Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice.

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout (, which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of knockout on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls.

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice.

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout ( -/-), which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of knockout ( -/-) on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls.

Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.

The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is an early site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC-NE loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown.

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease.

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms.

Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine beta-hydroxylase deficient mice.

Norepinephrine (NE), and specific adrenoceptors, have been reported to influence distinct aspects of adult hippocampal neurogenesis, including latent stem cell activation, progenitor proliferation, and differentiation. These findings are predominantly based on the use of pharmacological approaches in both and systems. Here, we sought to assess the consequences of genetic ablation of NE on adult hippocampal neurogenesis, by examining dopamine β hydroxylase knockout () mice, which lack NE from birth.

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice.

Exposure to unfamiliar odorants induces an array of repetitive defensive and non-defensive behaviors in rodents which likely reflect adaptive stress responses to the uncertain valence of novel stimuli. Mice genetically deficient for dopamine β-hydroxylase (Dbh-/-) lack the enzyme required to convert dopamine (DA) into norepinephrine (NE), resulting in globally undetectable NE and supranormal DA levels. Because catecholamines modulate novelty detection and reactivity, we investigated the effects of novel plant-derived odorants on repetitive behaviors in Dbh-/- mice and Dbh+/- littermate controls, which have catecholamine levels comparable to wild-type mice.

Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior.

Both the noradrenergic and galaninergic systems have been implicated in stress-related neuropsychiatric disorders, and these two neuromodulators are co-released from the stress-responsive locus coeruleus (LC); however, the individual contributions of LC-derived norepinephrine (NE) and galanin to behavioral stress responses are unclear. Here we aimed to disentangle the functional roles of co-released NE and galanin in stress-induced behavior. We used foot shock, optogenetics, and behavioral pharmacology in wild-type (WT) mice and mice lacking either NE (Dbh) or galanin (Gal) specifically in noradrenergic neurons to isolate the roles of these co-transmitters in regulating anxiety-like behavior in the elevated zero maze (EZM) either immediately or 24 h following stress.

Chronic Environmental or Genetic Elevation of Galanin in Noradrenergic Neurons Confers Stress Resilience in Mice.

The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise.

Noradrenergic circuits in the forebrain control affective responses to novelty.

Rationale: In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.

Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder.

Rationale: Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated.

Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors.

Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell type-specific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (Gal). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of Gal mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls.

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology.

Loss of β-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids.

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein-coupled receptors. β-arrestin2 (βarr2) desensitizes and internalizes these receptors and initiates G protein-independent signaling. Previous work revealed that mice with a global or cell-specific knockout of βarr2 have altered responses to certain drugs; however, the effects of βarr2 on the excitability of medium spiny neurons (MSNs), and its role in mediating the rewarding effects of drugs of abuse are unknown.

Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice.

The brainstem locus coeruleus (LC) supplies norepinephrine to the forebrain and degenerates in Alzheimer's disease (AD). Loss of LC neurons is correlated with increased severity of other AD hallmarks, including β-amyloid (Aβ) plaques, tau neurofibrillary tangles, and cognitive deficits, suggesting that it contributes to the disease progression. Lesions of the LC in amyloid-based transgenic mouse models of AD exacerbate Aβ pathology, neuroinflammation, and cognitive deficits, but it is unknown how the loss of LC neurons affects tau-mediated pathology or behavioral abnormalities.

Noradrenergic regulation of plasticity marker expression in the adult rodent piriform cortex.

The adult rodent piriform cortex has been reported to harbor immature neurons that express markers associated with neurodevelopment and plasticity, namely polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX). We characterized the expression of PSA-NCAM and DCX across the rostrocaudal axis of the rat piriform cortex and observed higher numbers of PSA-NCAM and DCX positive cells in the posterior subdivision. As observed in the rat piriform cortex, Nestin-GFP reporter mice also revealed a similar gradient of GFP-positive cells with an increasing rostro-caudal gradient of expression.

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial.

Norepinephrine is necessary for experience-dependent plasticity in the developing mouse auditory cortex.

Critical periods are developmental windows during which the stimuli an animal encounters can reshape response properties in the affected system to a profound degree. Despite this window's importance, the neural mechanisms that regulate it are not completely understood. Pioneering studies in visual cortex initially indicated that norepinephrine (NE) permits ocular dominance column plasticity during the critical period, but later research has suggested otherwise.

Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat.

Efficacy of augmenting a subacromial continuous-infusion pump with a preoperative interscalene block in outpatient arthroscopic shoulder surgery: a prospective, randomized, blinded, and placebo-controlled study.

Purpose: This study's purpose was to determine the effectiveness of adding a preoperative interscalene brachial plexus block to standard postoperative management, including oral narcotics and a subacromial bupivacaine infusion pump, after arthroscopic shoulder surgery.

Methods: After performing a prospective power analysis and obtaining institutional board approval, we conducted a randomized placebo-controlled trial of 53 patients separated into a preoperative interscalene brachial plexus group and a control group. Group 1 received an interscalene block with 30 mL of 0.

Central venous line placement in the superior vena cava and the azygos vein: differentiation on posteroanterior chest radiographs.

Objective: The purpose of this study was to determine, first, the accuracy with which radiologists reading posteroanterior chest radiographs differentiate whether a central venous line is in the superior vena cava or the azygos vein and, second, the circumstances in which radiologists may omit the lateral view to determine the position of a central venous line.

Materials And Methods: Twenty-four radiologists evaluated 60 posteroanterior chest radiographs to determine the position of a central venous line in the superior vena cava or azygos vein. Investigators evaluated the appearance of the central venous lines to refine rules for determining central venous line position on a frontal radiograph and omitting the lateral view.

Randomized prospective clinical trial comparing reamer irrigator aspirator (RIA) to standard reaming (SR) in both minimally injured and multiply injured patients with closed femoral shaft fractures treated with reamed intramedullary nailing (IMN).

Purpose: To investigate whether inflammatory markers are improved among patients with traumatic femur fractures who undergo RIA reamed intramedullary nailing (IMN) prior to fixation when compared to patients treated with standard reamed (SR) IMN.

Methods: A prospective, randomized, single-blind trial was conducted on patients who had a closed femoral shaft fracture amenable to reamed IMN. Patients were randomized to undergo IMN with standard reaming or IMN with the RIA in a 1:1 ratio.

Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action.

Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency).

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures.

The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat.

Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

Background: Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety.

Methods: In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety.