Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Nanotechnol ; 19(4): 514-523, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38212522

RESUMO

One of the critical factors determining the performance of neural interfaces is the electrode material used to establish electrical communication with the neural tissue, which needs to meet strict electrical, electrochemical, mechanical, biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin-film technology and its engineering to form flexible neural interfaces. The developed technology allows the fabrication of small microelectrodes (25 µm diameter) while achieving low impedance (∼25 kΩ) and high charge injection (3-5 mC cm-2). In vivo brain recording performance assessed in rodents reveals high-fidelity recordings (signal-to-noise ratio >10 dB for local field potentials), while stimulation performance assessed with an intrafascicular implant demonstrates low current thresholds (<100 µA) and high selectivity (>0.8) for activating subsets of axons within the rat sciatic nerve innervating tibialis anterior and plantar interosseous muscles. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical (12 week) and intraneural (8 week) implantation. This work describes a graphene-based thin-film microelectrode technology and demonstrates its potential for high-precision and high-resolution neural interfacing.


Assuntos
Grafite , Nanoporos , Ratos , Animais , Microeletrodos , Próteses e Implantes , Estimulação Elétrica
2.
Front Cell Neurosci ; 17: 1152248, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37066076

RESUMO

N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

4.
Int J Mol Sci ; 23(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36077512

RESUMO

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.


Assuntos
Animais Selvagens , Peixe-Zebra , Animais , Dopamina , Ligantes , Camundongos , Transmissão Sináptica
5.
Neurobiol Dis ; 173: 105841, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35988873

RESUMO

Stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to improve cognitive impairment due to intellectual disability, aging, and neurodegeneration, however the underlying neural mechanisms are poorly understood. We investigated the neural correlates of memory amelioration produced by postnatal environmental enrichment (EE) in diploid mice and the Ts65Dn mouse model of Down syndrome (trisomy 21). We recorded neural activities in brain structures key for memory processing, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in non-enriched or enriched environments. Enriched wild-type animals exhibited enhanced neural synchrony in the hippocampus across different brain states (increased gamma oscillations, theta-gamma coupling, sleep ripples). Trisomic females showed increased theta and gamma rhythms in the hippocampus and prefrontal cortex across different brain states along with enlarged ripples and disrupted circuit gamma signals that were associated with memory deficits. These pathological activities were attenuated in their trisomic EE-reared peers. Our results suggest distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE and put forward hippocampal-prefrontal hypersynchrony and miscommunication as major targets underlying the beneficial effects of EE in intellectual disability.


Assuntos
Síndrome de Down , Deficiência Intelectual , Animais , Feminino , Ritmo Gama , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal
6.
Cereb Cortex ; 32(16): 3472-3487, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34875009

RESUMO

Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.


Assuntos
Antipsicóticos , Clozapina , Transtornos Psicóticos , Receptor 5-HT1A de Serotonina , Receptor 5-HT2A de Serotonina , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Haloperidol/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Fenciclidina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Risperidona/farmacologia , Antagonistas da Serotonina/farmacologia
7.
Proc Natl Acad Sci U S A ; 117(21): 11788-11798, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393630

RESUMO

Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.


Assuntos
Síndrome de Down/fisiopatologia , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Modelos Animais de Doenças , Função Executiva/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Fármacos Neuroprotetores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos
8.
Neuropharmacology ; 158: 107743, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430459

RESUMO

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Risperidona/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anfetaminas/farmacologia , Animais , Ondas Encefálicas/efeitos dos fármacos , Sincronização Cortical/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Eletroencefalografia , Fluorbenzenos/farmacologia , Ritmo Gama/efeitos dos fármacos , Haloperidol/farmacologia , Hipocampo/metabolismo , Camundongos , Vias Neurais/efeitos dos fármacos , Piperazinas/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/metabolismo , Piridinas/farmacologia , Quimpirol/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
9.
Cereb Cortex ; 29(7): 2978-2997, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-30060068

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Disfunção Cognitiva/genética , Depressão/genética , Metilfenidato/farmacologia , Microglia/efeitos dos fármacos , Distrofia Miotônica , Afeto/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/genética , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo
11.
ACS Chem Neurosci ; 6(7): 1017-25, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25799292

RESUMO

There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field.


Assuntos
Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Animais , Humanos , Transtornos Mentais/metabolismo , Vias Neurais/metabolismo
12.
Cereb Cortex ; 25(9): 2980-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24814093

RESUMO

Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia.


Assuntos
Função Executiva/fisiologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Potenciais de Ação/efeitos dos fármacos , Ritmo alfa/efeitos dos fármacos , Análise de Variância , Animais , Aprendizagem por Associação/fisiologia , Benzazepinas/farmacologia , Sinais (Psicologia) , Dopaminérgicos/farmacologia , Análise de Fourier , Macaca mulatta , Imageamento por Ressonância Magnética , Memória/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Salicilamidas/farmacologia , Fatores de Tempo
13.
Artigo em Inglês | MEDLINE | ID: mdl-25140130

RESUMO

In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.


Assuntos
Dopamina/metabolismo , Aprendizagem/fisiologia , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Aves , Dopamina/farmacologia , Humanos , Aprendizagem/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Modelos Neurológicos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos
14.
Artigo em Inglês | MEDLINE | ID: mdl-23626526

RESUMO

The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.

15.
Neuron ; 74(5): 874-86, 2012 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-22681691

RESUMO

Dopamine is thought to play a major role in learning. However, while dopamine D1 receptors (D1Rs) in the prefrontal cortex (PFC) have been shown to modulate working memory-related neural activity, their role in the cellular basis of learning is unknown. We recorded activity from multiple electrodes while injecting the D1R antagonist SCH23390 in the lateral PFC as monkeys learned visuomotor associations. Blocking D1Rs impaired learning of novel associations and decreased cognitive flexibility but spared performance of already familiar associations. This suggests a greater role for prefrontal D1Rs in learning new, rather than performing familiar, associations. There was a corresponding greater decrease in neural selectivity and increase in alpha and beta oscillations in local field potentials for novel than for familiar associations. Our results suggest that weak stimulation of D1Rs observed in aging and psychiatric disorders may impair learning and PFC function by reducing neural selectivity and exacerbating neural oscillations associated with inattention and cognitive deficits.


Assuntos
Aprendizagem por Associação/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Benzazepinas/farmacologia , Mapeamento Encefálico , Antagonistas de Dopamina/farmacologia , Macaca mulatta , Neurônios/efeitos dos fármacos , Estimulação Luminosa , Córtex Pré-Frontal/efeitos dos fármacos , Curva ROC , Análise Espectral , Fatores de Tempo
16.
Mol Neurobiol ; 44(3): 449-64, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22076606

RESUMO

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.


Assuntos
Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/fisiologia , Serotonina/metabolismo , Animais , Interneurônios/citologia , Interneurônios/fisiologia , Rede Nervosa/anatomia & histologia , Neurônios/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Transmissão Sináptica/fisiologia
17.
J Neurosci ; 30(6): 2211-22, 2010 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-20147548

RESUMO

Alterations of the serotonergic system in the prefrontal cortex (PFC) are implicated in psychiatric disorders such as schizophrenia and depression. Although abnormal synchronous activity is observed in the PFC of these patients, little is known about the role of serotonin (5-HT) in cortical synchrony. We found that 5-HT, released by electrical stimulation of the dorsal raphe nucleus (DRN) in anesthetized rats, regulates the frequency and the amplitude of slow (<2 Hz) waves in the PFC via 5-HT(2A) receptors (5-HT(2A)Rs). 5-HT also modulates prefrontal gamma (30-80 Hz) rhythms through both 5-HT(1A)Rs and 5-HT(2A)Rs, but not 5-HT(2C)Rs, inducing an overall decrease in the amplitude of gamma oscillations. Because fast-spiking interneurons (FSi) are involved in the generation of gamma waves, we examined serotonergic modulation of FSi activity in vivo. Most FSi are inhibited by serotonin through 5-HT(1A)Rs, while a minority is activated by 5-HT(2A)Rs, and not 5-HT(2C)Rs. In situ hybridization histochemistry confirmed that distinct populations of FSi in the PFC express 5-HT(1A)Rs and 5-HT(2A)Rs, and that the number of FSi expressing 5-HT(2C)Rs is negligible. We conclude that 5-HT exerts a potent control on slow and gamma oscillations in the PFC. On the one hand, it shapes the frequency and amplitude of slow waves through 5-HT(2A)Rs. On the other hand, it finely tunes the amplitude of gamma oscillations through 5-HT(2A)R- and 5-HT(1A)R-expressing FSi, although it primarily downregulates gamma waves via the latter population. These results may provide insight into impaired serotonergic control of network activity in psychiatric illnesses such as schizophrenia and depression.


Assuntos
Interneurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Serotonina/fisiologia , Potenciais de Ação , Animais , Estimulação Elétrica , Hibridização In Situ , Masculino , Periodicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/biossíntese , Receptor 5-HT2A de Serotonina/biossíntese , Receptor 5-HT2C de Serotonina/biossíntese , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina
18.
Biol Psychiatry ; 64(5): 392-400, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18436196

RESUMO

BACKGROUND: Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms. METHODS: The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei. RESULTS: DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.). CONCLUSIONS: DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.


Assuntos
Anfetaminas/farmacologia , Antipsicóticos/farmacologia , Relógios Biológicos/efeitos dos fármacos , Clozapina/farmacologia , Alucinógenos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia , Eletrólise/métodos , Potenciais Evocados/efeitos dos fármacos , Fluorbenzenos/farmacologia , Análise de Fourier , Masculino , Neurônios/efeitos dos fármacos , Piperidinas/farmacologia , Córtex Pré-Frontal/citologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Tálamo/lesões , Tálamo/fisiologia
19.
Cereb Cortex ; 15(1): 1-14, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15238448

RESUMO

Serotonin is involved in psychiatric disorders exhibiting abnormal prefrontal cortex (PFC) function (e.g. major depression, schizophrenia). We examined the effect of the stimulation of the dorsal and median raphe nuclei (DR and MnR, respectively) on the activity of PFC neurons. Electrical stimulation of DR/MnR inhibited 66% (115/173) of pyramidal neurons in the medial PFC (mPFC). The rest of the cases exhibited orthodromic excitations, either pure (13%) or preceded by short-latency inhibitions (20%). Excited neurons had a lower pre-stimulus firing rate than those inhibited. Excitations evoked by MnR stimulation had a shorter latency than those evoked by DR stimulation. WAY-100635 [a 5-hydroxytryptamine1A (5-HT1A) antagonist] and the selective gamma aminobutyric acidA (GABAA) antagonist picrotoxinin partially antagonized DR/MnR-evoked inhibitions, suggesting the involvement of 5-HT1A- and GABAA-mediated components. The presence of a direct DR/MnR-mPFC GABAergic component is suggested by the short latency of evoked inhibitions (9 +/- 1 ms), faster than those evoked in the secondary motor area (20 +/- 3 ms), and that of antidromic spikes evoked by DR/MnR stimulation in mPFC pyramidal neurons (15 +/- 1 ms). Stimulation of the DR/MnR with paired pulses enhanced the duration of inhibitions and turned some excitations into inhibitions. Thus, the DR/MnR control the activity of mPFC pyramidal neurons in vivo in a complex manner, involving 5-HT-mediated excitations and GABA- and 5-HT-mediated inhibitions.


Assuntos
Córtex Pré-Frontal/citologia , Células Piramidais/fisiologia , Núcleos da Rafe/citologia , Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Masculino , Córtex Motor/citologia , Córtex Motor/fisiologia , Inibição Neural/fisiologia , Vias Neurais , Piperazinas/farmacologia , Córtex Pré-Frontal/fisiologia , Piridinas/farmacologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia
20.
Cereb Cortex ; 14(12): 1365-75, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15166106

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors. Here we report that the physiological stimulation of the raphe nuclei excites local, putatively GABAergic neurons in the prelimbic and cingulate areas of the rat PFC in vivo. These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i.v. administration of the 5-HT3 receptor antagonists ondansetron and tropisetron. The latency and duration were shorter than those elicited through 5-HT2A receptors in pyramidal neurons of the same areas. Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5-HT3 receptor mRNA in PFC. These cells were more abundant in the cingulate, prelimbic and infralimbic areas, particularly in superficial layers. The percentages of GAD mRNA-positive neurons expressing 5-HT3 receptor mRNA in prelimbic cortex were 40, 18, 6 and 8% in layers I, II-III, V and VI, respectively, a distribution complementary to that of cells expressing 5-HT2A receptors. Overall, these results support an important role of 5-HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial PFC through the activation of 5-HT3 receptors in GABAergic interneurons.


Assuntos
Interneurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores 5-HT3 de Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Estimulação Elétrica/métodos , Interneurônios/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...