, but that the asymmetry of these effects does not differ between menstrual and follicular phase. The observed cycle-related modulations in neurophysiology and behavior could relate to the effects of estradiol on the locus ceruleus norepinephrine (LC-NE) system, which is known to play a major role in arousal, attention and stress response.

A Role for the Locus Ceruleus in Reward Processing: Encoding Behavioral Energy Required for Goal-Directed Actions.

The locus ceruleus (LC) is a small nucleus in the dorsal pons that innervates most of the forebrain, with the exception of the striatum. The LC is the main source of norepinephrine (NE) in the brain, and this LC–NE system is typically associated with arousal, vigilance states, attention, and

The impact of psychosocial stress on healthy skin.

Dermatologists are only too aware of the significant role psychosocial stress plays in the exacerbation of skin disease; indeed, it is often the first precipitant patients mention when they attend outpatient clinics. Of late, research has focused on understanding the 'brain-skin' axis, a complex interplay between the nervous and immune systems and the skin. In particular, there is an evolving body of literature exploring the underlying pathophysiological mechanisms by which psychosocial stress influences skin homeostasis. This article provides a broad overview of the literature, emphasizing the importance of individual stress perception and summarizing the varied roles of the major cutaneous stress-response pathways. Both central [the hypothalamic-pituitary-adrenal (HPA) axis and the locus ceruleus-norepinephrine (LC-NE) sympathetic adrenomedullary system] and peripheral (the intracutaneous HPA axis and the release of mediators from peripheral sensory and autonomic nerves) pathways are discussed. Moreover, how activation of these pathways affects the skin's immune system, barrier function, wound healing and susceptibility to infection is reviewed. Although this field of research is rapidly expanding, several important questions remain unanswered, including: what is the precise role of mast cells in the cutaneous stress response?; what is the role of regulatory T-cells?; can therapeutic intervention be harnessed to prevent the stress-induced exacerbation of skin disease? It is anticipated that an improved understanding of the underlying mechanisms through which psychosocial stress affects the homeostasis of healthy skin will not only increase knowledge of the brain-skin axis but will also improve the holistic management of stress-responsive cutaneous disease.

Simultaneous EEG-fMRI Reveals Temporal Evolution of Coupling between Supramodal Cortical Attention Networks and the Brainstem

Cortical and subcortical networks have been identified that are commonly associated with attention and task engagement, along with theories regarding their functional interaction. However, a link between these systems has not yet been demonstrated in healthy humans, primarily because of data acquisition and analysis limitations. We recorded simultaneous EEG-fMRI while subjects performed auditory and visual oddball tasks and used these data to investigate the BOLD correlates of single-trial EEG variability at latencies spanning the trial. We focused on variability along task-relevant dimensions in the EEG for identical stimuli and then combined auditory and visual data at the subject level to spatially and temporally localize brain regions involved in endogenous attentional modulations. Specifically, we found that anterior cingulate cortex (ACC) correlates strongly with both early and late EEG components, whereas brainstem, right middle frontal gyrus (rMFG), and right orbitofrontal cortex (rOFC) correlate significantly only with late components. By orthogonalizing with respect to event-related activity, we found that variability in insula and temporoparietal junction is reflected in reaction time variability, rOFC and brainstem correlate with residual EEG variability, and ACC and rMFG are significantly correlated with both. To investigate interactions between these correlates of temporally specific EEG variability, we performed dynamic causal modeling (DCM) on the fMRI data. We found strong evidence for reciprocal effective connections between the brainstem and cortical regions. Our results support the adaptive gain theory of locus ceruleus-norepinephrine (LC-NE) function and the proposed functional relationship between the LC-NE system, right-hemisphere ventral attention network, and P300 EEG response.

The locus ceruleus norepinephrine system

The locus ceruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the CNS. The LC-NE system has a major role in arousal, attention, and stress response. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis, and control of local blood blow. The LC is severely affected in neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Dysregulation of LC-NE system has been implicated in sleep and arousal disorders, attention deficit hyperactivity disorder, and posttraumatic stress disorder and constitutes a target for pharmacologic treatment of these conditions. The neurobiology of the LC–noradrenergic system has been the subject of several excellent reviews.1–9 The LC is a cluster of NE-containing neurons located in the upper dorsolateral pontine tegmentum (figure 1). These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus.1,2 Despite its widespread distribution, noradrenergic innervation shows regional specificity. For example, brain areas involved in spatial attention (such as the prefrontal and parietal cortices) receive particularly dense LC-NE inputs. In general, individual LC neurons send axon collaterals to multiple targets that process the same sensory information. Norepinephrine is released both at typical synapses and at nonsynaptic release sites; extrasynaptic NE mediates paracrine effects on neurons, glial cells, and microvessels.1–4,8 Figure 1 Anatomic organization of the locus ceruleus–norepinephrine system The norepinephrine (NE) neurons of the locus ceruleus (LC) are located in the upper dorsolateral pontine tegmentum and can be identified by their immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus. Modified, …

Optimality and Robustness of a Biophysical Decision-Making Model under Norepinephrine Modulation

The locus ceruleus (LC) can exhibit tonic or phasic activity and release norepinephrine (NE) throughout the cortex, modulating cellular excitability and synaptic efficacy and thus influencing behavioral performance. We study the effects of LC-NE modulation on decision making in two-alternative forced-choice tasks by changing conductances in a biophysical neural network model, and we investigate how it affects performance measured in terms of reward rate. We find that low tonic NE levels result in unmotivated behavior and high levels in impulsive, inaccurate choices, but that near-optimal performance can occur over a broad middle range. Robustness is greatest when pyramidal cells are less strongly modulated than interneurons, and superior performance can be achieved with phasic NE release, provided only glutamatergic synapses are modulated. We also show that network functions such as sensory information accumulation and short-term memory can be modulated by tonic NE levels, and that previously observed diverse evoked cell responses may be due to network effects.

Norepinephrine induces a samaritan phenotype of microglia in an Alzheimer disease mouse model

Loss of locus ceruleus (LC) neurons, degeneration of noradrenergic projections and decrease of norepinephrine (NE) in projection areas represent an early feature of Alzheimer's disease (AD). To elucidate the effect of NE loss on AD pathology, we evaluated NE effects on microglial functions including cytokine generation, migration and phagocytosis in vitro and in vivo. NE stimulation abolished amyloid beta (Aß) induced microglia chemokine and cytokine secretion, but increased microglial migration and phagocytosis of fibrillar Aß in a concentration dependent manner. Similary, DSP4 induced LC degeneration and NE depletion increased mRNA and protein levels of cytokines and inflammatory enzyme systems in APP transgenic mice. NE depleted APPV717I transgenic mice showed more Aß 1–40 and 1–42 deposits within the hippocampus and frontal cortex compared to APP transgenic mice with an intact NE innervation. Confocal analysis of microglial cells and Aß revealed that the number of colabelled cells was higher in control compared to NE depleted APPV717I transgenic mice, suggesting that NE levels modulate microglial phagocytosis in vivo. These data indicate that early LC degeneration and concomitant decrease of NE concentration in LC projection areas such as the neocortex and hippocampus facilitate the inflammatory reaction of microglial cells in the AD brain. At the same time, loss of NE innervation impairs key microglial functions such as migration and phagocytosis and thus contribute to reduced Aß clearance in AD. Therefore, therapies targeting microglial phagocytosis should be tested under NE depletion.

Presynaptic Inhibition of Diverse Afferents to the Locus Ceruleus by -Opiate Receptors: A Novel Mechanism for Regulating the Central Norepinephrine System

The norepinephrine nucleus, locus ceruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAAs), corticotropin-releasing factor (CRF), and endogenous opioids acting at mu-opiate receptors. Because the LC is also innervated by the endogenous kappa-opiate receptor (kappa-OR) ligand dynorphin and expresses kappa-ORs, this study investigated kappa-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of kappa-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the kappa-OR agonist (trans)-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)-cyclo-hexyl] benzeneacetamide (U50488) into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the kappa-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that kappa-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-norepinephrine system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate kappa-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism.

Beta-adrenergic Modulation of Cognitive Flexibility during Stress

Stress-induced activation of the locus ceruleus-norepinephrine (LC-NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC-NE system may produce deleterious effects. The aim of the present study was to determine the effect of pharmacological modulation of the LC-NE system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuo-spatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system.

Locus Ceruleus Regulates Sensory Encoding by Neurons and Networks in Waking Animals

Substantial evidence indicates that the locus ceruleus (LC)-norepinephrine (NE) projection system regulates behavioral state and state-dependent processing of sensory information. Tonic LC discharge (0.1-5.0 Hz) is correlated with levels of arousal and demonstrates an optimal firing rate during good performance in a sustained attention task. In addition, studies have shown that locally applied NE or LC stimulation can modulate the responsiveness of neurons, including those in the thalamus, to nonmonoaminergic synaptic inputs. Many recent investigations further indicate that within sensory relay circuits of the thalamus both general and specific features of sensory information are represented within the collective firing patterns of like-modality neurons. However, no studies have examined the impact of NE or LC output on the discharge properties of ensembles of functionally related cells in intact, conscious animals. Here, we provide evidence linking LC neuronal discharge and NE efflux with LC-mediated modulation of single-neuron and neuronal ensemble representations of sensory stimuli in the ventral posteriomedial thalamus of waking rats. As such, the current study provides evidence that output from the LC across a physiologic range modulates single thalamic neuron responsiveness to synaptic input and representation of sensory information across ensembles of thalamic neurons in a manner that is consistent with the well documented actions of LC output on cognition.

Unique neural circuitry for neonatal olfactory learning.

Imprinting ensures that the infant forms the caregiver attachment necessary for altricial species survival. In our mammalian model of imprinting, neonatal rats rapidly learn the odor-based maternal attachment. This rapid learning requires reward-evoked locus ceruleus (LC) release of copious amounts of norepinephrine (NE) into the olfactory bulb. This imprinting ends at postnatal day 10 (P10) and is associated with a dramatic reduction in reward-evoked LC NE release. Here we assess whether the functional emergence of LC alpha2 inhibitory autoreceptors and the downregulation of LC alpha1 excitatory autoreceptors underlie the dramatic reduction in NE release associated with termination of the sensitive period. Postsensitive period pups (P12) were implanted with either LC or olfactory bulb cannulas, classically conditioned with intracranial drug infusions (P14), and tested for an odor preference (P15). During conditioning, a novel odor was paired with either olfactory bulb infusion of abeta-receptor agonist (isoproterenol) to assess the target effects of NE or direct LC cholinergic stimulation combined with alpha2 antagonists and alpha1 agonists in a mixture to reinstate neonatal levels of LC autoreceptor activity to assess the source of NE. Pups learned an odor preference when the odor was paired with either olfactory bulb isoproterenol infusion or reinstatement of neonatal LC receptor activity. These results suggest that LC autoreceptor functional changes rather than olfactory bulb changes underlie sensitive period termination.

Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress

The stress system coordinates the adaptive responses of the organism to stressors of any kind. 1 1 “Stress” is defined as a state of disharmony or threatened homeostasis. The concepts of stress and homeostasis can be traced back to ancient Greek history, however, the integration of these notions with related physiologic and pathophysiologic mechanisms and their association with specific illnesses are much more recent. In the present overview, we focus on the cellular and molecular infrastructure of the physiologic and behavioral adaptive responses to stress and we define the pathophysiologic effects of the dysregulation of the stress response, which may result in vulnerability to several disease entities, such as anxiety or depression and chronic inflammatory processes. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus–norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary–adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic β-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic–pituitary–adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and β-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5′ deiodinase, which converts the relatively inactive tetraiodothyronine (T 4) to triiodothyronine (T 3), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing “low turnover” osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation ( immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.

Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons.

Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucose-induced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K(+) channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K(m)) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and gamma-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca(2+) imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca(2+) oscillations were inhibited and GI neurons whose Ca(2+) oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain.

Noradrenergic Depletion Potentiates β-Amyloid-Induced Cortical Inflammation: Implications for Alzheimer's Disease

Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid β (Aβ). Adult rats were injected with the selective neurotoxinN-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Aβ (aggregated 1–42 peptide). DSP4 treatment potentiated the Aβ-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1β, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Aβ induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Aβ increased IL-1β expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1β expression were attenuated by coinjection with NE or the β-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Aβ and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.

Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease.

Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid beta (Abeta). Adult rats were injected with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Abeta (aggregated 1-42 peptide). DSP4 treatment potentiated the Abeta-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1beta, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Abeta induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Abeta increased IL-1beta expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1beta expression were attenuated by coinjection with NE or the beta-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Abeta and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.