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Plasticity of central and peripheral sources of noradrenaline in rats during ontogenesis.
Bondarenko N, Dilmukhametova L, Kurina A, Murtazina A, Sapronova A, Sysoeva A, Ugrumov M (2017) Plasticity of central and peripheral sources of noradrenaline in rats during ontogenesis. Biochemistry (Mosc) 82:373-379.. doi: 10.1134/S0006297917030166
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Featured Article: The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease.
Kelly SC, Nelson PT, Counts SE (2017) Featured Article: The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Targeting Trends 18
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The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease.
Kelly SC, Nelson PT, Counts SE (2016) The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Neuroscience 2016 Abstracts 786.11 / H7. Society for Neuroscience, San Diego, CA.
Summary: Noradrenergic locus coeruleus (LC) neuron loss is a major feature of Alzheimer’s disease (AD). The LC is the primary source of norepinephrine (NE) in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex and hippocampus. Furthermore, LC-mediated NE signaling is thought to play a role in blood brain barrier maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease (CVD) and AD. However, the extent to which LC projection system degeneration occurs in the earliest stages of AD is not fully characterized to date. To address these issues, we analyzed LC tissue samples from University of Kentucky AD Center subjects who died with a premortem diagnosis of no cognitive impairment (NCI) and Braak stages 0-II at autopsy, NCI subjects with Braak stages III-V thought to be in a preclinical AD (PCAD) stage, and subjects with mild cognitive impairment (MCI) or mild AD (n = 5-6 cases/group). Paraffin-embedded pontine tissue blocks containing the LC were cut at 20µm, immunostained with tyrosine hydroxylase (TH, a marker for NE synthesis), and analyzed by stereology to estimate total LC neuron number (total number of neuromelanin-containing LC neurons) and the percentage of TH+ LC neurons. Preliminary analysis reveal a ~20% loss of both total and TH+ LC neurons in PCAD (p = 0.08), a ~30-35% loss of these neurons in MCI (p < 0.05), and a ~45-50% loss of total and TH+ neurons in AD (p < 0.01) compared to NCI. Studies were also performed to compare additional LC neuronal pathologies (phospho-tau, TDP-43, and 8dOHG) in the diagnostic groups. A substantial increase in 8dOHG and phospho-tau is observed in PCAD compared to NCI. The morphometric data will be correlated with postmortem neuropathologic and CVD variables (e.g., microinfarcts and cerebral amyloid angiopathy) to gauge the relationship between LC neurodegeneration and cerebral AD and vascular pathology. To model these relationships in vivo, we stereotactically lesioned LC projection neurons innervating the PFC, a major LC projection zone, in the TgF344-19 rat model of AD (6 months old) using the noradrenergic immunotoxin, dopamine-β-hydroxylase-saporin, or a control lesion (n = 8/group). Prior to sacrifice at 9 months, immunotoxin- and control-lesioned rats will be tested behaviorally on the Barnes maze task. Postmortem PFC will be analyzed for LC fiber innervation, NE and NE metabolite levels, CVD pathology and AD-like pathology. Taken together, these data will shed light on the multifactorial noradrenergic pathways contributing to neuronal and vascular pathologies during the onset of AD.
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Catecholaminergic innervation and the neuronal activation of hypothalamic glucose sensitive regions during rapid- and slow-onset hypoglycemia in adult male rats..
Jokiaho A, Watts AG (2016) Catecholaminergic innervation and the neuronal activation of hypothalamic glucose sensitive regions during rapid- and slow-onset hypoglycemia in adult male rats.. Neuroscience 2016 Abstracts 256.21 / CCC20. Society for Neuroscience, San Diego, CA.
Summary: Hypoglycemic counterregulation is mediated by glucosensors located in the hypothalamus, hindbrain, and portal-mesenteric veins. But which are engaged is rate-dependent, with portal vein sensors being obligatory for slow- but not rapid-onset hypoglycemia. Slow-onset hypoglycemia is particularly prevalent with insulin therapy in type 1 diabetes. We have previously shown that hindbrain-to-hypothalamus catecholaminergic (CA) projections are required for sympathoadrenal responses to slow- but not rapid-onset hypoglycemia, and that rapid- but not slow-onset hypoglycemia significantly increases CA/Fos colocalization in the ventrolateral medulla. These results show that the organization of a hypoglycemia-responsive brain networks is rather complex, and involves a set of what are likely parallel but interactive networks, each of which is responsible for controlling epinephrine, glucagon, and glucocorticoid responses. We now examine how various forebrain cell groups known to be important for glycemic regulation respond to , and how these responses are impacted by removing hindbrain-to-hypothalamus CA projections using injections of the immunotoxin, saporin conjugated to anti-DBH (DSAP) into the hypothalamic paraventricular nucleus (PVH). These injections remove CA inputs to the PVH and other regions within the medial hypothalamus. We then examined whether DSAP lesions affected Fos responses to slow- and rapid-onset insulin-induced hypoglycemia in key forebrain regions. We found that removing CA innervation differentially influences regional hypothalamic Fos responses to slow- and rapid-onset insulin-induced hypoglycemia. Rapid-onset hypoglycemia produced significantly greater Fos activations in the medial and lateral parvocellular and lateral parts of the PVH, parts of the lateral hypothalamus (LHA), the bed nucleus of the stria terminalis that was significantly reduced in all these regions with DSAP lesions. Of particular interest was the altered Fos in LHA regions that contain orexin neurons. We found that 27% of Fos activated neurons colocalized with orexin neurons in rapid-onset hypoglycemia, but this colocalization was significantly reduced by DSAP lesions. Furthermore we used a retrogradely transported polysynaptic neurotropic virus (PRV-152) injected into adrenal gland to show that 25% of PRV-labeled neurons in the LHA colocalized with orexin neurons. These results show that hindbrain-to-hypothalamus CA projections provide hypoglycemia-related information to regions of the forebrain in a rate-dependent way, with orexin neurons playing a particularly prominent role for sympathoadrenal responses.
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Diacylglycerol lipase-α expression increases in the coeruleo-cortical pathway in dopamine-β-hydroxylase knockout mice as well as rats treated with DSP-4
Urquhart M, Reyes BAS, Thomas SA, Mackie K, Van Bockstaele EJ (2016) Diacylglycerol lipase-α expression increases in the coeruleo-cortical pathway in dopamine-β-hydroxylase knockout mice as well as rats treated with DSP-4. Neuroscience 2016 Abstracts 77.09 / AAA24. Society for Neuroscience, San Diego, CA.
Summary: Endocannabinoids are involved in the regulation of many physiological processes including behavioral responses to stress. Endocannabinoids modulate norepinephrine (NE) signaling primarily via involvement of CB1 cannabinoid receptors (CB1r). Our previous studies have shown that acute and repeated administration of a CB1r agonist increases multiple indices of noradrenergic activity involving the locus coeruleus (LC)-frontal cortex (FC) pathway. Diacylglycerol lipase-α (DGL-α), a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) is localized to both the FC and the LC. Using electron microscopy, we have recently shown that in the rat FC DGL-α is localized in postsynaptic profiles that are targeted by dopamine-β-hydroxylase (DβH), the enzyme that converts dopamine to norepinephrine and represents a marker of noradrenergic neurons (Hartman et al., 1972). In this study, we also described interactions between DGL-α, CB1r and DβH in the FC using confocal microscopy. In the present study, we investigated expression levels of DGL-α under two conditions of NE deletion: in a rat model using a systemic injection of saporin conjugated with antibody against DβH (DSP-4) and in a genetically engineered mouse that lacked the enzyme DβH (DβH-knockout, KO). We compared expression levels of DGL-α to either control rats or wild type (WT) mice using Western blot analysis. Protein extracts from micropunches of FC and LC were obtained and probed for DGL-α. Results showed that DGL-α expression was significantly increased in FC (P < 0.05) of both DSP-4 treated rats and DβHKO mice when compared to WT mice. DGL-α expression was also significantly increased in the LC (P < 0.05) of DβHKO when compared to WT mice. These data add to the accumulating evidence that dysregulation of NE transmission results in significant adaptations in the brain endocannabinoid system.
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GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex.
Kaushal R, Taylor B, Jamal A, Zhang L, Ma F, Donahue R, Westlund K (2016) GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex. Neuroscience 334:148-159. doi: 10.1016/j.neuroscience.2016.08.005
Summary: The goal of this study was to investigate the role of the locus coeruleus (LC) in a rat orofacial pain model of trigeminal neuropathy induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Mechanical thresholds to von Frey filaments were tested on whisker pads to evaluate neuropathic pain behavior; pain was indicated by development of mechanical hypersensitivity. Noradrenergic (NA) neurons were lesioned with 5-mcg injections of Anti-DBH-SAP (Cat. #IT-03) into the left lateral ventricle. Mouse-IgG-SAP (Cat. #IT-18) was used as a control. After ablation of NA neurons there was a notable increase in the mechanical threshold compared to control animals. They also targeted coeruleotrigeminal NA neurons by injecting Anti-DBH-SAP into the trigeminal brainstem nuclei bilaterally in one animal and saw similar results. Injecting a GABAA receptor antagonist into the LC after injury had an inhibitory effect on nerve injury induced hypersensitivity. Injection of a NAα1 receptor antagonist, but not a NAα2 receptor antagonist, into the medial prefrontal cortex (mPFC) alleviates mechanical hypersensitivity. They conclude that GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC, and that the LC is a chronic pain generator.
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Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat.
Benn A, Robinson E (2017) Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat. Psychopharmacology (Berl) 234:255-266.. doi: 10.1007/s00213-016-4458-8
Summary: Atomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder. Although atomoxetine has established efficacy, the mechanisms which mediate its effects are not well understood. In this study, the authors investigated the role of cortical versus sub-cortical noradrenaline by using focal dopamine beta hydroxylase-saporin-induced lesions, to the prefrontal cortex (PFC) or nucleus accumbens shell (NAcSh). Male Lister hooded rats received bilateral lesions by using stereotaxic injections of the immunotoxin Anti-DβH-SAP (Cat. #IT-03), 0.02 μg in 0.5 μL per injection into the PFC and 0.004 μg in 0.2 μL per injection for NAcSh lesions. The data suggest that noradrenaline in the nucleus accumbens shell plays an important role in the effects of atomoxetine. Under these conditions, prefrontal cortex noradrenaline did not appear to contribute to atomoxetine’s effects suggesting a lack of cortical-mediated “top-down” modulation. Noradrenaline in the prefrontal cortex appears to contribute to the modulation of impulsive responding in amphetamine-treated animals, with a loss of noradrenaline associated with potentiation of its effects. These data demonstrate a potential dissociation between cortical and sub-cortical noradrenergic mechanisms and impulse control in terms of the actions of atomoxetine and amphetamine.
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A2 noradrenergic neurons regulate forced swim test immobility.
Nam H, Kerman I (2016) A2 noradrenergic neurons regulate forced swim test immobility. Physiol Behav 165:339-349. doi: 10.1016/j.physbeh.2016.08.020
Summary: Wistar-Kyoto rats are often used as a model of depression, and exhibit high levels of immobility when subjected to a forced swim test (FST). Researchers discovered relative hyperactivation in the locus coeruleus of WKY rats compared to the genetically related Wistar rats when exposed to one- and two-day FSTs. Lesser activation of A2 noradrenergic cell group was seen by diminished levels of FOS after both days of the FST. A2 noradrenergic neurons of Winstar rats were lesioned by injecting 2.2 ug of Anti-DBH-SAP (Cat. #IT-03) into the nucleus tractus solitaris (NTS). Lesioned rats exhibited increased FST immobility on both days of the test, similar to natural WKY behavior in the same test. These data indicate that the A2 noradrenergic cell group regulates FST behavior and that its hypoactivation may contribute to the unique behavioral phenotype of WKY rats.
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Acute hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the C1 region.
Silva T, Takakura A, Moreira T (2016) Acute hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the C1 region. Exp Neurol 285:1-11. doi: 10.1016/j.expneurol.2016.08.016
Summary: Catecholaminergic C1 cells reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM) and can be activated by hypoxia. These neurons regulate the hypothalamic pituitary axis via direct projections to the hypothalamic paraventricular nucleus (PVH) and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The present results suggest that catecholaminergic C1-PVH projection is hypoxia-sensitive and the pathway between these two important brain areas can be one more piece in the complex puzzle of neural control of autonomic regulation during hypoxia. Male Wistar rats were injected with the targeted toxin Anti-DβH-SAP (Cat. #IT-03), 21 ng/100 nl, or saline, unilaterally into the PVH using the following coordinates: 1.2 mm caudal to bregma, 0.4 mm lateral to the midline and 7.8 mm below the dura mater. The author’s work adds a piece in the complex puzzle of the physiological role of the C1 cells by showing that this catecholaminergic group of cells must be activated only in emergency situations such as acute hypoxia, producing autonomic, metabolic, and neuroendocrine responses designed to help the organism survive major acute physical stresses.
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Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis.
Coradazzi M, Gulino R, Fieramosca F, Falzacappa L, Riggi M, Leanza G (2016) Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis. Neurobiol Aging 48:93-102. doi: 10.1016/j.neurobiolaging.2016.08.012
Summary: Neuronal loss in the locus coeruleus (LC) of Alzheimer’s patients is well known, but the contribution of LC-derived noradrenergic afferents to learning and memory function is unknown. To model noradrenergic neuron degeneration in the LC, rats were bilaterally injected directly into the LC with 0.2 ug of Anti-DBH-SAP (Cat. #IT-03). Lesioned and sham-lesioned animals were tested behaviorally and exhibited robust working memory deficits but lesioning did not affect reference memory. They concluded that ascending noradrenergic afferents might be involved in more complex aspects of working memory, possibly via newly generated progenitors in the hippocampus.
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