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1.
Science ; 372(6537)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795429

RESUMO

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.


Assuntos
Giro Denteado/fisiologia , Córtex Entorrinal/fisiologia , Ritmo Gama , Aprendizagem , Neurônios/fisiologia , Aprendizagem Espacial , Potenciais de Ação , Animais , Masculino , Aprendizagem em Labirinto , Rememoração Mental , Vias Neurais/fisiologia , Optogenética , Células Piramidais/fisiologia , Ratos , Ratos Long-Evans , Navegação Espacial
2.
Biol Res ; 54(1): 4, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557947

RESUMO

BACKGROUND: Early-life stress in the form of maternal separation can be associated with alterations in offspring neurodevelopment and brain functioning. Here, we aimed to investigate the potential impact of prolonged maternal separation on proteomic profiling of prefrontal cortex, hippocampus and cerebellum of juvenile and young adult rats. A special attention was devoted to proteins involved in the process of cell death and redox state maintenance. METHODS: Long-Evans pups were separated from their mothers for 3 h daily over the first 3 weeks of life (during days 2-21 of age). Brain tissue samples collected from juvenile (22-day-old) and young adult (90-day-old) rats were used for label-free quantitative (LFQ) proteomic analysis. In parallel, selected oxidative stress markers and apoptosis-related proteins were assessed biochemically and by Western blot, respectively. RESULTS: In total, 5526 proteins were detected in our proteomic analysis of rat brain tissue. Approximately one tenth of them (586 proteins) represented those involved in cell death processes or regulation of oxidative stress balance. Prolonged maternal separation caused changes in less than half of these proteins (271). The observed alterations in protein expression levels were age-, sex- and brain region-dependent. Interestingly, the proteins detected by mass spectrometry that are known to be involved in the maintenance of redox state were not markedly altered. Accordingly, we did not observe any significant differences between selected oxidative stress markers, such as the levels of hydrogen peroxide, reduced glutathione, protein carbonylation and lipid peroxidation in brain samples from rats that underwent maternal separation and from the corresponding controls. On the other hand, a number of changes were found in cell death-associated proteins, mainly in those involved in the apoptotic and autophagic pathways. However, there were no detectable alterations in the levels of cleaved products of caspases or Bcl-2 family members. Taken together, these data indicate that the apoptotic and autophagic cell death pathways were not activated by maternal separation either in adolescent or young adult rats. CONCLUSION: Prolonged maternal separation can distinctly modulate expression profiles of proteins associated with cell death pathways in prefrontal cortex, hippocampus and cerebellum of juvenile rats and the consequences of early-life stress may last into adulthood and likely participate in variations in stress reactivity.


Assuntos
Encéfalo/fisiopatologia , Morte Celular , Privação Materna , Proteoma , Animais , Animais Recém-Nascidos , Feminino , Masculino , Proteômica , Ratos , Ratos Long-Evans
3.
Neuron ; 109(6): 1029-1039.e8, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33567253

RESUMO

The theta rhythm organizes neural activity across hippocampus and entorhinal cortex. A role for theta oscillations in spatial navigation is supported by half a century of research reporting that theta frequency encodes running speed linearly so that displacement can be estimated through theta frequency integration. We show that this relationship is an artifact caused by the fact that the speed of freely moving animals could not be systematically disentangled from acceleration. Using an experimental procedure that clamps running speed at pre-set values, we find that the theta frequency of local field potentials and spike activity is linearly related to positive acceleration, but not negative acceleration or speed. The modulation by positive-only acceleration makes rhythmic activity at theta frequency unfit as a code to compute displacement or any other kinematic variable. Temporally precise variations in theta frequency may instead serve as a mechanism for speeding up entorhinal-hippocampal computations during accelerated movement.


Assuntos
Aceleração , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Navegação Espacial/fisiologia , Ritmo Teta/fisiologia , Animais , Artefatos , Células de Grade/fisiologia , Masculino , Ratos , Ratos Long-Evans , Corrida/fisiologia
4.
Nat Neurosci ; 24(3): 391-400, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589832

RESUMO

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Aprendizagem/fisiologia , Animais , Sinais (Psicologia) , Feminino , Masculino , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans , Ratos Transgênicos , Recompensa
5.
Psychopharmacology (Berl) ; 238(4): 1069-1085, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33432392

RESUMO

RATIONALE: There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively. OBJECTIVES: We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist. METHODS: Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1-0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects). RESULTS: d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter "improvement" attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol. CONCLUSIONS: These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.


Assuntos
Alcaloides de Berberina/farmacologia , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Animais , Benzazepinas/farmacologia , Alcaloides de Berberina/química , Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Aprendizagem/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Psicologia do Esquizofrênico , Estereoisomerismo
6.
Psychopharmacology (Berl) ; 238(4): 1087-1098, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33442771

RESUMO

RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS: GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Indóis/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Maleato de Dizocilpina , Relação Dose-Resposta a Droga , Dronabinol/farmacologia , Antagonistas de Aminoácidos Excitatórios , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Fosforilação , Inibição Pré-Pulso/efeitos dos fármacos , Psicoses Induzidas por Substâncias/tratamento farmacológico , Psicoses Induzidas por Substâncias/psicologia , Ratos , Ratos Long-Evans
7.
Nat Commun ; 12(1): 253, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431847

RESUMO

Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells' ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.


Assuntos
Células de Grade/citologia , Neurônios/citologia , Potenciais de Ação/fisiologia , Animais , Simulação por Computador , Córtex Entorrinal/citologia , Hipocampo/fisiologia , Masculino , Modelos Neurológicos , Ratos Long-Evans , Ritmo Teta/fisiologia , Fatores de Tempo
8.
Nat Commun ; 12(1): 211, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431878

RESUMO

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.


Assuntos
Encéfalo/fisiologia , Grafite/química , Tecnologia sem Fio , Animais , Comportamento Animal , Ritmo Gama/fisiologia , Teste de Materiais , Ratos Long-Evans , Processamento de Sinais Assistido por Computador , Sono/fisiologia , Fatores de Tempo , Transistores Eletrônicos
9.
Neuron ; 109(4): 597-610.e6, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33412101

RESUMO

Decision-making strategies evolve during training and can continue to vary even in well-trained animals. However, studies of sensory decision-making tend to characterize behavior in terms of a fixed psychometric function that is fit only after training is complete. Here, we present PsyTrack, a flexible method for inferring the trajectory of sensory decision-making strategies from choice data. We apply PsyTrack to training data from mice, rats, and human subjects learning to perform auditory and visual decision-making tasks. We show that it successfully captures trial-to-trial fluctuations in the weighting of sensory stimuli, bias, and task-irrelevant covariates such as choice and stimulus history. This analysis reveals dramatic differences in learning across mice and rapid adaptation to changes in task statistics. PsyTrack scales easily to large datasets and offers a powerful tool for quantifying time-varying behavior in a wide variety of animals and tasks.


Assuntos
Percepção Auditiva/fisiologia , Tomada de Decisões/fisiologia , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica/métodos , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa/métodos , Ratos , Ratos Long-Evans , Adulto Jovem
10.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498409

RESUMO

Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5-8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58-80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR.


Assuntos
Antioxidantes/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Ratos , Ratos Long-Evans , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Visão Ocular
11.
J Ethnopharmacol ; 264: 113360, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32918993

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Labiatae; lemon balm) is a traditional medicinal plant with hypoglycemic and hypolipidemic effects; however, how it imparts its beneficial effects remains unclear. We thus hypothesized that the herbal extract ALS-L1023, isolated from Melissa officinalis, inhibits obesity and diabetes, and tested our hypothesis using Otsuka Long-Evans Tokushima fatty (OLETF) rats, which are an established animal model of type 2 diabetes. MATERIALS AND METHODS: In this study, 28-week-old OLETF rats were fed a high-fat diet for 4 weeks to induce a marked impairment of the insulin response and were treated with or without ALS-L1023. Subsequently, the variables and determinants of glucose metabolism and pancreatic function were assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: The administration of ALS-L1023 resulted in a weight reduction without changes in food intake. It also markedly inhibited hyperglycemia and hypoinsulinemia, and restored ß-cell mass that was severely impaired in OLETF rats. There was a decrease in lipid accumulation in the liver and skeletal muscle of the obese rats after treatment with ALS-L1023. Concomitantly, there was an increase in the expression levels of fatty acid-oxidizing enzymes (AMPKα2, ACOX, MCAD, and VLCAD) in the liver and skeletal muscle after ALS-L1023 treatment. Furthermore, ALS-L1023 attenuated the pancreatic inflammation including the infiltration of CD68-positive macrophages and mast cells, in addition to attenuating the expression of inflammatory factors (IL-6 and CD68). CONCLUSIONS: These results suggest that treatment with ALS-L1023 may reduce weight gain, elevated glucose levels, and ß-cell loss, by changing the expression of fatty acid-oxidizing enzymes in the liver and skeletal muscle, including inflammatory factors in the pancreas. These findings indicate that ALS-L1023 may be an effective therapeutic strategy to treat human obesity and type 2 diabetes.


Assuntos
Glicemia/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Melissa , Obesidade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ganho de Peso/efeitos dos fármacos , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Células Secretoras de Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Obesidade/etiologia , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Endogâmicos OLETF , Ratos Long-Evans , Ganho de Peso/fisiologia
12.
Methods Mol Biol ; 2225: 227-239, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108666

RESUMO

Severe inflammatory disease initiated by neurotrauma and stroke is of primary concern in these intractable pathologies as noted in recent studies and understanding of the pathogenesis of spinal cord injury (SCI) in the rat model. Successful anti-inflammatory treatments should result in neuroprotection and limit the loss of neurological function to injury caused by the initial damage. Continuous subdural infusion offers direct access to the cavity of injury (COI) that forms after balloon crush SCI deep in the spinal cord. Some anti-inflammatory compounds are not likely capable of crossing the blood-spinal cord barrier. Subdural infusion of myxoma virus-derived Serp-1, an anti-thrombotic/anti-thrombolytic, and also of M-T7, a chemokine inhibitor, improved the locomotor scores and pain sensation scores as well as reduced the numbers of macrophages in the COI by 50 and 80%, respectively, while intraperitoneal infusion of either protein had little effect. Injection of a chitosan hydrogel loaded with Serp-1 into the dorsal spinal column crush also resulted in improved neurological deficits and in reduction of the size of the crush lesion 4 weeks after injury. While neurological scores in a simplified hind-end (HE) locomotor test together with a toe-pinch withdrawal test demonstrated improvement in all balloon crush injury and dorsal spinal crush injury rats, a severe inflammation is induced by the injury indicating additional damage to the spinal cord. Thus neurological function testing can be contradictory, rather than corresponding, to the pathogenesis of SCI. The count of macrophages in the COI offers a precise, reliable method of measuring the effectiveness of a neuroprotective treatment of SCI in preclinical studies.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores Imunológicos/farmacologia , Myxoma virus/química , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Anti-Inflamatórios/imunologia , Quitosana/química , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Fatores Imunológicos/imunologia , Injeções Epidurais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/imunologia , Ratos , Ratos Long-Evans , Receptores de Interferon/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Proteínas Virais/imunologia
13.
Nature ; 590(7847): 606-611, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33361819

RESUMO

How do we learn about what to learn about? Specifically, how do the neural elements in our brain generalize what has been learned in one situation to recognize the common structure of-and speed learning in-other, similar situations? We know this happens because we become better at solving new problems-learning and deploying schemas1-5-through experience. However, we have little insight into this process. Here we show that using prior knowledge to facilitate learning is accompanied by the evolution of a neural schema in the orbitofrontal cortex. Single units were recorded from rats deploying a schema to learn a succession of odour-sequence problems. With learning, orbitofrontal cortex ensembles converged onto a low-dimensional neural code across both problems and subjects; this neural code represented the common structure of the problems and its evolution accelerated across their learning. These results demonstrate the formation and use of a schema in a prefrontal brain region to support a complex cognitive operation. Our results not only reveal a role for the orbitofrontal cortex in learning but also have implications for using ensemble analyses to tap into complex cognitive functions.


Assuntos
Aprendizagem/fisiologia , Modelos Neurológicos , Córtex Pré-Frontal/fisiologia , Aceleração , Animais , Cognição/fisiologia , Lógica , Masculino , Neurônios/fisiologia , Odorantes/análise , Córtex Pré-Frontal/citologia , Ratos , Ratos Long-Evans , Recompensa
14.
PLoS One ; 15(12): e0230544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378325

RESUMO

Mycobacterium ulcerans is a non-tuberculous environmental mycobacterium responsible for extensive cutaneous and subcutaneous ulcers in mammals, known as Buruli ulcer in humans. M. ulcerans has seldom been detected in the faeces of mammals and has not been detected in human faeces. Nevertheless, the detection and isolation of M. ulcerans in animal faeces does not fit with the current epidemiological schemes for the disease. Here, using an experimental model in which rats were fed with 109 colony-forming units of M. ulcerans, we detected M. ulcerans DNA in the faeces of challenged rats for two weeks and along their digestive tract for 10 days. M. ulcerans DNA was further detected in the lymphatic system including in the cervical and axillary lymph nodes and the spleen, but not in any other tissue including healthy and broken skin, 10 days post-challenge. These observations indicate that in some herbivorous mammals, M. ulcerans contamination by the digestive route may precede translocation and limited contamination of the lymphatic tissues without systemic infection. These herbivorous mammals may be sources of M. ulcerans for exposed populations but are unlikely to be reservoirs for the pathogen.


Assuntos
Fezes/microbiologia , Trato Gastrointestinal/microbiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium ulcerans/isolamento & purificação , Animais , DNA Bacteriano/genética , Ratos , Ratos Long-Evans
15.
PLoS Biol ; 18(12): e3001019, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33347436

RESUMO

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with "no-repetition" controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.


Assuntos
Córtex Auditivo/fisiologia , Potenciais Evocados Auditivos/fisiologia , Córtex Pré-Frontal/fisiologia , Estimulação Acústica , Animais , Córtex Auditivo/metabolismo , Percepção Auditiva/fisiologia , Eletroencefalografia/métodos , Feminino , Neurônios/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Long-Evans , Tempo de Reação/fisiologia
16.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321932

RESUMO

How ion channels impact the response of the ocular surface to dry eye is only beginning to be explored. Here, we review recent progress and provide new experimental data clarifying the exocytosis-altering actions of ion channels in conjunctival goblet cells whose release of tear-stabilizing mucin is a key adaptive response to the pre-ocular hyperosmolarity that characterizes dry eye. Patch-clamp recordings of goblet cells located in freshly excised rat conjunctiva reveal that these mucin-releasing cells respond to sustained hyperosmolarity by sequentially activating their ATP-sensitive potassium (KATP), nonspecific cation (NSC), voltage-gated calcium (VGCC), and P2X7 channels; each of which modulates exocytosis. Based on these and other new findings, we now identify four stages in the bioelectric response of conjunctival goblet cells to extracellular hyperosmolarity. To better characterize these stages, we report that high-resolution membrane capacitance (Cm) measurements of the exocytotic activity of single goblet cells demonstrate that the replenishment of mucin-filled granules after neural-evoked exocytosis is a multi-hour process, which VGCCs markedly accelerate. Yet, we also discovered that VGCC activation is high-risk since hyperosmotic-induced goblet cell death is boosted. With dry eye treatments being far from optimal, elucidating the physiologic and pathobiologic impact of the KATP/NSC/VGCC/P2X7 pathway provides a new opportunity to identify novel therapeutic strategies.


Assuntos
Canais de Cálcio/metabolismo , Síndromes do Olho Seco/metabolismo , Exocitose , Células Caliciformes/metabolismo , Canais KATP/metabolismo , Potenciais da Membrana , Receptores Purinérgicos P2X7/metabolismo , Animais , Sobrevivência Celular , Túnica Conjuntiva/citologia , Túnica Conjuntiva/metabolismo , Células Caliciformes/fisiologia , Mucinas/metabolismo , Concentração Osmolar , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
17.
Elife ; 92020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33357380

RESUMO

The prefrontal cortex (PFC)'s functions are thought to include working memory, as its activity can reflect information that must be temporarily maintained to realize the current goal. We designed a flexible spatial working memory task that required rats to navigate - after distractions and a delay - to multiple possible goal locations from different starting points and via multiple routes. This made the current goal location the key variable to remember, instead of a particular direction or route to the goal. However, across a broad population of PFC neurons, we found no evidence of current-goal-specific memory in any previously reported form - that is differences in the rate, sequence, phase, or covariance of firing. This suggests that such patterns do not hold working memory in the PFC when information must be employed flexibly. Instead, the PFC grouped locations representing behaviorally equivalent task features together, consistent with a role in encoding long-term knowledge of task structure.


Assuntos
Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Memória Espacial/fisiologia , Animais , Objetivos , Masculino , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Long-Evans
18.
Int J Mol Sci ; 22(1)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374645

RESUMO

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.


Assuntos
Consolidação da Memória , Córtex Perirrinal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Masculino , Rememoração Mental , Córtex Perirrinal/fisiologia , Ratos , Ratos Long-Evans , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Receptores de N-Metil-D-Aspartato/genética
19.
Nat Commun ; 11(1): 4605, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929073

RESUMO

From starlight to sunlight, adaptation alters retinal output, changing both the signal and noise among populations of retinal ganglion cells (RGCs). Here we determine how these light level-dependent changes impact decoding of retinal output, testing the importance of accounting for RGC noise correlations to optimally read out retinal activity. We find that at moonlight conditions, correlated noise is greater and assuming independent noise severely diminishes decoding performance. In fact, assuming independence among a local population of RGCs produces worse decoding than using a single RGC, demonstrating a failure of population codes when correlated noise is substantial and ignored. We generalize these results with a simple model to determine what conditions dictate this failure of population processing. This work elucidates the circumstances in which accounting for noise correlations is necessary to take advantage of population-level codes and shows that sensory adaptation can strongly impact decoding requirements on downstream brain areas.


Assuntos
Retina/fisiologia , Adaptação Ocular/efeitos da radiação , Animais , Teorema de Bayes , Luz , Modelos Lineares , Visão Noturna/fisiologia , Estimulação Luminosa , Ratos Long-Evans , Retina/efeitos da radiação , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação
20.
Nat Commun ; 11(1): 4634, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929078

RESUMO

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.


Assuntos
Cromatina/metabolismo , Corpo Estriado/enzimologia , Dependência de Heroína/enzimologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Animais , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Genoma , Células HEK293 , Heroína/efeitos adversos , Humanos , Masculino , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Ratos Long-Evans , Autoadministração , Transcrição Genética/efeitos dos fármacos , Proteínas tau/metabolismo
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