RESUMO
Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer's disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. Methods: TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14-16 months old during DMS testing and PET. Results: In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. Conclusions: TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact.
RESUMO
The object recognition and object location task (ORT and OLT, respectively) have been applied in preclinical research to evaluate the effects of treatments on memory. Although both tasks look quite similar, they differ with respect to the brain structures involved in the memory performance. The characterization of the memory performance in both tasks is important to understand treatment effects. Since there are no previous studies that compared strain differences in delay-dependent forgetting in both tasks, Wistar and Long Evans rats were tested in both the ORT and the OLT at different intervals. The data showed that in the ORT the delay-dependent forgetting was similar for Wistar and Long Evans rats. However, the forgetting curve was different for both strains in the OLT: the Long Evans rats the forgetting took a longer interval. This study indicates that delay-dependent forgetting in the ORT and OLT is strain and test dependent. It is suggested that before testing treatments the forgetting curve of a specific strain should be tested in this type of tasks.
Assuntos
Encéfalo , Cognição , Ratos , Animais , Ratos Long-Evans , Ratos WistarRESUMO
Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been shown to exert promising therapeutical effects in a pilot study with patients suffering from Alzheimer's disease (AD). We aimed at comparing the cognitive effects of intermittent and continuous NBM stimulation paradigms in an animal model for AD. In this exploratory study, aged Tgf344-AD rats were behaviorally tested pre-, and post implantation, while being stimulated with unilateral- or bilateral-intermittent and bilateral-continuous patterns. Bilateral-intermittent NBM DBS lead to supernormal performance in a spatial memory task. These findings suggest that NBM DBS could be further refined, thereby improving patient care.
Assuntos
Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Núcleo Basal de Meynert , Estimulação Encefálica Profunda/métodos , Doença de Alzheimer/genética , Animais , Cognição , Eletrodos Implantados , Humanos , Masculino , Atividade Motora , Projetos Piloto , Desempenho Psicomotor , Ratos , Ratos Transgênicos , Memória EspacialRESUMO
The nucleus basalis of Meynert (nbM) was first described at the end of the 19th century and named after its discoverer, Theodor Meynert. The nbM contains a large population of cholinergic neurons that project their axons to the entire cortical mantle, the olfactory tubercle, and the amygdala. It has been functionally associated with the control of attention and maintenance of arousal, both key functions for appropriate learning and memory formation. This structure is well-conserved across vertebrates, although its degree of organization varies between species. Since early in the investigation of its functional and pathological significance, its degeneration has been linked to various major neuropsychiatric disorders. For instance, Lewy bodies, a hallmark in the diagnosis of Parkinson's disease, were originally described in the nbM. Since then, its involvement in other Lewy body and dementia-related disorders has been recognized. In the context of recent positive outcomes following nbM deep brain stimulation in subjects with dementia-associated disorders, we review the literature from an historical perspective focusing on how the nbM came into focus as a promising therapeutic option for patients with Alzheimer's disease. Moreover, we will discuss what is needed to further develop and widely implement this approach as well as examine novel medical indications for which nbM deep brain stimulation may prove beneficial.
Assuntos
Núcleo Basal de Meynert , Transtornos Cognitivos/terapia , Estimulação Encefálica Profunda , Doença de Alzheimer/história , Doença de Alzheimer/terapia , Núcleo Basal de Meynert/anatomia & histologia , Núcleo Basal de Meynert/fisiologia , Transtornos Cognitivos/história , Estimulação Encefálica Profunda/história , História do Século XIX , História do Século XX , História do Século XXI , HumanosRESUMO
Subcortical neuronal activity is highly relevant for mediating communication in large-scale brain networks. While electroencephalographic (EEG) recordings provide appropriate temporal resolution and coverage to study whole brain dynamics, the feasibility to detect subcortical signals is a matter of debate. Here, we investigate if scalp EEG can detect and correctly localize signals recorded with intracranial electrodes placed in the centromedial thalamus, and in the nucleus accumbens. Externalization of deep brain stimulation (DBS) electrodes, placed in these regions, provides the unique opportunity to record subcortical activity simultaneously with high-density (256 channel) scalp EEG. In three patients during rest with eyes closed, we found significant correlation between alpha envelopes derived from intracranial and EEG source reconstructed signals. Highest correlation was found for source signals in close proximity to the actual recording sites, given by the DBS electrode locations. Therefore, we present direct evidence that scalp EEG indeed can sense subcortical signals.
Assuntos
Encéfalo/fisiologia , Eletroencefalografia/métodos , Fenômenos Eletrofisiológicos , Núcleos Intralaminares do Tálamo/fisiologia , Núcleo Accumbens/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico , Estimulação Encefálica Profunda/métodos , Eletrodos , Eletroencefalografia/instrumentação , Humanos , Núcleos Intralaminares do Tálamo/diagnóstico por imagem , Núcleos Intralaminares do Tálamo/fisiopatologia , Imageamento por Ressonância Magnética , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiopatologia , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/terapia , Couro Cabeludo/diagnóstico por imagem , Couro Cabeludo/fisiologia , Couro Cabeludo/fisiopatologia , Tomografia Computadorizada por Raios X , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/fisiopatologia , Síndrome de Tourette/terapiaRESUMO
Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD.
Assuntos
Doença de Huntington/fisiopatologia , Motivação/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Recompensa , Animais , Modelos Animais de Doenças , Proteína Huntingtina/genética , Masculino , Vias Neurais/fisiopatologia , Optogenética , Ratos TransgênicosRESUMO
High-frequency stimulation of the nucleus accumbens, also known as deep brain stimulation (DBS), is currently used to alleviate obsessive compulsive symptoms when pharmacotherapy is ineffective. However, the mechanism by which DBS achieves its therapeutic actions is not understood. Imaging studies and the actions of dopaminergic drugs in untreated patients suggest that the dopamine (DA) system likely plays a role in the pathophysiology of obsessive compulsive disorder. Therefore, we examined whether DBS would impact the DA system as a potential component of its therapeutic actions. The activity of DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were recorded in anesthetized rats under high-frequency stimulation. DA neuron activity was measured in terms of number of neurons firing, average firing rate and firing pattern. DBS of the nucleus accumbens core did not significantly affect VTA activity or discharge pattern. On the other hand, DBS caused a potent decrease in the number of SNc DA neurons firing spontaneously. Such an effect could contribute to the disruption of pathological habit formation in the SNc-dorsal striatal projection system that may have therapeutic implications for the treatment of obsessive compulsive disorder.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Estimulação Elétrica/métodos , Núcleo Accumbens/fisiologia , Substância Negra/citologia , Área Tegmentar Ventral/citologia , Potenciais de Ação/fisiologia , Animais , Biofísica , Masculino , Vias Neurais/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Obsessive compulsive disorder (OCD) is a psychiatric condition defined by intrusive thoughts (obsessions) associated with compensatory and repetitive behaviour (compulsions). However, advancement in our understanding of this disorder has been hampered by the absence of effective animal models and correspondingly analysis of the physiological changes that may be present in these models. To address this, we have evaluated two current rodent models of OCD; repeated injection of dopamine D2 agonist quinpirole and repeated adolescent injection of the tricyclic agent clomipramine in combination with a behavioural paradigm designed to produce compulsive lever pressing. These results were then compared with their relative impact on the state of activity of the mesolimbic dopaminergic system using extracellular recoding of spontaneously active dopamine neurons in the ventral tegmental area (VTA). The clomipramine model failed to exacerbate compulsive lever pressing and VTA dopamine neurons in clomipramine-treated rats had mildly diminished bursting activity. In contrast, quinpirole-treated animals showed significant increases in compulsive lever pressing, which was concurrent with a substantial diminution of bursting activity of VTA dopamine neurons. Therefore, VTA dopamine activity correlated with the behavioural response in these models. Taken together, these data support the view that compulsive behaviours likely reflect, at least in part, a disruption of the dopaminergic system, more specifically by a decrease in baseline phasic dopamine signalling mediated by burst firing of dopamine neurons.
Assuntos
Comportamento Compulsivo/psicologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/fisiologia , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/patologia , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Clomipramina/toxicidade , Condicionamento Operante , Agonistas de Dopamina/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Quimpirol/toxicidade , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/patologiaAssuntos
Transtornos Dissociativos/metabolismo , Motivação/efeitos dos fármacos , Nicotina/efeitos adversos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Animais , MasculinoRESUMO
The multifaceted concept of impulsivity implies that different impulsivity aspects, mediated by different neural processes, influence behavior at different levels. The nucleus accumbens (NAc) is a key component of the neural processes regulating impulsivity. In this review, we discuss the findings of lesion studies in animals and functional imaging studies in humans focusing on the role of the NAc in impulsivity. Evidence supports that the extent and pattern of involvement of the NAc, and its subregions, the core and the shell, vary among different facets of impulsivity. Data from imaging studies reviewed in this article suggest the involvement of the ventral striatum/NAc in impulsive choice. Findings of animal studies indicate that lesions of the NAc core subregion facilitated impulsivity in tasks involving intertemporal choice, and promoted a risk-averse, less impulsive, tendency in tasks involving options with probability differences. Modification of neurotransmitter activity, especially of dopamine, which is proposed to underlie the changes observed in functional imaging studies, has been shown to influence afferent input pattern in the NAc and the generation of the behavioral output. Parameters of behavioral tasks reflecting response inhibition function are altered by neurochemical interventions and local electrical stimulation in both the core and the shell subregions. In toto, NAc's pattern of neuronal activity, either genetically determined or acquired, has a critical impact on the interindividual variation in the expression of impulsivity. Nevertheless, the NAc is not the only substrate responsible for impulsivity and it is not involved in each facet of impulsivity to the same extent.
Assuntos
Comportamento Impulsivo , Núcleo Accumbens/fisiologia , Animais , Atenção/fisiologia , Comportamento de Escolha/fisiologia , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Humanos , Comportamento Impulsivo/tratamento farmacológico , Comportamento Impulsivo/patologia , Inibição Psicológica , Vias Neurais/fisiologia , Núcleo Accumbens/anatomia & histologia , Serotonina/metabolismoRESUMO
Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) has frequently been shown to induce escape and freezing/decreased locomotion responses which mimic panic- and fear-like behaviour. In the present study we tested whether such spontaneous fear-like behaviour could be observed in an open-field test 12 h after dlPAG stimulation. Further, we tested whether this fear-like behaviour could be attenuated by acute or chronic administration of buspirone and escitalopram. Our data demonstrate for the first time that animals showed fear-like behaviour 12 h after dlPAG stimulation, which may possibly reflect panic disorder with anticipatory anxiety/agoraphobic symptoms. Acute and chronic escitalopram, but not buspirone, treatment attenuated the fear-related behaviour. Besides, our data also showed that the stimulation intensities to evoke an escape reaction, a panicogenic response, were significantly higher after chronic buspirone and escitalopram treatment. These results suggest that the fear-like response, which was observed 12 h after dlPAG stimulation, could be considered as a relevant animal model for panic disorder with anticipatory anxiety/agoraphobic symptoms.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Citalopram/farmacologia , Estimulação Encefálica Profunda , Medo/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Animais , Ansiolíticos/farmacologia , Buspirona/farmacologia , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Medo/psicologia , Locomoção/efeitos dos fármacos , Masculino , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects.
Assuntos
Dopamina/metabolismo , Comportamento Impulsivo/fisiopatologia , Núcleo Accumbens/fisiopatologia , Serotonina/metabolismo , Análise de Variância , Animais , Comportamento Animal/fisiologia , Cromatografia Líquida de Alta Pressão , Estimulação Encefálica Profunda , Comportamento Impulsivo/metabolismo , Masculino , Atividade Motora/fisiologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Endogâmicos Lew , Tempo de Reação/fisiologiaRESUMO
Recent anatomical and clinical evidence has shown that the cerebellum, primarily considered a motor control structure, is also involved in higher cognitive functions and behavioural changes, such as impulsive behaviour. Impulsive behaviour has been shown in several studies to be increased by lesions of the mediodorsal (MD) thalamic nucleus. We performed deep brain stimulation (DBS) of the mediodorsal and ventrolateral (VL) thalamic nuclei in rats, clinically mimicking such a lesion, and tested them for changes in impulsive behaviour in a choice reaction time test. We then analysed the effects of this stimulation on c-Fos expression in both the deep cerebellar nuclei (DCbN) and the prefrontal cortex (PFC), and correlated these outcomes to the measured changes in impulsive behaviour. DBS of the MD thalamic nucleus increased impulsive behaviour without changing motor parameters. This was accompanied by a decrease in the c-Fos expression in all cerebellar nuclei; with a corresponding increase in c-Fos expression in the PFC. DBS of the VL thalamic nucleus caused no significant change in behaviour or c-Fos expression in either region. The present study demonstrates that impulsive behaviour involves the cerebellar nuclei, possibly through a decreased selective attention caused by a disruption of the cerebello-thalamo-cortical pathways through the MD thalamic nucleus.
Assuntos
Núcleos Cerebelares/fisiopatologia , Comportamento Impulsivo/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Núcleos Cerebelares/metabolismo , Estimulação Encefálica Profunda , Imuno-Histoquímica , Masculino , Núcleo Mediodorsal do Tálamo/fisiopatologia , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Núcleos Ventrais do Tálamo/fisiologia , Núcleos Ventrais do Tálamo/fisiopatologiaRESUMO
The use of deep brain stimulation (DBS) to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of neuroscience. Deep brain stimulation has generally the same clinical effects as a lesion with respect to the improvement of clinical disability, but has more advantages such as its adjustability and reversibility. To this day, fundamental knowledge regarding the application of electrical currents to deep brain structures is far from complete. Despite improving key symptoms in movement disorders, DBS can be associated with the occurrence of a variety of changes in cognitive and limbic functions both in humans and animals. Furthermore, in psychiatric disorders, DBS is primarily used to evoke cognitive and limbic changes to reduce the psychiatric disability. Preclinical DBS experiments have been carried out to investigate the mechanisms underlying the clinical effects of DBS for at least three (interrelated) reasons: to increase our scientific knowledge, to optimize/refine the technology, or to prevent/reduce side-effects. In this review, we will discuss the limbic and cognitive effects of DBS in preclinical studies.
Assuntos
Cognição , Sistema Límbico/fisiopatologia , Animais , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Doença de Huntington/terapia , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , RatosRESUMO
The nucleus accumbens is gaining interest as a target for deep brain stimulation in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. Here, we tested the hypothesis that stimulation of the nucleus accumbens core and shell would have different effects on impulsivity. Rats received bilateral stimulation at the level of the nucleus accumbens core or shell during a reaction time task. Stimulation of the nucleus accumbens core significantly decreased impulsivity, while stimulation of the shell increased it. Our results support the hypothesis that the nucleus accumbens is a potential target to treat neuropsychiatric disorders related to impulsivity by deep brain stimulation. However, different behavioral effects resulting from stimulation of the subterritories should be taken into account.
Assuntos
Comportamento Animal/fisiologia , Comportamento Impulsivo , Núcleo Accumbens/fisiologia , Análise de Variância , Animais , Estimulação Encefálica Profunda , Masculino , Desempenho Psicomotor/fisiologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Tempo de Reação/fisiologiaRESUMO
Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) and one of its target structures, the ventromedial hypothalamus (VMH), produces a typical behaviour in rats consisting of vigorous running and jumping which is known as "escape behaviour". Escape behaviour in rodents closely mimics panic attacks in humans. Since electrical stimulation at higher frequencies generally inhibits the stimulated region, we tested in this study the hypothesis that deep brain stimulation (DBS) of the dlPAG and VMH at higher frequencies (> 100 Hz) would not induce escape behaviour. More specifically, we evaluated whether experimental DBS could be used to inhibit panic-like behaviour. Rats underwent implantation of DBS-electrodes at the level of the dlPAG and VMH and the effects of various stimulation parameters were assessed. In addition, we studied the neural activation pattern resulting from DBS of the dlPAG and VMH using c-Fos immunohistochemistry. We found that stimulation amplitude is the most important stimulation parameter in the induction of escape behaviour. Remarkably, stimulation frequency (1-300 Hz) had no effect on stimulation-induced escape behaviour and therefore it was not possible to prevent the induction of escape behaviour with higher frequencies. The neuronal activation pattern resulting from dlPAG and VMH DBS was similar. These findings suggest that DBS of the dlPAG and VMH induces panic-related behaviours even at higher frequencies.