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1.
Sci Transl Med ; 11(523)2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852801

RESUMO

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2 Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação a Poli(A)/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Animais , Proteínas de Transporte/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Proteína I de Ligação a Poli(A)/genética , Proteína I de Ligação a Poli(A)/metabolismo , Proteínas de Ligação a Poli(A)/genética , Proteínas tau/genética
2.
Int J Geriatr Psychiatry ; 33(5): 763-768, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29446123

RESUMO

OBJECTIVE: This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD. METHODS: Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n = 305), participants with aMCI (n = 22), and AD dementia (n = 94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index. RESULTS: Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients ± standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0 ± 0.2, P = 1.0; MCI, 1.4 ± 0.7, P = .14; and AD 1.1 ± 0.4, P = .032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2 ± 0.3, P = .007). CONCLUSIONS: Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress.


Assuntos
Amnésia/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Hidrocortisona/líquido cefalorraquidiano , Norepinefrina/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiologia , Adulto Jovem
3.
Neuroscience ; 355: 9-21, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28456715

RESUMO

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, exactly how neuroinflammation leads to, or contributes to, these central disorders is unclear. The objective of the study was to examine and compare the expression of mRNAs for interleukin-6 (IL-6), IL-7, IL-10 and the receptors for IL-6 (IL-6R) and IL-7 (IL-7R) using in situ hybridization in discrete brain regions and in the spleen after multiple injections of 3mg/kg lipopolysaccharide (LPS), a model of neuroinflammation. In the spleen, LPS significantly elevated IL-6 mRNA expression, then IL-10 mRNA, with no effect on IL-7 or IL-7R mRNA, while significantly decreasing IL-6R mRNA expression. In the CNS, LPS administration had the greatest effect on IL-6 and IL-6R mRNA. LPS increased IL-6 mRNA expression only in non-neuronal cells throughout the brain, but significantly elevated IL-6R mRNA in neuronal populations, where observed, except the cerebellum. LPS resulted in variable effects on IL-10 mRNA, and had no effect on IL-7 or IL-7R mRNA expression. These studies indicate that LPS-induced neuroinflammation has substantial but variable effects on the regional and cellular patterns of CNS IL-6, IL-7 and IL-10, and for IL-6R and IL-7R mRNA expression. It is apparent that administration of LPS can affect non-neuronal and neuronal cells in the brain. Further research is required to determine how CNS inflammatory changes associated with IL-6, IL-10 and IL-6R could in turn contribute to the development of CNS neurological disorders.


Assuntos
Encéfalo/metabolismo , Interleucinas/metabolismo , RNA Mensageiro/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores de Interleucina-7/metabolismo , Baço/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Interleucinas/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfopiruvato Hidratase/metabolismo , Receptores de Interleucina-6/genética , Receptores de Interleucina-7/genética , Baço/efeitos dos fármacos
4.
PLoS One ; 11(5): e0154864, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27148966

RESUMO

Dopamine ß-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. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice.


Assuntos
Cromossomos Artificiais Bacterianos/fisiologia , Dopamina beta-Hidroxilase/metabolismo , Técnicas de Transferência de Genes , Glândulas Suprarrenais/química , Neurônios Adrenérgicos/metabolismo , Animais , Química Encefálica , Cromossomos Artificiais Bacterianos/genética , Dopamina/análise , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/fisiologia , Humanos , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora , Miocárdio/química , Norepinefrina/análise , Reação em Cadeia da Polimerase em Tempo Real
5.
Neuropharmacology ; 101: 76-86, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26362360

RESUMO

Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer's disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 µg/µl), animals administered the 5 µg/µl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 µg/µl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 µg/µl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 µg/µl dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 µg/µl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or l-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 µg/µl) demonstrated compensatory changes of increased firing frequency, a more irregular firing pattern, and a higher percentage of cells firing in bursts. These results indicate that depressive-like behavior in mice is observed following the administration of 6-OHDA and the loss of LC noradrenergic neurons; however, the depressive-like behavior correlates positively with the number of surviving LC neurons with 6-OHDA administration. This data suggests the depression observed in MCI subjects and in the early stages of AD may due to the hypothesized early, minimal loss of LC neurons with remaining LC neurons being more active than normal.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Adrenérgicos/toxicidade , Catecolaminas/metabolismo , Depressão/induzido quimicamente , Locus Cerúleo/patologia , Neurônios/fisiologia , Oxidopamina/toxicidade , Animais , Depressão/patologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Preferências Alimentares , Levodopa/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Fenazinas/farmacologia , Sacarose/administração & dosagem , Natação/psicologia , Fatores de Tempo
6.
Front Pharmacol ; 3: 184, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23129999

RESUMO

Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and dopaminergic system in PD.

7.
Epilepsia ; 53 Suppl 1: 61-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22612810

RESUMO

The neurodegenerative disorders Alzheimer's disease (AD) and Parkinson's disease (PD) share in common the neuropathologic loss of locus coeruleus (LC) noradrenergic neurons. In addition, these two neurodegenerative disorders share two symptoms that define these disorders: cognitive impairment and depression. The hippocampus is a region that is known to play a role in cognition and depression, and the hippocampus receives sole noradrenergic innervation from LC neurons. However, it is unclear how the loss of LC noradrenergic neurons contributes to these common symptoms in these two disorders. Epilepsy is not considered a neurodegenerative disorder, but the hippocampus is severely affected in temporal lobe epilepsy. Of interest, cognitive impairment and depression are also common comorbid disorders in temporal lobe epilepsy. This article describes common symptoms among these three neurologic disorders and a possible role of the noradrenergic nervous system.


Assuntos
Neurônios Adrenérgicos/patologia , Doença de Alzheimer/patologia , Epilepsia/patologia , Neuroglia/patologia , Norepinefrina/fisiologia , Doença de Parkinson/patologia , Sistema Nervoso Simpático/patologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Humanos , Locus Cerúleo/patologia
8.
Neurosurgery ; 69(6): 1281-90, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21566538

RESUMO

BACKGROUND: Recent interest has demonstrated the nucleus accumbens (NAcc) as a potential target for the treatment of depression with deep brain stimulation (DBS). OBJECTIVE: To demonstrate that DBS of the NAcc is an effective treatment modality for depression and that chemical and structural changes associated with these behavioral changes are markers of neuroplasticity. METHODS: A deep brain stimulator was placed in the NAcc of male Wistar-Kyoto rats. Groups were divided into sham (no stimulation), intermittent (3 h/d for 2 weeks), or continuous (constant stimulation for 2 weeks). Exploratory and anxietylike behaviors were evaluated with the open-field test before and after stimulation. Tissue samples of the prefrontal cortex (PFC) were processed with Western blot analysis of markers of noradrenergic activity that included the noradrenergic synthesizing enzyme tyrosine hydroxylase. Analysis of tissue levels for catecholamines was achieved with high-performance liquid chromatography. Morphological properties of cortical pyramidal neurons were assessed with Golgi-Cox staining. RESULTS: Subjects undergoing intermittent and continuous stimulation of the NAcc exhibited an increase in exploratory behavior and reduced anxietylike behaviors. Tyrosine hydroxylase expression levels were decreased in the PFC after intermittent and continuous DBS, and dopamine and norepinephrine levels were decreased after continuous stimulation. Golgi-Cox staining indicated that DBS increased the length of apical and basilar dendrites in pyramidal neurons of the PFC. CONCLUSION: Deep brain stimulation induces behavioral improvement in and neurochemical and morphological alterations of the PFC that demonstrate changes within the circuitry of the brain different from the target area of stimulation. This observed dendritic plasticity may underlie the therapeutic efficacy of this treatment.


Assuntos
Estimulação Encefálica Profunda/métodos , Depressão/terapia , Comportamento Exploratório/fisiologia , Plasticidade Neuronal/fisiologia , Núcleo Accumbens/fisiologia , Animais , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo , Cromatografia Líquida de Alta Pressão , Depressão/patologia , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Células Piramidais/fisiopatologia , Células Piramidais/ultraestrutura , Distribuição Aleatória , Ratos , Ratos Endogâmicos WKY , Coloração pela Prata , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Biol Psychiatry ; 70(5): 441-8, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21251647

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system. METHODS: An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2 mA, 10 sec) followed by exposure to six contextual 1-minute reminders of the shock over a 25-day period. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice). RESULTS: Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic α(1)-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice. CONCLUSIONS: These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress.


Assuntos
Agressão/fisiologia , Modelos Animais de Doenças , Norepinefrina/fisiologia , Comportamento Social , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Estimulação Acústica/métodos , Agressão/efeitos dos fármacos , Animais , Mapeamento Encefálico/métodos , Clonidina/farmacologia , Estimulação Elétrica/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prazosina/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/psicologia
10.
Brain Res ; 1373: 240-52, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21147074

RESUMO

In Parkinson's disease (PD), there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) in addition to the loss of dopaminergic neurons in the substantia nigra (SN). The goal of this study was to determine if the surviving LC noradrenergic neurons in PD demonstrate compensatory changes in response to the neuronal loss, as observed in Alzheimer's disease (AD). Tyrosine hydroxylase (TH) and dopamine ß-hydroxylase (DBH) mRNA expression in postmortem LC tissue of control and age-matched PD subjects demonstrated a significant reduction in the number of noradrenergic neurons in the LC of PD subjects. TH mRNA expression/neuron did not differ between control and PD subjects, but DBH mRNA expression/neuron was significantly elevated in PD subjects compared to control. This increase in DBH mRNA expression in PD subjects is not a response to neuronal loss because the amount of DBH mRNA expression/neuron in AD subjects was not significantly different from control. Norepinephrine transporter (NET) binding site concentration in the LC of PD subjects was significantly reduced over the cell body region as well as the peri-LC dendritic zone. In PD subjects, the loss of dendrites from surviving noradrenergic neurons was also apparent with TH-immunoreactivity (IR). This loss of LC dendritic innervation in PD subjects as measured by TH-IR was not due to LC neuronal loss because TH-IR in AD subjects was robust, despite a similar loss of LC neurons. These data suggest that there is a differential response of the noradrenergic nervous system in PD compared to AD in response to the loss of LC neurons.


Assuntos
Doença de Alzheimer/patologia , Locus Cerúleo/patologia , Neurônios/fisiologia , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Contagem de Células/métodos , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Trítio/farmacocinética , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
11.
Neurosci Lett ; 463(1): 93-7, 2009 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-19631722

RESUMO

Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several animal models of AD have been developed that exhibit some of the pathophysiological changes in the CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression. Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no difference between 6 and 12 months. These observations indicate that any study comparing the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested and limit age differences between control and experimental groups to the absolute minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish between potential therapeutic and strain-specific developmental or age-related alterations.


Assuntos
Envelhecimento/metabolismo , Precursor de Proteína beta-Amiloide/genética , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Animais , Locus Cerúleo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/enzimologia , RNA Mensageiro/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética
12.
Brain Res ; 1285: 109-18, 2009 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-19524553

RESUMO

An important factor in determining the adverse consequences of a stress experience is the degree to which an individual can exert control over the stressor. Stressor controllability is known to influence brain norepinephrine levels, but its impact on activity in noradrenergic cell bodies is unknown. In the present study we investigated whether noradrenergic neurons within the locus coeruleus (LC), the major source of forebrain norepinephrine, are sensitive to stressor controllability. We exposed adult male Sprague-Dawley rats to escapable or yoked inescapable tailshock and assessed LC activity by measuring changes in the immediate early gene c-fos and the enzyme tyrosine hydroxylase (TH). We used in situ hybridization to measure levels of c-fos mRNA, TH mRNA, and TH primary transcript in the LC. In all three cases stress exposure increased expression relative to an unstressed homecage control group, but expression did not differ between controllable and uncontrollable stress. To further examine whether stressor controllability influences the number of stress-responsive LC neurons we performed double-label immunohistochemistry for TH and Fos. Again we detected an overall effect of stress, which did not differ between controllable and uncontrollable stress. We conclude that exposure to stress robustly increases expression of TH and c-fos in the LC, but this effect is not influenced by stressor controllability. To the extent that the expression of these genes reflects degree of neuronal activation, our results suggest that stress-induced activity of noradrenergic cell bodies in the LC is not sensitive to stressor controllability.


Assuntos
Medo/fisiologia , Locus Cerúleo/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Estresse Psicológico/fisiopatologia , Volição/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Estimulação Elétrica , Regulação da Expressão Gênica/fisiologia , Desamparo Aprendido , Imuno-Histoquímica , Hibridização In Situ , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/fisiologia
13.
Brain Res ; 1109(1): 45-53, 2006 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-16854392

RESUMO

The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-beta-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh-/-) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (alpha1-AR, alpha2-AR and beta-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh-/- mice with those in Dbh heterozygotes (Dbh+/-), which have normal levels of norepinephrine throughout life. The densities of alpha1-AR, alpha2-AR and beta-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The alpha2-AR agonist high affinity state was examined with [125I]-para-iodoclonidine autoradiography and alpha2-AR functionality by alpha2-AR agonist-stimulated [35S]GTPgammaS autoradiography. The density of alpha1-AR in Dbh-/- mice was similar to Dbh+/- mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in alpha2-AR were found in septum, hippocampus and amygdala, but these were not reflected in alpha2-AR functionality. The density of beta-AR was up-regulated to varying degrees in many brain regions of Dbh-/- mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region.


Assuntos
Encéfalo/metabolismo , Dopamina beta-Hidroxilase/deficiência , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Autorradiografia/métodos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Idazoxano/análogos & derivados , Idazoxano/metabolismo , Isótopos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pindolol/metabolismo , Prazosina/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 2/genética
14.
J Neurosci ; 26(2): 467-78, 2006 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-16407544

RESUMO

In Alzheimer's disease (AD), there is a significant loss of locus ceruleus (LC) noradrenergic neurons. However, functional and anatomical evidence indicates that the remaining noradrenergic neurons may be compensating for the loss. Because the noradrenergic system plays an important role in learning and memory, it is important to determine whether compensation occurs in noradrenergic neurons in the LC and hippocampus of subjects with AD or a related dementing disorder, dementia with Lewy bodies (DLB). We observed profound neuronal loss in the LC in AD and DLB subjects with three major changes in the noradrenergic system consistent with compensation: (1) an increase in tyrosine hydroxylase (TH) mRNA expression in the remaining neurons; (2) sprouting of dendrites into peri-LC dendritic zone, as determined by alpha2-adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by alpha2-ARs. In AD and DLB subjects, the postsynaptic alpha1-ARs were normal to elevated. Expression of alpha1A- and alpha2A-AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of alpha1D- and alpha2C-AR mRNA was significantly reduced in the hippocampus of AD and DLB subjects. Therefore, in AD and DLB subjects, there is compensation occurring in the remaining noradrenergic neurons, but there does appear to be a loss of specific AR in the hippocampus. Because changes in these noradrenergic markers in AD versus DLB subjects were similar (except neuronal loss and the increase in TH mRNA were somewhat greater in DLB subjects), the presence of Lewy bodies in addition to plaques and tangles in DLB subjects does not appear to further affect the noradrenergic compensatory changes.


Assuntos
Doença de Alzheimer/patologia , Hipocampo/patologia , Doença por Corpos de Lewy/patologia , Locus Cerúleo/patologia , Proteínas do Tecido Nervoso/análise , Norepinefrina/fisiologia , RNA Mensageiro/análise , Receptores Adrenérgicos alfa 1/análise , Receptores Adrenérgicos alfa 2/análise , Tirosina 3-Mono-Oxigenase/análise , Antagonistas Adrenérgicos alfa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Dendritos/ultraestrutura , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/metabolismo , Hipocampo/química , Humanos , Idazoxano/análogos & derivados , Idazoxano/metabolismo , Hibridização In Situ , Doença por Corpos de Lewy/metabolismo , Locus Cerúleo/química , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/análise , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Prazosina/metabolismo , RNA Mensageiro/biossíntese , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Tetralonas/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética
15.
Brain Res Mol Brain Res ; 139(2): 367-71, 2005 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-16039007

RESUMO

Alpha1-adrenoreceptors (AR), of which three subtypes exist (alpha1A-, alpha1B- and alpha1D-AR) are G-protein-coupled receptors that mediate the actions of norepinephrine and epinephrine both peripherally and centrally. In the CNS, alpha1-ARs are found in the hippocampus where animal studies have shown the ability of alpha1-AR agents to modulate long-term potentiation and memory; however, the precise distribution of alpha1-AR expression and its subtypes in the human brain is unknown making functional comparisons difficult. In the human hippocampus, 3H-prazosin (alpha1-AR antagonist) labels only the dentate gyrus (molecular, granule and polymorphic layers) and the stratum lucidum of the CA3 homogeneously. Human alpha1A-AR mRNA in the hippocampus is observed only in the dentate gyrus granule cell layer, while alpha1D-AR mRNA expression is observed only in the pyramidal cell layers of CA1, CA2 and CA3, regions where 3H-prazosin did not bind. alpha1B-AR mRNA is not expressed at detectable levels in the human hippocampus. These results confirm a difference in hippocampal alpha1-AR localization between rat and humans and further describe a difference in the localization of the alpha1A- and alpha1D-AR mRNA subtype between rats and humans.


Assuntos
Expressão Gênica/fisiologia , Hipocampo/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Ligação Proteica/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ensaio Radioligante/métodos , Receptores Adrenérgicos alfa 1/classificação , Receptores Adrenérgicos alfa 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Trítio/farmacocinética
16.
Brain Res Mol Brain Res ; 135(1-2): 285-9, 2005 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-15857691

RESUMO

Seizure-induced activity has been shown to increase the expression of immediate early genes (IEGs) c-fos and c-Jun in the CNS. Anti-epileptic drugs (AEDs) can suppress the induction of a seizure, but it is unknown if AEDs affect the expression of seizure-induced IEGs. We found that valproic acid (VPA), but not lamotrigine (LTG), was capable of suppressing seizure-induced c-fos and c-Jun mRNA expression in rats despite a similar anticonvulsant effect. LTG in some regions of the CNS enhanced seizure-induced IEG expression. These studies indicate that the older AED (VPA), as compared to the newer AED (LTG), can suppress seizure-induced IEG expression. The consequence of this suppression of IEGs following a generalized seizure may be viewed either as a neuroprotective or detrimental effect upon the brain.


Assuntos
Anticonvulsivantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Convulsões/metabolismo , Ácido Valproico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Flurotila , Regulação da Expressão Gênica/fisiologia , Hibridização In Situ/métodos , Lamotrigina , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Convulsões/induzido quimicamente , Triazinas/farmacologia
17.
Epilepsy Res ; 62(1): 35-9, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15519130

RESUMO

Neuropeptide Y (NPY) and galanin are neuropeptides that are regulated by energy states and are also anticonvulsant. We tested the hypothesis that the anticonvulsant efficacy of the ketogenic diet (KD) is mediated by increased expression of NPY and galanin via alterations in food intake and energy metabolism. In situ hybridization revealed no effect of the KD on NPY or galanin mRNA expression, suggesting that increased expression of NPY and galanin do not contribute to the anticonvulsant effect of the KD.


Assuntos
Química Encefálica/efeitos dos fármacos , Epilepsia/dietoterapia , Galanina/biossíntese , Neuropeptídeo Y/biossíntese , Ácido 3-Hidroxibutírico/sangue , Animais , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Hibridização In Situ , Cetonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Convulsões/induzido quimicamente , Convulsões/dietoterapia
18.
Dev Neurosci ; 24(4): 294-9, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12457067

RESUMO

Numerous studies have examined the brain regional distribution of the immediate early gene (IEG), c-fos, following seizures induced by a variety of chemical or electrical provocations in the rat. Very little is known concerning the regional and temporal distribution of IEG expression following seizures in mice, and even less regarding the effects of development. In the present study, seizures of varying severities were induced in immature (postnatal day 17-18) and mature male (postnatal day 55-60) C3H mice with flurothyl, a volatile convulsant. In the immature mouse, neither c-fos nor c-jun mRNA were statistically elevated following any type of acute seizure activity. In the mature mouse, seizures of different severity resulted in differential effects on regional c-fos and c-jun mRNA expression. We conclude that the c-fos and c-jun are not reliable indicators of seizure activity in immature mice, whereas they remain indirect markers of neuronal activity in mature mice.


Assuntos
Encéfalo/metabolismo , Convulsivantes/farmacologia , Flurotila/farmacologia , Genes fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/efeitos dos fármacos , Convulsões/induzido quimicamente , Fatores Etários , Animais , Genes fos/genética , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-jun/genética , RNA Mensageiro/análise
19.
Brain Res ; 946(2): 239-46, 2002 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-12137927

RESUMO

The norepinephrine transporter (NET) regulates adrenoreceptor signaling by controlling the availability of synaptic norepinephrine (NE), and it is a direct target for some classes of antidepressant drugs. NET levels are normal in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE, demonstrating that the NET does not require endogenous NE for appropriate regulation under physiological conditions. In contrast, tyrosine hydroxylase knockout (Th -/-) mice that lack both NE and dopamine (DA) have reduced levels of NET, suggesting that it is down-regulated by a complete absence of catecholamines and not NE per se. Chronic treatment with the NET inhibitor, desipramine (DMI), reduced NET levels in both control and Dbh -/- mice, demonstrating that NE is not required for the regulation of NET by antidepressant drugs. There are some qualitative and quantitative differences in the down-regulation of the NET by catecholamine depletion and DMI treatment, suggesting that different mechanisms may be involved.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Catecolaminas/farmacologia , Desipramina/farmacologia , Simportadores/metabolismo , Animais , Dopamina/metabolismo , Dopamina beta-Hidroxilase/deficiência , Dopamina beta-Hidroxilase/genética , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , RNA Mensageiro/biossíntese , Simportadores/biossíntese , Tirosina 3-Mono-Oxigenase/deficiência , Tirosina 3-Mono-Oxigenase/genética
20.
Pharmacol Ther ; 94(3): 213-33, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12113799

RESUMO

The catecholamines norepinephrine and dopamine are abundant in the CNS, and modulate neuronal excitability via G-protein-coupled receptor signaling. This review covers the history of research concerning the role of catecholamines in modulating seizure susceptibility in animal models of epilepsy. Traditionally, most work on this topic has been anatomical, pharmacological, or physiological in nature. However, the recent advances in transgenic and knockout mouse technology provide new tools to study catecholamines and their roles in seizure susceptibility. New results from genetically engineered mice with altered catecholamine signaling, as well as possibilities for future experiments, are discussed.


Assuntos
Catecolaminas/fisiologia , Convulsões/fisiopatologia , Animais , Suscetibilidade a Doenças , Camundongos , Camundongos Knockout
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