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1.
Medicine (Baltimore) ; 98(39): e17130, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574813

RESUMO

Animal studies have demonstrated that autophagy was involved in neuronal damage after intracerebral hemorrhage (ICH). Several studies showed thrombin-antithrombin (TAT) plasma levels were elevated in patients with ICH. In this study, we aimed to evaluate if autophagy occurred in patients with ICH; and the relationship between the severity of brain injury and plasma TAT levels.A novel tissue harvesting device was used during hematoma removal surgery to collect loose fragments of tissue surrounding the affected brain area in 27 ICH patients with hematoma volumes of >30 mL in the basal ganglia. Control tissues were obtained from patients who underwent surgery for arteriovenous malformation (n = 25). Transmission electron microscopy (TEM) and immunohistochemistry for autophagy-related proteins were used to evaluate the ultrastructural and morphologic cellular characteristics; and the extent of autophagy in the recovered tissue specimens. Stroke severity was assessed by using the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma TAT levels.Transmission electron microscopy showed autophagosomes and autolysosomes exist in neurons surrounding the hematoma, but not in the control tissues. The number of cells containing autophagic vacuoles correlated with the severity of brain injury. Immunohistochemistry showed strong LC3, beclin 1, and cathepsin D staining in ICH tissue specimens. Plasma TAT levels correlated positively with autophagic cells and ICH severity (P < .01).Autophagy was induced in perihematomal neurons after ICH. Autophagy and plasma TAT levels correlated positively with severity of brain injury. These results suggest that autophagy and increased plasma TAT levels may contribute to the secondary damage in ICH patients.


Assuntos
Autofagia , Hemorragia Cerebral/sangue , Hematoma/sangue , Neurônios/fisiologia , Peptídeo Hidrolases/sangue , Adulto , Idoso , Antitrombina III , Gânglios da Base/metabolismo , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/cirurgia , Feminino , Escala de Coma de Glasgow , Hematoma/fisiopatologia , Hematoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade
2.
Acta Histochem ; 121(4): 383-391, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30846200

RESUMO

The claustrum is a bilateral subcortical nucleus situated between the insular cortex and the striatum in the brain of all mammals. It consists of two embryologically distinct subdivisions - dorsal and ventral claustrum. The claustrum has high connectivity with various areas of the cortex, subcortical and allocortical structures. It has long been suggested that the various claustral connections have different types of synaptic contacts at the claustral neurons. However, to the best of our knowledge, the literature data on the ultrastructural organization of the different types of synaptic contacts in the dorsal claustrum are very few. Therefore, the aim of our study was to observe and describe the synaptic organization of the dorsal claustrum in the cat. We used a total of 10 adult male cats and conducted an ultrastructural study under a transmission electron microscope as per established protocol. We described a multitude of dendritic spines, which were subdivided into two types - with and without foot processes. Based on the size and shape of the terminal boutons, the quantity and distribution of vesicles and the characteristic features of the active synaptic zone, we described six types of synaptic boutons, most of which formed asymmetrical synaptic contacts. Furthermore, we reported the presence of axo-dendritic, axo-somatic, dendro-dendritic and axo-axonal synapses. The former two likely represent the morphological substrate of the corticoclaustral pathway, while the remaining two types have the ultrastructural features of inhibitory synapses, likely forming a local inhibitory circuit in the claustrum. In conclusion, the present study shares new information about the neuropil of the claustrum and proposes a systematic classification of the types of synaptic boutons and contacts observed in the dorsal claustrum of the cat, thus supporting its key and complex role as a structure integrating various information within the brain.


Assuntos
Sinapses/ultraestrutura , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Gânglios da Base/metabolismo , Gânglios da Base/ultraestrutura , Gatos , Dendritos/metabolismo , Dendritos/ultraestrutura , Masculino , Neurônios/metabolismo , Neurônios/ultraestrutura , Sinapses/metabolismo
3.
Neuroscience ; 401: 106-116, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668973

RESUMO

The striatum of the basal ganglia is pivotal for voluntary movements and is implicated in debilitating movement disorders such as Parkinsonism and dystonia. Striatum projects to downstream nuclei through direct (dSPN) and indirect (iSPN) pathway projection neurons thought to exert opposite effects on movement. In rodent models of striatal function, unilateral dopamine deprivation induces ipsiversive rotational behavior. The dSPNs of the dorsal striatum are believed to engage distinct motor programs but underlying mechanisms remain unclear. Here, we show by employing chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] that unilateral inhibition of dorsomedial dSPNs is sufficient to selectively impair contraversive movement and elicit ipsiversive rotational behavior in mice. Adeno-associated virus (AAV) encoding Cre-dependent Gi-coupled DREADD was injected unilaterally into the dorsomedial striatum of Drd1-Cre mice, resulting in expression of the modified human M4 muscarinic receptor (hM4Di) in ∼20% of dorsostriatal dSPNs. Upon hM4Di activation, a striking positive linear correlation was found between turn ratio and viral expression, which corroborates a relationship between unilateral inhibition of dorsomedial dSPNs and rotational behavior. Bursts of ipsiversive rotations were interspersed with normal ambulation. However, partial unilateral inhibition of ∼20% of dorsostriatal dSPNs did not affect horizontal and vertical locomotion or forelimb use preference. Overall, our results substantiate a unique role of dSPNs in promoting response bias in rotational behavior and show this to be a highly sensitive measure of dSPN performance.


Assuntos
Drogas Desenhadas/farmacologia , Neostriado/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Animais , Gânglios da Base/metabolismo , Comportamento Animal , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neostriado/citologia , Neostriado/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Neuritos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Receptor Muscarínico M4/metabolismo , Receptores de Dopamina D1/metabolismo , Rotação
5.
Mol Metab ; 20: 178-193, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528281

RESUMO

OBJECTIVE: The supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and motivated behavior. Here neuroanatomical, molecular, and behavior approaches are utilized to determine whether SuM contributes to ingestive and food-motivated behavior control. METHODS: Through the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion. Glucagon-like peptide-1 (GLP-1) is a clinically targeted neuro-intestinal hormone with a well-established role in regulating energy balance and reward behaviors. Here we determine that GLP-1 receptors (GLP-1R) are expressed throughout the SuM of both sexes, and also directly on SuM LH-projecting neurons and investigate the role of SuM GLP-1R in the regulation of ingestive and motivated behavior in male and female rats. RESULTS: SuM microinjections of the GLP-1 analogue, exendin-4, reduced ad libitum intake of chow, fat, or sugar solution in both male and female rats, while food-motivated behaviors, measured using the sucrose motivated operant conditioning test, was only reduced in male rats. These data contrasted with the results obtained from a neighboring structure well known for its role in motivation and reward, the VTA, where females displayed a more potent response to GLP-1R activation by exendin-4. In order to determine the physiological role of SuM GLP-1R signaling regulation of energy balance, we utilized an adeno-associated viral vector to site-specifically deliver shRNA for the GLP-1R to the SuM. Surprisingly, and in contrast to previous results for the two SuM neighboring sites, LH and VTA, SuM GLP-1R knockdown increased food seeking and adiposity in obese male rats without altering food intake, body weight or food motivation in lean or obese, female or male rats. CONCLUSION: Taken together, these results indicate that SuM potently contributes to ingestive and motivated behavior control; an effect contingent on sex, diet/homeostatic energy balance state and behavior of interest. These data also extend the map of brain sites directly responsive to GLP-1 agonists, and highlight key differences in the role that GLP-1R play in interconnected and neighboring nuclei.


Assuntos
Gânglios da Base/metabolismo , Ingestão de Alimentos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipotálamo/metabolismo , Motivação , Animais , Gânglios da Base/citologia , Gânglios da Base/fisiologia , Condicionamento Operante , Metabolismo Energético , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipotálamo/citologia , Hipotálamo/fisiologia , Masculino , Vias Neurais/citologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
6.
Neurobiol Dis ; 124: 176-182, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30471418

RESUMO

To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Globo Pálido/metabolismo , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Substância Negra/diagnóstico por imagem
7.
Neuroimage ; 184: 826-833, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296554

RESUMO

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [18F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [18F]PSS232 BPND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [18F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation.


Assuntos
Acetilcisteína/administração & dosagem , Gânglios da Base/metabolismo , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Adulto , Gânglios da Base/efeitos dos fármacos , Glutamina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/efeitos dos fármacos , Adulto Jovem
8.
Curr Stem Cell Res Ther ; 14(2): 191-195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30027854

RESUMO

BACKGROUND: Cell therapy is an important strategy for the treatment of incurable diseases including those that occur in the Central Nervous System (CNS). Among different strategies, the method of delivering or transplantation of cells into the brain has shown significant effects on regeneration. In this study, a new protocol has been developed for the transplantation of adipose tissuederived stem cells into the brain through Cerebrospinal Fluid (CSF) in rat models. METHODS: For this purpose, a wide range of ages (7-30 days old) of male neonates of Wistar rats was used. Moreover, human adipose tissue was obtained from a superficial layer of abdomen through liposuction surgery. The size of the inserted part of needle to access middle cranial fossa and subarachnoid space in animals with an average weight of 10-80 g was determined. In addition, to confirm the entrance of needle into the subarachnoid space, CSF was aspirated slowly and then injection was done within two minutes. RESULTS: The findings showed the presence of transplanted human Adipose-Derived Stem Cells (hADSC) in the cerebellum and basal ganglia following three days and also after two months that confirmed the entrance of transplanted cells into the cerebrospinal fluid and migration of them into the brain tissue. All the animals survived after the transplantation process, with the lowest side effects compared to the available conventional methods. CONCLUSION: It can be concluded that the cells could be efficiently transplanted into CSF through subarachnoid space by injection via superior orbital fissure with a minimally invasive technique.


Assuntos
Doenças do Sistema Nervoso Central/terapia , Líquido Cefalorraquidiano/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Animais Recém-Nascidos , Gânglios da Base/crescimento & desenvolvimento , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/patologia , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Humanos , Lipectomia , Ratos , Espaço Subaracnóideo/crescimento & desenvolvimento , Espaço Subaracnóideo/metabolismo
9.
Curr Neuropharmacol ; 17(2): 165-175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29512464

RESUMO

Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson's disease and Huntington's disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson's disease and Huntington's disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson's disease and Huntington's disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.


Assuntos
Gânglios da Base/metabolismo , Corpo Estriado/metabolismo , Doença de Huntington/metabolismo , Doença de Parkinson/metabolismo , Transmissão Sináptica , Acetilcolina/metabolismo , Adenosina/metabolismo , Animais , Canabinoides/metabolismo , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neuropeptídeos/metabolismo , Ácido gama-Aminobutírico/metabolismo
10.
Elife ; 72018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30566076

RESUMO

Dopamine neurotransmission is suspected to play important physiological roles in multiple sparsely innervated brain nuclei, but there has not been a means to measure synaptic dopamine release in such regions. The globus pallidus externa (GPe) is a major locus in the basal ganglia that displays a sparse innervation of en passant dopamine axonal fibers. Due to the low levels of innervation that preclude electrochemical analysis, it is unknown if these axons engage in neurotransmission. To address this, we introduce an optical approach using a pH-sensitive fluorescent false neurotransmitter, FFN102, that exhibits increased fluorescence upon exocytosis from the acidic synaptic vesicle to the neutral extracellular milieu. In marked contrast to the striatum, FFN102 transients in the mouse GPe were spatially heterogeneous and smaller than in striatum with the exception of sparse hot spots. GPe transients were also significantly enhanced by high frequency stimulation. Our results support hot spots of dopamine release from substantia nigra axons.


Assuntos
Axônios/fisiologia , Dopamina/metabolismo , Globo Pálido/fisiologia , Neurotransmissores/metabolismo , Transmissão Sináptica/fisiologia , Animais , Axônios/metabolismo , Gânglios da Base/citologia , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Feminino , Globo Pálido/citologia , Globo Pálido/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Substância Negra/citologia , Substância Negra/metabolismo , Substância Negra/fisiologia , Transmissão Sináptica/genética
11.
Addict Biol ; 23(6): 1251-1261, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30421559

RESUMO

A dual probe microdialysis study was designed to characterize GABA and dopamine (DA) release in the basal ganglia of cannabinoid-dependent Wistar rats. Whereas chronic administration of the cannabinoid receptor agonist WIN55,212 (WIN) resulted in increased basal GABA release, the D2 agonist receptor-mediated control of GABA and DA release elicited by quinpirole was similar in both cannabinoid-dependent and non dependent animals. However, quinpirole did induce a greater number of more stereotypies in cannabinoid-dependent animals, indicating a dysregulated behavioral response.


Assuntos
Canabinoides/farmacologia , Dopamina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Animais , Gânglios da Base/metabolismo , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canabinoides/administração & dosagem , Agonistas de Dopamina/farmacologia , Endocanabinoides/metabolismo , Globo Pálido/efeitos dos fármacos , Globo Pálido/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Microdiálise , Morfolinas/farmacologia , Naftalenos/farmacologia , Quimpirol/farmacologia , RNA Mensageiro/metabolismo , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transtornos Relacionados ao Uso de Substâncias
12.
Mov Disord ; 33(12): 1961-1965, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30345538

RESUMO

BACKGROUND: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A). OBJECTIVE: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations. METHODS: We studied 6 subjects with PDE10A and ADCY5 mutations using [11 C]IMA107 PET, [123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively. RESULTS: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices. CONCLUSIONS: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society.


Assuntos
Adenilil Ciclases/genética , Gânglios da Base/patologia , Mutação/genética , Diester Fosfórico Hidrolases/genética , Gânglios da Base/metabolismo , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Globo Pálido/metabolismo , Humanos , Neostriado/metabolismo , Neurônios/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Substância Negra/metabolismo , Substância Negra/patologia
14.
Transl Psychiatry ; 8(1): 189, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30202011

RESUMO

Combined increases in peripheral inflammation and brain glutamate may identify a subtype of depression with distinct neuroimaging signatures. Two contrasting subgroups of depressed subjects-with and without combined elevations in plasma C-reactive protein (CRP) and basal ganglia glutamate (high and low CRP-Glu, respectively) were identified by hierarchical clustering using plasma CRP (indexing peripheral inflammation) and magnetic resonance spectroscopy (MRS)-based measurement of left basal ganglia glutamate. High CRP-Glu group status was associated with greater severity of anhedonia and cognitive and motor slowing. Local- and network-level measures of functional integrity were determined using brain oxygen level-dependent (BOLD)-oscillatory activity and graph theory. Greater decreases in concordance of oscillatory activity between neighboring voxels (Regional Homogeneity 'ReHo', p < 0.01) within the MRS volume-of-interest was associated with the High CRP-Glu subgroup. Using brain-wide, CRP-Glu ReHo contrast maps, a covariance network of 41 regions-of-interest (ROIs) with similar ReHo decreases was identified in the High CRP-Glu group and was located to brain structures previously implicated in depression. The 41-ROI network was further decomposed into four subnetworks. ReHo decreases within Subnetwork4-comprised of reward processing regions -was associated with anhedonia. Subnetwork4 ReHo also predicted decreased network integrity, which mediated the link between local ReHo and anhedonia in the Low but not High CRP-Glu group. These findings suggest that decreased ReHo and related disruptions in network integrity may reflect toxic effects of inflammation-induced increases in extrasynaptic glutamate signaling. Moreover, local BOLD oscillatory activity as reflected in ReHo might be a useful measure of target-engagement in the brain for treatment of inflammation-induced behaviors.


Assuntos
Gânglios da Base/metabolismo , Gânglios da Base/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Ácido Glutâmico/metabolismo , Inflamação/metabolismo , Adulto , Anedonia/fisiologia , Mapeamento Encefálico , Transtorno Depressivo Maior/fisiopatologia , Feminino , Ácido Glutâmico/análise , Humanos , Inflamação/fisiopatologia , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Escalas de Graduação Psiquiátrica , Descanso , Recompensa
15.
Neuroimage ; 183: 142-149, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30102997

RESUMO

Recent evidence indicates that the relationship between increased beta-amyloid (Aß) deposition and functional task-activation can be characterized by a non-linear trajectory of change in functional activation (Foster et al., 2017), explaining mixed results in prior literature showing both increases and decreases in activation as a function of beta-amyloid burden in cognitively normal adults. Here we sought to replicate this nonlinear effect in the same sample using a different functional paradigm to test the generalizability of this phenomenon. Participants (N = 68 healthy adults aged 49-94) underwent fMRI (0-, 2-, 3-, 4-back working memory task; WM) and 18F-Florbetapir PET scanning. A parametric WM load contrast was used as the dependent variable in a model with age, mean cortical Aß, and Aß2 as predictors. Results revealed that nonlinear amyloid (Aß2) was a significant negative predictor of modulation of activation to WM load in two large inferior clusters: bilateral subcortical nuclei and bilateral lateral cerebellum. Individuals with slightly elevated Aß burden evidenced greater modulation as compared to individuals with little or no Aß burden, whereas individuals with the greatest Aß burden evidenced lesser modulation as compared to individuals with slightly elevated Aß. Increased modulation to WM load predicted better task accuracy and executive function measured outside the scanner. The current study provides further evidence for a dose-response, nonlinear relationship between increasing Aß burden and alteration in brain activation in cognitively healthy adults, extending the existing evidence to dynamic range of activation to task difficulty, and reconciling seemingly discrepant effects of amyloid on brain function.


Assuntos
Envelhecimento/fisiologia , Peptídeos beta-Amiloides/metabolismo , Gânglios da Base/fisiologia , Cerebelo/fisiologia , Função Executiva/fisiologia , Memória de Curto Prazo/fisiologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
16.
Neuroimage ; 183: 1-6, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30077742

RESUMO

Animal studies have suggested that dopamine and opioid neurotransmitter systems interact in brain regions that are relevant for reward functions, but data in humans are very limited. The interaction is potentially important in disorders affecting these neurotransmitter systems, such as addiction. Here, we investigated whether subcortical µ-opioid receptor (MOR) availability and presynaptic dopamine synthesis capacity are correlated in the healthy human brain or in pathological gamblers (PGs) using positron emission tomography with 6-[18F]fluoro-l-dopa and [11C]carfentanil. The specificity of the findings was further investigated by including a serotonin transporter ligand, [11C]MADAM, as a negative control. Thirteen PG patients and 15 age-, sex- and weight-matched controls underwent the scans. In both groups, presynaptic dopamine synthesis capacity was associated with MOR availability in the putamen, caudate nucleus and globus pallidus. No similar associations were observed between dopamine synthesis capacity and [11C]MADAM binding, supporting a specific interplay between presynaptic dopamine neurotransmission and opioid receptor function in the basal ganglia. Correlations were similar between the groups, suggesting that the dopamine-opioid link is general and unaffected by behavioral addiction. The results provide in vivo human evidence of a connection between endogenous opioid and dopamine signaling in the brain.


Assuntos
Gânglios da Base/metabolismo , Dopamina/metabolismo , Jogo de Azar/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores Opioides mu/metabolismo , Adulto , Gânglios da Base/diagnóstico por imagem , Feminino , Jogo de Azar/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Traçadores Radioativos , Compostos Radiofarmacêuticos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
17.
Prog Neurobiol ; 169: 55-75, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077774

RESUMO

The basal ganglia (BG) include structures pivotal for motor and cognitive functions. Such structures are affected in neurodegenerative disorders and toxic or ischemic insults. The peculiar vulnerability of BG to toxic and ischemic damage has been the focus of preclinical research for all over the last century. This comprehensive review collects all evidences supporting a specific susceptibility of BG to energy deprivation, highlighting the pathways through which neuronal survival is jeopardized, and the consequent clinical correlates. In particular, we addressed intrinsic and extrinsic factors participating in BG neuronal vulnerability. The terminal blood supply, the main extrinsic factor, is crucial to the low threshold for hypoxic hazard. Specific, the lack of anastomoses between second and third order branches represents the frailty of an archaic terminal network, unable to guarantee collateral supply and resistance to oxygen deprivation. In addition, BG neurons survival is jeopardized by several intrinsic molecular factors. Among them, the subunit composition of ionotropic and metabotropic glutamate receptors, the impairment of mitochondria, the deficit in neurotransmitter clearance, the poor control of intracellular calcium homeostasis and the glutamatergic-dopaminergic pro-excitotoxic interplay, all play a significant role. Intrinsic and extrinsic factors represent two faces of the same coin, producing excitotoxic damage and poor ability to deal with energy deprivation. The clinical correlates of BG vulnerability are represented by ischemic lesions, such as striatocapsular infarcts and lacunar infarcts, and local toxic-induced damage, mainly associated with energy production impairment, due to carbon monoxide, cyanide and manganese.


Assuntos
Gânglios da Base/metabolismo , Isquemia Encefálica/patologia , Metabolismo Energético/fisiologia , Intoxicação por Metais Pesados/patologia , Síndromes Neurotóxicas/patologia , Animais , Gânglios da Base/efeitos dos fármacos , Cálcio/metabolismo , Humanos , Receptores de Glutamato/metabolismo
18.
Med Hypotheses ; 119: 41-53, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30122490

RESUMO

Complex Regional Pain Syndrome (CRPS) has defied a clear unified pathological explanation to date. Not surprisingly, treatments for the condition are limited in number, efficacy and their ability to enact a cure. Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn't develop CRPS remains unclear. We propose a new overarching hypothesis to explain the condition that invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. We outline pathophysiological changes that may initiate a cascade of events involving dendritic cells and the cholinergic anti-inflammatory pathway resulting in the condition, and the changes that maintain the condition into its chronic phase. This hypothesis should provide fertile ground for further investigations and development of new treatments that holistically address the nature of the disorder along its developmental continuum.


Assuntos
Síndromes da Dor Regional Complexa/fisiopatologia , Animais , Autoimunidade , Sistema Nervoso Autônomo , Gânglios da Base/metabolismo , Células Dendríticas/metabolismo , Humanos , Sistema Imunitário , Linfonodos/patologia , Microglia , Neuralgia , Medula Espinal/patologia
19.
J Mol Neurosci ; 66(1): 59-67, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30091081

RESUMO

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including serotonin and adrenoceptors. We examined the long-term effects of multiple doses of iloperidone (0.5, 1.5, or 5 mg/kg) on serotonin (5-HT) 5-HT1A, 5-HT2A receptor subtypes, and adrenoceptors α1 and α2 subtypes. Rats received daily intraperitoneal injections of different doses of iloperiodone or vehicle for 4 weeks. Receptor autoradiography quantified the levels of 5-HT and adrenoceptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampal CA1 (HIP-CA1) and CA3 (HIP-CA3) regions. Four weeks of iloperidone treatment significantly and dose-dependently increased 5-HT1A and decreased 5-HT2A receptors in the MPC and DFC. Higher doses of iloperidone (1.5 and 5 mg/kg) increased 5-HT1A and decreased 5-HT2A receptors in HIP-CA1 and HIP-CA3 regions. In addition, repeated iloperidone treatment produced significant increases in α1- and α2-adrenoceptors in MPC, DFC, HIP-CA1, and HIP-CA3 regions. No changes in 5-HT and adrenoceptors were observed in other brain regions examined. These results suggest that long-term iloperidone treatment exerts region- and dose-specific effects on forebrain 5-HT and adrenoceptors, which may contribute to its therapeutic benefits in improving positive and negative symptoms of schizophrenia as well as maintaining a benign safety profile.


Assuntos
Antipsicóticos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Isoxazóis/farmacologia , Piperidinas/farmacologia , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Receptores Adrenérgicos alfa/genética , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo
20.
Nat Commun ; 9(1): 3339, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131490

RESUMO

Striatum processes a wide range of functions including goal-directed behavior and habit formation, respectively encoded by the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). GABAergic feedforward inhibition is known to control the integration of cortical information by striatal projection neurons (SPNs). Here we questioned whether this control is specific between distinct striatal functional territories. Using opto-activation and opto-inhibition of identified GABAergic interneurons, we found that different circuits are engaged in DLS and DMS, both ex vivo and in vivo: while parvalbumin interneurons efficiently control SPNs in DLS, somatostatin interneurons control SPNs in DMS. Moreover, both parvalbumin and somatostatin interneurons use a dual hyperpolarizing/depolarizing effect to control cortical input integration depending on SPN activity state: GABAergic interneurons potently inhibit spiking SPNs while in resting SPNs, they favor cortical activity summation via a depolarizing effect. Our findings establish that striatal GABAergic interneurons exert efficient territory-specific and state-dependent control of SPN activity and functional output.


Assuntos
Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Neostriado/metabolismo , Potenciais de Ação/fisiologia , Animais , Gânglios da Base/metabolismo , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Substância Negra/metabolismo
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