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1.
Transl Psychiatry ; 9(1): 264, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636253

RESUMO

The anterior hippocampus and prefrontal cortex are regions linked to symptoms of schizophrenia. The anterior hippocampus is believed to be a key regulator of the mesolimbic dopamine system and is thought to be the driving force contributing to positive symptoms, while the prefrontal cortex is involved in cognitive flexibility and negative symptoms. Aberrant activity in these regions is associated with decreases in GABAergic markers, indicative of an interneuron dysfunction. Specifically, selective decreases are observed in interneurons that contain parvalbumin (PV) or somatostatin (SST). Here, we used viral knockdown in rodents to recapitulate this finding and examine the region-specific roles of PV and SST on neuronal activity and behaviors associated with positive, negative and cognitive symptoms. We found that PV and SST had differential effects on neuronal activity and behavior when knocked down in the ventral hippocampus (vHipp) or medial prefrontal cortex (mPFC). Specifically, SST or PV knockdown in the vHipp increased pyramidal cell activity of the region and produced downstream effects on dopamine neuron activity in the ventral tegmental area (VTA). In contrast, mPFC knockdown did not affect the activity of VTA dopamine neuron activity; however, it did produce deficits in negative (social interaction) and cognitive (reversal learning) domains. Taken together, decreases in PV and/or SST were sufficient to produce schizophrenia-like deficits that were dependent on the region targeted.

3.
Schizophr Res ; 206: 263-270, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30522798

RESUMO

Adolescent cannabis use has been implicated as a risk factor for schizophrenia; however, it is neither necessary nor sufficient. Previous studies examining this association have focused primarily on the role of the cannabinoid receptor 1 (CB1R) with relatively little known about a key regulatory protein, the cannabinoid receptor interacting protein 1 (CNRIP1). CNRIP1 is an intracellular protein that interacts with the C-terminal tail of CB1R and regulates its intrinsic activity. Previous studies have demonstrated aberrant CNRIP1 DNA promoter methylation in post-mortem in human patients with schizophrenia, and we have recently reported decreased methylation of the CNRIP1 DNA promoter in the ventral hippocampus (vHipp) of a rodent model of schizophrenia susceptibility. To examine whether augmented CNRIP1 expression could contribute to the pathology of schizophrenia, we performed viral-mediated overexpression of CNRIP1 in the vHipp of Sprague Dawley rats. We then tested these rats for behavioral correlates of schizophrenia symptoms, followed by electrophysiology to determine the effects on the dopamine system, known to underlie psychosis. Here, we report that overexpression of vHipp CNRIP1 induces impairments in latent inhibition and social interaction, similar to those observed in individuals with schizophrenia and in rodent models of the disease. Furthermore, rats overexpressing vHipp CNRIP1 displayed a significant increase in ventral tegmental area (VTA) dopamine neuron population activity, a putative correlate of psychosis. These data provide evidence that alterations in CNRIP1 may contribute to the pathophysiology of schizophrenia, as overexpression is sufficient to produce neurophysiological and behavioral correlates consistently observed in rodent models of the disease.

4.
Neuropsychopharmacology ; 43(8): 1789-1798, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29453447

RESUMO

Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system. Specifically, people with autism have a reduction in parvalbumin (PV)-containing interneurons in the PFC, leading to the suggestion that restoring interneuron function in this region may be a novel therapeutic approach for ASD. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of PV-positive interneurons, which were transplanted into the medial prefrontal cortex (mPFC) of the Poly I:C rodent model of autism. PV interneuron transplants were able to decrease pyramidal cell firing in the mPFC and alleviated deficits in social interaction and cognitive flexibility. Our results suggest that restoring PV interneuron function in the mPFC may be a novel and effective treatment strategy to reduce the core symptoms of autism.


Assuntos
Transtorno Autístico/terapia , Células-Tronco Embrionárias/transplante , Interneurônios/transplante , Potenciais de Ação/fisiologia , Animais , Atenção , Transtorno Autístico/patologia , Transtorno Autístico/fisiopatologia , Linhagem Celular , Modelos Animais de Doenças , Células-Tronco Embrionárias/patologia , Células-Tronco Embrionárias/fisiologia , Função Executiva , Interneurônios/patologia , Interneurônios/fisiologia , Masculino , Camundongos , Poli I-C , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Inibição Pré-Pulso , Células Piramidais/patologia , Células Piramidais/fisiologia , Ratos Sprague-Dawley , Comportamento Social , Vocalização Animal
5.
Neuroimage ; 119: 382-9, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26143203

RESUMO

Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2(⁎)-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2(⁎)-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal.


Assuntos
Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Imagem por Ressonância Magnética , Acoplamento Neurovascular , Oxigênio/metabolismo , Pressão do Ar , Animais , Estimulação Elétrica , Frequência Cardíaca , Hemodinâmica , Hemoglobinas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Taxa Respiratória , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/fisiologia , Percepção do Tato/fisiologia
6.
Psychopharmacology (Berl) ; 232(17): 3123-33, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25986748

RESUMO

RATIONALE: Acute low-dose administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST) and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). OBJECTIVE: In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine's therapeutic action. RESULTS: Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine's antidepressant-like effects on the forced swim test and AST, but not on the SPDB. CONCLUSION: These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Adaptação Psicológica/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Eletrochoque , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/psicologia , Natação/psicologia
7.
Schizophr Res ; 157(1-3): 238-43, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24888524

RESUMO

Postmortem studies in schizophrenia patients have demonstrated robust alterations in GABAergic markers throughout the neuraxis. It has been suggested that these alterations are restricted to subpopulations of interneurons, such as those containing the calcium binding protein parvalbumin. Indeed, a reduction in parvalbumin expression is a consistent observation in human postmortem studies, as well as, in a wide and diverse variety of animal models. However, it still remains to be determined whether this decrease in parvalbumin expression contributes to, or is a consequence of the disease. Here we utilize lentiviral delivered shRNA and demonstrate that a selective reduction in parvalbumin mRNA expression induces hyperactivity within the ventral hippocampus. In addition, we observe downstream increases in dopamine neuron population activity without changes in average firing rate or percent burst firing. These changes in dopamine neuron activity were associated with an enhanced locomotor response to amphetamine administration. These data therefore demonstrate that a reduction in ventral hippocampal parvalbumin expression is sufficient, in and of itself, to induce an augmented dopamine system function and behavioral hyper-responsivity to amphetamine, implicating a potential key role for parvalbumin in the pathophysiology of schizophrenia.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Hipocampo/fisiopatologia , Parvalbuminas/metabolismo , Esquizofrenia/fisiopatologia , Potenciais de Ação/fisiologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Vetores Genéticos , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Lentivirus/genética , Masculino , Microeletrodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Parvalbuminas/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Ratos Sprague-Dawley , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiopatologia
8.
Hippocampus ; 18(4): 411-24, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18189311

RESUMO

It is thought that CA3 pyramidal neurons communicate mainly through bursts of spikes rather than so-called trains of regular firing action potentials. Reports of both burst firing and nonburst firing CA3 cells suggest that they may fire with more than one output pattern. With the use of whole-cell recording methods we studied the firing properties of rat hippocampal pyramidal neurons in vitro within the CA3b subregion and found three distinct types of firing patterns. Approximately 37% of cells were regular firing where spikes generated by minimal current injection (rheobase) were elicited with a short latency and with stronger current intensities trains of spikes exhibited spike frequency adaptation (SFA). Another 46% of neurons exhibited a delayed onset at rheobase with a weakly-adapting firing pattern upon stronger stimulation. The remaining 17% of cells showed a burst-firing pattern, though only elicited in response to strong current injection and spontaneous bursts were never observed. Control experiments indicated that the distinct firing patterns were not due to our particular slicing methods or recording techniques. Finally, computer modeling was used to identify how relative differences in K+ conductances, specifically K(C), K(M), and K(D), between cells contribute to the different characteristics of the three types of firing patterns observed experimentally.


Assuntos
Potenciais de Ação/fisiologia , Membrana Celular/fisiologia , Hipocampo/fisiologia , Canais de Potássio/fisiologia , Células Piramidais/fisiologia , Animais , Simulação por Computador , Modelos Neurológicos , Vias Neurais/fisiologia , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Células Piramidais/citologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Fatores de Tempo
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