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1.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
2.
PLoS One ; 14(1): e0210949, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677060

RESUMO

We show that in an animal model of anxiety the overall excitation, particularly in the infralimbic region of the medial prefrontal cortex (IL), is increased and that the activity ratio between excitatory pyramidal neurons and inhibitory interneurons (AR PN/IN) is shifted towards excitation. The same change in AR PN/IN is evident for wildtype mice, which have been exposed to an anxiety stimulus. We hypothesize, that an elevated activity and the imbalance of excitation (PN) and inhibition (IN) within the neuronal microcircuitry of the prefrontal cortex is responsible for anxiety behaviour and employed optogenetic methods in freely moving mice to verify our findings. Consistent with our hypothesis elevation of pyramidal neuron activity in the infralimbic region of the prefrontal cortex significantly enhanced anxiety levels in several behavioural tasks by shifting the AR PN/IN to excitation, without affecting motor behaviour, thus revealing a novel mechanism by which anxiety is facilitated.


Assuntos
Ansiedade/patologia , Ansiedade/fisiopatologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/patologia , Células Piramidais/fisiologia , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Ansiedade/etiologia , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/fisiopatologia , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/patologia , Núcleo Dorsal da Rafe/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Optogenética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor 5-HT1A de Serotonina/deficiência , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/fisiologia , Transmissão Sináptica
3.
Sleep Med ; 49: 53-63, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30078667

RESUMO

The dorsal raphe nucleus (DRN) through its extensive efferent projections has been implicated in a great variety of physiological and behavioral functions including the regulation of the sleep-wake cycle. This nucleus is composed of five sub-regions defined according to the distribution of its serotonergic (5-HT) neurons. In addition to its heterogeneity in neuronal populations, the DRN contains a great diversity of 5-HT neuronal subtypes identified based on their electrophysiological characteristics, morphology and sub-regional distribution. This suggests that the DRN sub-regions may play different functional roles. Recent studies reported long-range inputs specific to the 5-HT neurons of the DRN; but they did not differentiate whether some inputs were specific to a DRN sub-region, or another region. To fulfill this gap, we have previously described the forebrain afferents to the different sub-regions of the DRN using cholera toxin b subunit and Phaseolus vulgaris-leucoagglutinin, as retrograde and anterograde tracers respectively. In the present work, we provide a detailed map of the brainstem projections to these different sub-regions. We show that if some brainstem structures project homogeneously to all sub-regions, most of the brainstem long-range inputs project in a topographically organized manner onto the DRN and, moreover, that a rich interconnected network is present within the DRN.


Assuntos
Tronco Encefálico/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Vias Neurais/fisiologia , Neurotransmissores/fisiologia , Serotonina/metabolismo , Animais , Toxina da Cólera , Núcleo Dorsal da Rafe/anatomia & histologia , Núcleo Dorsal da Rafe/patologia , França , Imuno-Histoquímica/métodos , Masculino , Vias Neurais/anatomia & histologia , Neurônios/fisiologia , Fito-Hemaglutininas , Ratos , Pesquisa , Vigília/fisiologia
4.
Neuropharmacology ; 137: 268-274, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29778010

RESUMO

The endocannabinoid (eCB) system is involved in the modulation of the reward system and participates in the reinforcing effects of different drugs of abuse, including alcohol. The most abundant receptor of the eCB system in the central nervous system is the CB1 receptor (CB1R), which is predominantly expressed in areas involved in drug addiction, such as the nucleus accumbens, the ventral tegmental area, the substantia nigra and the raphe nucleus. CB1R is expressed in early stages during development, and reaches maximum levels during early adolescence. In addition, cannabinoid receptor 2 has been found expressed also in the central nervous system at postsynaptic level. In order to analyze the participation of the eCB system on ethanol (EtOH) preference, mice were exposed to cannabinoid agonist WIN 55,212-2 (WIN) for 5 consecutive days during early adolescence. Anxiety tests were performed the day after WIN treatment withdrawal, and EtOH preference was measured throughout adolescence. Mice exposed to WIN during early adolescence exhibited a significant increase in EtOH intake and preference after treatment. Moreover, WIN exposure during early adolescence induced an anxiogenic effect. Morphometric analysis revealed higher dendritic ramifications and fewer dendritic spines in neurons of the substantia nigra pars compacta in WIN-treated mice. On the other hand, immunohistochemical analysis revealed an increase in the number of tryptophan hydroxylase-expressing neurons in the dorsal raphe nucleus but no differences were found in the ventral tegmental area or substantia nigra pars compacta for tyrosine hydroxylase-expressing neurons. These results demonstrate that exposure to WIN in early adolescence can affect neural development and induce alcohol preference and anxiety-like behavior during late adolescence.


Assuntos
Consumo de Bebidas Alcoólicas , Ansiedade/etiologia , Benzoxazinas/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Morfolinas/efeitos adversos , Naftalenos/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/patologia , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Depressores do Sistema Nervoso Central/administração & dosagem , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/crescimento & desenvolvimento , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Etanol/administração & dosagem , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/crescimento & desenvolvimento , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Distribuição Aleatória , Receptores de Canabinoides/metabolismo , Serotonina/metabolismo , Maturidade Sexual , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/crescimento & desenvolvimento , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia
5.
Sud Med Ekspert ; 61(1): 49-51, 2018.
Artigo em Russo | MEDLINE | ID: mdl-29405190

RESUMO

The objective of the present study was to evaluate the possibilities for the use of the changes in the AgNOR staining patterns in the neurons of the dorsal raphe nucleus (DRN) for the purposes of the medical differential diagnostics of the cases of death from chronic alcohol intoxication. We elucidated the characteristics of the activity of protein biosynthesis including the number and the area of the nucleoli in the nuclei of the neurons of the individuals who had died from chronic alcohol intoxication (n=20) in comparison with the subjects of the control group (n=13). To reveal the morphological structures associated with protein biosynthesis in the nucleoli of the serotoninergic neurons of the dorsal raphe nucleus in the brain, the histological preparations were stained with the use of the silver-staining technique for nucleolar organizer regions (AgNOR). The comparative statistical analysis of the results thus obtained with the calculated confidence coefficients was carried out. The aggregated analysis of all the dorsal raphe subnuclei revealed the impairment of the AgNOR staining characteristics in the neurons of the subjects who had died from chronic alcohol intoxication in comparison with those of the subjects comprising the control group. It is concluded that the results of the study can be used for differential diagnostics of deaths from chronic alcohol intoxication and other causes.


Assuntos
Alcoolismo/metabolismo , Encéfalo/metabolismo , Patologia Legal/métodos , Biossíntese de Proteínas , Neurônios Serotoninérgicos/metabolismo , Adulto , Alcoolismo/patologia , Autopsia , Encéfalo/patologia , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Serotoninérgicos/patologia
6.
Biol Psychiatry ; 83(12): 1024-1035, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29357981

RESUMO

BACKGROUND: Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. METHODS: We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. RESULTS: SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. CONCLUSIONS: Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.


Assuntos
Anestésicos Locais/administração & dosagem , Cocaína/administração & dosagem , Comportamento Compulsivo/patologia , Núcleo Dorsal da Rafe/patologia , Núcleos da Rafe do Mesencéfalo/patologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Anestésicos Locais/metabolismo , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Cocaína/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Motivação/efeitos dos fármacos , Motivação/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Wistar , Autoadministração , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Fatores de Tempo , Transdução Genética
7.
J Neurosci ; 37(26): 6214-6223, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28546314

RESUMO

The current study examined the neurochemical mechanisms and neuroanatomical changes underlying coexisting behavioral effects associated with chronic-stress-induced alterations in serotonin (5HT) neurons. Chronic unpredictable stress (CUS) to adult male rats produced depression-like changes with cognitive dysfunction and selective cell death in the interfascicular nucleus of the dorsal raphe (DRif), resulting in decreased 5HTergic innervation of medial prefrontal cortex (mPFC). Twenty-one days of CUS decreased basal plasma levels of corticosterone and produced a shorter latency to immobility and longer durations of immobility in the force-swim test that persisted for 1 month after CUS. Deficits in acquisition, recall, perseveration, and reversal learning were evident 1 month after CUS. MK801 treatment during CUS blocked the changes in the forced-swim test and deficits in memory recall. These behavioral changes were associated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive soma and the eventual loss of 5HT neurons in the DRif and its projections to the mPFC as evidenced by fewer labeled cells in the DRif after retrograde tracer injections into the mPFC of stressed rats. Similar to the effects of MK801 on behavior, MK801 pretreatment during stress blocked the CUS-induced decreases in 5HT soma within the DRif and its projections to the mPFC. Finally, the depression-like behaviors were blocked by acute injection of the 5HT2A/C agonist (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride into the mPFC before forced-swim testing. These results identify a cause and mechanism of 5HTergic dysfunction of the mPFC and associated mood and cognitive behaviors.SIGNIFICANCE STATEMENT Chronic stress causes persistent mood and cognitive changes typically associated with dysregulated serotonin (5HT) transmission in the medial prefrontal cortex (mPFC), but the cause of this dysregulation is unknown. Prior studies have focused on 5HTergic terminals in this region, but this study shows that chronic stress causes NMDA-receptor-dependent and subregion-specific cell death of 5HT neurons in the dorsal raphe. The consequent decreased 5HT innervation of the mPFC was associated with mood and cognitive changes that persisted long after the termination of stress. These findings identify a mechanism of subregion-selective death of 5HT neurons in the dorsal raphe, a defined neuroanatomical pathway, and a behavioral phenotype that mirror stress-associated diseases such as major depressive disorder.


Assuntos
Apoptose , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Transtornos Mentais/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Estresse Psicológico/fisiopatologia , Animais , Doença Crônica , Masculino , Transtornos Mentais/etiologia , Transtornos Mentais/patologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/patologia
8.
Proc Natl Acad Sci U S A ; 114(17): E3526-E3535, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28396432

RESUMO

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.


Assuntos
Tonsila do Cerebelo , Catalepsia , Núcleo Dorsal da Rafe , Neurônios Serotoninérgicos/metabolismo , Transdução de Sinais , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Catalepsia/genética , Catalepsia/metabolismo , Catalepsia/patologia , Catalepsia/fisiopatologia , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Núcleo Dorsal da Rafe/fisiopatologia , Movimentos Oculares , Masculino , Camundongos , Camundongos Knockout , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismo
10.
Brain Dev ; 39(6): 475-482, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28233694

RESUMO

OBJECTIVE: There is concern that bisphenol A (BPA), an endocrine-disrupting chemical, affects brain development when exposed to a fetus and/or infant. We previously reported that increased serotonin (5-HT) and its metabolite (5-HIAA) in the dorsal raphe nucleus (DRN) in murine adult brains when they were prenatally exposed to low doses of BPA. This study investigates the morphological alteration of the dorsal raphe nucleus (DRN) in order to explain the disrupted serotonergic system after prenatal and lactational exposure to bisphenol A (BPA). METHODS: The murine dams were orally administrated with 500µg/kg/day of BPA from embryonic day 0 to postnatal 3weeks. The DRN, the main region of serotonin production, was morphometrically analyzed at 14weeks, using immunohistochemistry and image analysis combined with 3-dimensional reconstruction. RESULTS: No significant differences were revealed in the number of tryptophan hydroxylase 2-immunoreactive neurons in any of the DRN sub-regions or the morphometric parameters, including the whole volume, ventrodorsal, longitudinal, and wing lengths of the DRN among the BPA treatment and sex groups. CONCLUSIONS: The murine DRN was not morphologically affected by prenatal and lactational exposure to low doses of BPA. Further studies are necessary regarding the function of serotonergic neurons and the activity of different kinds of related receptors in the brain.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos Benzidrílicos/toxicidade , Núcleo Dorsal da Rafe/patologia , Lactação/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Neurônios Serotoninérgicos/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Núcleo Dorsal da Rafe/diagnóstico por imagem , Feminino , Glutamato Descarboxilase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
11.
Eur Arch Psychiatry Clin Neurosci ; 267(5): 403-415, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28229240

RESUMO

An involvement of the central serotonergic system has constantly been reported in the pathogenesis of suicide. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour, in which an abnormal microglia reaction seems to play a role. In our present study, the density of microglia immunostained for the HLA-DR antigen was evaluated in the DRN. These analyses were carried out on paraffin-embedded brains from 24 suicidal and 21 non-suicidal patients; among them, 27 depressed (15 major depressive disorder and 12 bipolar disorder) and 18 schizophrenia (9 residual and 9 paranoid) patients and 22 matched controls without mental disorders. Only the non-suicidal depressed subgroup revealed significantly lower microglial reaction, i.e., a decreased density of HLA-DR positive microglia versus both depressed suicide victims and controls. The effect was not related to antidepressant or antipsychotic medication, as the former correlated positively with microglial density in non-suicidal depressed patients, and the latter had no effect. Moreover, the comparison of these results with previously published data from our workgroup in the same cohort (Krzyzanowska et al. in Psychiatry Res 241:43-46, 4) suggested a positive impact of microglia on ribosomal DNA transcription in DRN neurons in the non-suicidal depressed subgroup, but not in depressed suicidal cases. Therefore, the interaction between microglia and neurons in the DRN may be potentially involved in opposite ways regarding suicide facilitation and prevention in the tested subgroups of depressed patients.


Assuntos
Núcleo Dorsal da Rafe/patologia , Antígenos HLA-DR/metabolismo , Microglia/metabolismo , Transtornos do Humor/patologia , Transtornos do Humor/psicologia , Suicídio/psicologia , Adulto , Idoso , Transtorno Bipolar/patologia , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Contagem de Células , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Estatísticas não Paramétricas
12.
Neuropathol Appl Neurobiol ; 43(5): 393-408, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28117917

RESUMO

AIMS: Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages. METHODS: We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-µm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases. RESULTS: In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN. CONCLUSIONS: LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.


Assuntos
Doença de Alzheimer/patologia , Núcleo Dorsal da Rafe/patologia , Locus Cerúleo/patologia , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Progressão da Doença , Núcleo Dorsal da Rafe/metabolismo , Feminino , Humanos , Corpos de Inclusão/patologia , Locus Cerúleo/metabolismo , Masculino , Pessoa de Meia-Idade
13.
Cell Mol Life Sci ; 74(3): 509-523, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27628303

RESUMO

Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Tronco Encefálico/patologia , Metilação de DNA , Epigênese Genética , Animais , Tronco Encefálico/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Humanos
14.
J Alzheimers Dis ; 55(4): 1605-1619, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27814296

RESUMO

Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate in patients with Alzheimer's disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome-changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)-a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.


Assuntos
Doença de Alzheimer , Densidade Óssea/fisiologia , Doenças Ósseas/etiologia , Núcleo Dorsal da Rafe/patologia , Serotonina/metabolismo , Proteínas tau/genética , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Composição Corporal/genética , Peso Corporal/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Tauopatias/complicações , Tauopatias/genética , Triptofano Hidroxilase/metabolismo , Proteínas tau/metabolismo
15.
Behav Brain Res ; 321: 193-200, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28034802

RESUMO

One of the main neurochemical systems associated with anxiety/panic is the serotonergic system originating from the dorsal raphe nucleus (DR). Previous evidence suggests that the DR is composed of distinct subpopulations of neurons, both morphologically and functionally distinct. It seems that mainly the dorsal region of the DR (DRD) regulates anxiety-related reactions, while lateral wings DR (lwDR) serotonin (5-HT) neurons inhibit panic-related responses. In this study we used the technique of deep brain stimulation (DBS) to investigate the role played by the DRD and lwDR in defense. Male Wistar rats were submitted to high-frequency stimulation (100µA, 100Hz) in one of the two DR regions for 1h and immediately after tested in the avoidance or escape tasks of the elevated T-maze (ETM). In clinical terms, these responses have been related to generalized anxiety and panic disorder, respectively. After being submitted to the ETM, animals were placed in an open field for locomotor activity assessment. An additional group of rats was submitted to DBS of the DRD or the lwDR and used for quantification of c-Fos immunoreactive (Fos-ir) neurons in brain regions related to the modulation of defense. Results showed that stimulation of the DRD decreased avoidance latencies, an anxiolytic-like effect. DRD stimulation also led to increases in Fos-ir in the medial amygdala, lateral septum and cingulate cortex. DBS applied to the lwDR increased escape latencies, a panicolytic-like effect. This data highlights the importance of raphe topography and the potential benefit of the DBS technique for the treatment of anxiety-related disorders.


Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Estimulação Encefálica Profunda , Núcleo Dorsal da Rafe/fisiopatologia , Reação de Fuga/fisiologia , Pânico/fisiologia , Animais , Núcleo Dorsal da Rafe/patologia , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Neurônios/patologia , Prosencéfalo/patologia , Prosencéfalo/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar
16.
Psychiatry Res ; 241: 43-6, 2016 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-27155286

RESUMO

The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour. We have evaluated the transcriptional activity of ribosomal DNA (rDNA) in DRN neurons by AgNOR silver staining method. The cohort (containing 24 suicidal and 20 non-suicidal patients, and 28 controls) was previously analysed regarding diagnosis-related differences between schizophrenia and affective disorders. Significant decreases in both AgNOR and nuclear areas suggestive of attenuated rDNA activity were currently found in suicidal versus non-suicidal patients. This effect, which was more accentuated in affective disorders patients, was not explained by antidepressant and antipsychotic medication.


Assuntos
Transtorno Bipolar/metabolismo , DNA Ribossômico/metabolismo , Transtorno Depressivo Maior/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismo , Suicídio , Transtorno Bipolar/patologia , Estudos de Coortes , Transtorno Depressivo Maior/patologia , Núcleo Dorsal da Rafe/patologia , Humanos , Esquizofrenia/patologia , Coloração pela Prata
17.
Sleep ; 39(6): 1249-52, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27091531

RESUMO

STUDY OBJECTIVES: Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI. METHODS: Postmortem examination of 8 TBI patients and 10 controls. RESULTS: Compared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls. CONCLUSIONS: TBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries.


Assuntos
Nível de Alerta , Lesões Encefálicas Traumáticas/patologia , Tronco Encefálico/patologia , Neurônios/patologia , Neurônios Adrenérgicos/patologia , Autopsia , Estudos de Casos e Controles , Neurônios Colinérgicos/citologia , Núcleo Dorsal da Rafe/patologia , Humanos , Hipotálamo/patologia , Locus Cerúleo/patologia , Vias Neurais , Neurônios/citologia , Ponte/citologia , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/patologia
19.
Cell ; 164(4): 617-31, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26871628

RESUMO

The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PAPERCLIP.


Assuntos
Neurônios Dopaminérgicos/patologia , Núcleo Dorsal da Rafe/patologia , Solidão , Animais , Dopamina/metabolismo , Núcleo Dorsal da Rafe/fisiopatologia , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Optogenética , Técnicas de Patch-Clamp , Recompensa , Sinapses , Área Tegmentar Ventral/fisiologia
20.
Br J Pharmacol ; 173(13): 2135-46, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26805402

RESUMO

BACKGROUND AND PURPOSE: L-DOPA is still the most efficacious pharmacological treatment for Parkinson's disease. However, in the majority of patients receiving long-term therapy with L-DOPA, its efficacy is compromised by motor complications, notably L-DOPA-induced dyskinesia. Evidence suggests that the serotonergic system is involved in the therapeutic and the side effects of L-DOPA. Here, we investigate if long-term L-DOPA treatment alters the activity of the dorsal raphe nucleus (DRN) and its responses to serotonergic drugs. EXPERIMENTAL APPROACH: We measured the responses of serotonergic neurons to acute and chronic L-DOPA treatment using in vivo electrophysiological single unit-extracellular recordings in the 6-OHDA-lesion rat model of Parkinson's disease. KEY RESULTS: The results showed that neither acute nor chronic L-DOPA administration (6 mg·kg(-1)  s.c.) altered the properties of serotonergic-like neurons. Furthermore, no correlation was found between the activity of these neurons and the magnitude of L-DOPA-induced dyskinesia. In dyskinetic rats, the inhibitory response induced by the 5-HT1A receptor agonist 8-OH-DPAT (0.0625-16 µg·kg(-1) , i.v.) was preserved. Nonetheless, L-DOPA impaired the ability of the serotonin reuptake inhibitor fluoxetine (0.125-8 mg·kg(-1) , i.v) to inhibit DRN neuron firing rate in dyskinetic animals. CONCLUSIONS AND IMPLICATIONS: Although serotonergic neurons are involved in the dopaminergic effects of L-DOPA, we provide evidence that the effect of L-DOPA is not related to changes of the activity of DRN neurons. Rather, L-DOPA might reduce the efficacy of drugs that normally enhance the extracellular levels of serotonin. LINKED ARTICLES: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.


Assuntos
Dopaminérgicos/farmacologia , Núcleo Dorsal da Rafe/citologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Animais , Dopaminérgicos/administração & dosagem , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Discinesia Induzida por Medicamentos/patologia , Levodopa/administração & dosagem , Oxidopamina , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismo
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