UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE
CURSO DE GRADUAÇÃO EM FARMÁCIA
Izabela Lima Paiva
Investigation of CA1 and DG delta oscillations in response to systemic administration of the NMDAr antagonist ketamine
Natal – RN 2019
Izabela Lima Paiva
Investigation of CA1 and DG delta oscillations in response to systemic administration of the NMDAr antagonist ketamine
Trabalho de Conclusão de Curso apresentado ao Curso de Graduação em Farmácia da Universidade Federal do Rio Grande do Norte, como requisito parcial para obtenção do título de Bacharel em Farmácia.
Orientador: Prof. Dr. Hindiael Aeraf Belchior
Natal – RN 2019
Izabela Lima Paiva
Investigation of CA1 and DG delta oscillations in response to systemic administration of the NMDAr antagonist ketamine
Trabalho de Conclusão de Curso apresentado ao Curso de Graduação em Farmácia da Universidade Federal do Rio Grande do Norte, como requisito parcial para obtenção do título de Bacharel em Farmácia.
Orientador: Prof. Dr. Hindiael Aeraf Belchior
_______________________________________________________________ Presidente: Hindiael Aeraf Belchior, Dr. – Orientador, UFRN
________________________________________________________ Membro: Janine Inez Rossato, Drª., UFRN
________________________________________________________ Membro: Adriano Bretanha Lopes Tort, Dr., UFRN
AGRADECIMENTOS
À universidade que proporcionou agregar conhecimento através de vivências acadêmicas formais e não formais.
Ao CNPq e UFRN por meio de bolsas de pesquisa concedidas durante o período de graduação que me auxiliaram a permanecer na pesquisa.
A todos os docentes do Departamento de Farmácia e demais departamentos da instituição, ao qual tive a oportunidade de aprender e que me ajudaram nesse processo de formação.
Agradeço especialmente ao meu orientador Prof. Dr. Hindiael Aeraf Belchior, por me acompanhar no processo de produção desse trabalho e na vivência como aluna de iniciação científica; a Prof. Drª. Janine Inez Rossato que me inspirou a vivência de pesquisa e ao Prof. Dr. Adriano Bretanha Lopes Tort por me receber como aluna no Laboratório de Neurociência Computacional do Instituto do Cérebro da UFRN.
A Bryan Souza, por toda atenção, pelos ensinamentos compartilhados e pela assistência durante a construção das rotinas de análises de dados.
Aos amados colegas e amigos do Laboratório de Neurociência Computacional do Instituto do Cérebro da UFRN, André Lockman; Alan M. B. Furtunato; Lucas Caiã; José Henrique; Rodrigo Santiago; Robson Teixeira.
A Fábio Caixeta pela disponibilização dos dados coletados durante sua pesquisa no Laboratório de Neurociência Computacional.
A Juliana Brandão pelos ensinamentos das técnicas de laboratório e por todo carinho.
As minhas amigas e amigos de graduação, Jaíne, Ingrid, Franco, Emily, Vanessa, Marcel, Ingrid Leite, Ana Flávia, Pâmela, Bruna, Ana Beatriz, Luíza com quem foi possível construir uma rede de cuidado companheirismo durante os últimos anos.
A Marcia, Elza e Ana Maria por terem me acolhido com muito amor e cuidado.
As minhas amadas amigas Micarla, Natália, Lívia, Viviane, Marina, Otaciana, Annie e Daiane por e meu amado amigo Bruno por estarem ao meu lado em tantos momentos decisivos acolhendo minhas dúvidas e fazendo a vida mais leve.
Aos meus pais e família que sempre estiveram ao meu lado me amparando financeira e emocionalmente de maneira incondicional com muito amor.
Apresentação do Trabalho de Conclusão de Curso
A esquizofrenia é um transtorno mental que implica no comprometimento das funções cognitivas, emocionais e de memória do indivíduo. Acredita-se que a esquizofrenia afete diversas regiões cerebrais, desde áreas corticais superficiais até regiões sub corticais profundas como: córtex pré-frontal, córtex entorrinal, tálamo, amígdala e hipocampo (Tamminga et al., 2010; Tamminga and Holcomb, 2005). Os sintomas da esquizofrenia podem ser classificados como positivos (alucinações, delírios, escuta de vozes e paranoia) e negativos (retraimento social, perda de sensação de prazer e pensamentos descoordenado) (Schultz et al., 2007). A compreensão de como a esquizofrenia acomete o cérebro ainda não está totalmente clara, todavia, existem três principais hipóteses baseadas na disfunção dos sistemas de neurotransmissão.
A hipótese dopaminérgica foi a primeira a ser estabelecida, na década de 1960. Essa hipótese surgiu em virtude da ampla distribuição dos receptores dopaminérgicos em diversas vias neuronais e em especial pela capacidade de indução de psicoses como delírios e alucinações por meio da indução de uma hiperativação dopaminérgica em algumas regiões. Acredita-se que durante crises de esquizofrenia haja uma hiperativação dopaminérgica em regiões subcorticais concomitante a uma hipoativação em regiões pré-frontais. Apesar de explicar como aconteceriam os sintomas positivos da doença, a hipótese dopaminérgica não contempla a ocorrência dos sintomas negativos, uma vez que estes não podem ser induzidos por fármacos agonistas dopaminérgicos. Para tentar suprir esta lacuna, surgiram hipóteses alternativas baseadas em disfunções da atividade de neurônios excitatórios (hipótese glutamatérgica) e de interneurônios inibitórios (GABAérgica) (Tamminga and Holcomb, 2005).
Na neurotransmissão mediada por neurônios GABAérgicos percebeu-se, através de estudos post-mortem, que há uma disfunção desse sistema em pacientes portadores de esquizofrenia, e que há uma diminuição no tônus GABAérgico em regiões cortico-límbicas visualizada por meio de marcadores biológicos (Wassef et al., 2003).
Evidências farmacológicas e bioquímicas também mostraram que há uma hipoativação glutamatérgica em indivíduos esquizofrênicos (Lin et al., 2012). Estudos realizados em modelos animais tratados com doses sub-anestésicas de cetamina, um fármaco antagonista dos receptores glutamatérgicos do tipo NMDA, foram capazes de mimetizar não apenas os sintomas comportamentais positivos da doença, como na hipótese dopaminérgica, mas também os negativos e ainda as assinaturas eletrofisiológicas normalmente observadas em pacientes esquizofrênicos
(Stone et al., 2007). Sabe-se que a hipoativação glutamatérgica induzida pelo antagonismo do receptor NMDA no hipocampo leva a uma modulação na potência teta (8-12 Hz) e gama (30-100 Hz) nas sub-regiões CA1 e DG (Caixeta et al., 2013). Além dessas mudanças, estudos têm mostrado um aumento na amplitude da oscilação delta em CA1 minutos após a injeção de cetamina (Zhang et al., 2012). Esses achados reforçam seu envolvimento da hipoativação glutamatérgica no hipocampo durante a esquizofrenia.
Em condições fisiológicas saudáveis, a região hipocampal é de suma importância para a aquisição de novas memórias declarativas e para a navegação e localização espacial dos indivíduos (Knierim, 2015). Particularmente, pacientes esquizofrênicos sofrem com o comprometimento de memórias declarativas, que está diretamente associado com uma redução do volume hipocampal. Logo, a compreensão de como funcionam os sistemas biológicos que estão por trás da esquizofrenia tem sido um grande desafio da ciência há muitos anos. Para isso, muitas técnicas de investigação foram desenvolvidas e implementadas. A eletrofisiologia é uma dessas técnicas que permite a observação da atividade elétrica de células e tecidos biológicos excitáveis (Carter and Shieh, 2015). Através dela, é possível captar os potenciais elétricos das células excitáveis e os potenciais de campo gerados pelas suas interações com outras células que podem ser registrados por meio da inserção de eletrodos nas regiões envolvidas na fisiopatologia da esquizofrenia, o que possibilita a observação do perfil oscilatório em cada região.
Por meio dos registros eletrofisiológicos sabe-se que esses ritmos oscilatórios podem ser classificados como de baixa ou alta frequência. Como oscilações de baixa frequência temos teta (8-12 Hz), delta (1-4 Hz), beta (13-30 Hz); já para alta frequência há as oscilações gama, subdivididas em gama baixo (30-70 Hz) e gama alto (70-150 Hz) (Buzsáki, et al 2004). Em um registro eletrofisiológico, essas oscilações estão distribuídas no sinal bruto do potencial de campo local e estão fortemente relacionadas com o comportamento do animal. Em estados de locomoção ativa, por exemplo, temos uma alta expressão das oscilações na banda de frequência teta; já em estados de imobilidade podemos perceber uma maior predominância no sinal de oscilações na banda delta. Para o estudo de doenças complexas como a esquizofrenia, a análise dessas assinaturas eletrofisiológicas visualizadas por meio das oscilações neuronais é de extrema importância. Assim, dadas essas evidências e por meio do emprego dessas ferramentas eletrofisiológicas, durante este trabalho buscamos investigar as modificações ocorridas na oscilação delta hipocampal durante quadros miméticos a esquizofrenia em modelos animais induzidos pelo bloqueio de receptores glutamatérgicos do tipo NMDA pela ação da cetamina.
Resumo
A atividade oscilatória do cérebro gerada por populações neuronais proporcionou avanços em nossa compreensão da função cerebral em condições normais e patológicas. Estudos recentes tem utilizado a administração sistêmica do antagonista dos receptores NMDA cetamina como modelo animal para estudar a esquizofrenia. Através desses estudos foi possível registrar as modificações presentes na ativdade oscilatória normal em algumas áreas do cérebro, como o tálamo, o córtex pré-frontal e hipocampo. Uma dessas modificações é o aumento na amplitude das oscilações de baixa frequência delta (1-4 Hz) no hipocampo. No entanto, ainda não está claro se subáreas específicas do hipocampo são igualmente afetadas. Nosso objetivo nesse estudo foi investigar a modulação na amplitude da oscilação delta em CA1 e Giro Dentado (DG) do hipocampo de ratos em resposta à administração sistêmica de solução salina e três doses subestésicas de cetamina (25 mg/kg, 50 mg/kg e 75 mg/kg). Nossos resultados mostraram que as oscilações delta em CA1 e DG são moduladas pelo antagonista de NMDAr cetamina de maneira dependente da dose. Especificamente, a cetamina nas doses de 50 mg/kg e 75 mg/kg aumentou significativamente a amplitude das oscilações delta tanto em CA1 quanto em DG quando comparada à solução salina. Além disso, quando analisamos intervalos em que os animais apresentaram velocidade de locomoção menor que 5 cm/s, nossos resultados mostraram que a cetamina nas doses de 50mg/kg e 75 mg/kg aumentou significativamente a amplitude delta em CA1, mas não em DG. Esses resultados sugerem que as oscilações do delta no hipocampo são moduladas CA1 e DG sob efeito de cetamina, antagonista dos receptores NMDA.
Keywords: Esquizofrenia, modelo animal, antagonista glutamatérgico, oscilações cerebrais, hipocampo de ratos;
Abstract
Brain oscillatory activity generated by populations of neurons has provided advances in our understanding of brain function in normal and pathological conditions. Recent reports have used systemic administration of the NMDA receptor antagonist ketamine as an animal model to study schizophrenia. These studies revealed the disturbance of normal oscillatory activity in many brain areas like the thalamus, prefrontal cortex, and in the hippocampus. For instance, the amplitude of low-frequency oscillations in the delta band (1-4 Hz) increases in the hippocampus. However, it is still unclear whether specific subareas of the hippocampus are equally affected. Our aim was to investigate the amplitude modulation of delta oscillation in CA1 and Dentate Gyrus (DG) of the rat hippocampus in response to the systemic administration of saline and three sub anesthetic doses of ketamine (25 mg/kg, 50 mg/kg e 75 mg/kg). We found that the CA1 and DG delta oscillations are modulated by NMDAr antagonist ketamine in a dose-dependent manner. Specifically, ketamine at doses of 50 mg/kg and 75 mg/kg significantly increased the amplitude of delta oscillations both in CA1 and DG when compared to saline. In addition, when we analyzed intervals that animals presented locomotion speed lower than 5 cm/s, we found that ketamine at doses of 50 mg/kg and 75 mg/kg significantly increased delta amplitude in CA1, but not DG. These results suggest that hippocampal delta oscillations are modulated in CA1 and DG under effect on NMDA antagonist ketamine.
Keywords: Schizophrenia, animal model, glutamatergic antagonist, brain oscillations, rat
Investigation of CA1 and DG delta oscillations in response to systemic administration of the NMDAr antagonist ketamine
Paiva, I.L.¹, Caixeta, F.V. ², Tort, A.B.L.¹,Belchior. H.¹.
¹Instituto do cérebro, Universidade Federal do Rio Grande do Norte, Natal, RN, Brasil. ² Universidade de Brasília – UNB, Brasília,DF, Brasil.
Paiva, I.L. ORCID: 0000-0001-7600-4030 Caixeta, F.V. ORCID: 0000-0003-0919-342X Tort, A.B.L. ORCID: 0000-0002-9877-7816 Belchior. H. ORCID: 0000-0002-6898-3985
Introduction
Schizophrenia is a complex mental disorder that affects about 23 million people worldwide (OMS, 2018). Schizophrenic patients present impairments in sensoriomotor, emotional and cognitive functions associated with symptoms classified as positive (hallucinations, disorganized thoughts and delusions) and negative (flattened affect, loss of a sense of pleasure, loss of will or drive, and social withdrawal) (Robins and Guze, 1995). Postmortem and imaging studies of the human brain, as well as animal models of schizophrenia, indicate relevant physiological changes of superficial and deep brain areas, including the hippocampus, prefrontal cortex, thalamus and entorhinal cortex, during psychotic episodes (Tamminga et al., 2010; Tamminga and Holcomb, 2005). Imaging studies have shown impairment of hippocampal activity with reduced volume, hyperactivity of the CA1 sub-region, and changes in glutamatergic neurotransmission in DG (Hunt et al., 2017; Schobel et al., 2009; Tamminga et al., 2010). These modifications corroborate the prevalence of memory deficits presented by schizophrenic individuals.
However, the pathophysiological mechanism underlying schizophrenia remains unclear. Many studies indicate that schizophrenia involves a deregulation in the dopaminergic, glutamatergic and GABAergic neurotransmission in the central nervous system (Howes and Kapur, 2009; Nakazawa et al., 2012). The dopaminergic hypothesis was widely investigated in humans and animal models. However, dopaminergic drugs used to induce the positive symptoms of schizophrenia in animal models were not as effective to induce negative symptoms of the disease (Fone and Sciences, 2011). Related hypothesis based on the dysfunction of GABAergic and glutamatergic neurotransmission in interneurons and projection neurons, respectively, emerged as an alternative candidate to explain the pathophysiological mechanism of schizophrenia (Benes, 2009).
Pharmacological and biochemical evidence implied glutamatergic hypofunction in schizophrenic individuals (Lin et al., 2012). Studies performed in animal models treated with subanesthetic doses of ketamine, an NMDA-type glutamatergic receptor antagonist, mimic not only the behavioral symptoms but also the electrophysiological signatures typically observed in schizophrenic patients (Becker and Grecksch, 2004; Bubeníková-Valešová et al., 2008). Glutamatergic hypofunction induced by antagonism of NMDA receptor in the hippocampus modulates the amplitude of theta (8-12 Hz) and gamma (30-100 Hz) oscillations in CA1 and DG
sub-regions (Caixeta et al., 2013). In addition to these changes, the amplitude of delta oscillations increases in the CA1 region after ketamine injection (Zhang et al., 2012).
Considering the dysfunctional alterations in CA1 delta oscillations observed during schizophrenic episodes, and the dysrupted activity found in glutamatergic receptor neurotransmission in DG (Hunt et al., 2017; Tamminga et al., 2010), we sought to investigate the effects of the acute inhibition of NMDA receptors induced by three sub-anesthetic doses (25, 50 and 75 mg/kg) of ketamine in the amplitude of hippocampal delta oscillations in CA1 and DG sub-regions.
Materials and Methods
Animals and experimental conditions
We analyzed a dataset previously collected by our group (Caixeta et al., 2013). All experimental conditions and surgical protocols were approved by the Edmond and Lily Safra International Institute of Neuroscience of Natal Committee for Ethics in Animal Experimentation (permit 02/2011). The experiments used four male Wistar rats with 2-3 months old and weight between 280-380g, housed under a 12h light/dark cycle in a temperature and humidity controlled environment. All experiments were performed during the light phase. Animals were chronically implanted with one bundle of eight tungsten electrodes with 50 mm in diameter, spaced by 250 mm and placed in left dorsal hippocampus, including CA1 and dentate gyrus (coordinates: AP: 23.6 mm, ML: 22.5 mm, DV: 23.5 mm). For each individual, the implant was grounded in a screw placed at the epidural layer of the right parietal bone. Experimental procedures were made 7-10 days after surgery implant and the rats were individually habituated to the recording room for 3 days. Animals were then submitted to pharmacological treatments associated to video and electrophysiological recordings in a rectangular arena (50 x 04 x 40 cm). The duration of each interval was: one hour of basal state; one hour after saline injection; and three hours after a single ketamine injection in doses of 25, 50 and 75 mg/kg. A multi-channel acquisition processor (MAP, Plexon Inc) was used for the acquisition and recording of electrophysiological signals. Local field potentials (LFPs) were pre-amplified (1000x), filtered (0.7–300 Hz), and digitilized at 1000 Hz. Video recordings were made at 30 frames/second (Cineplex, Plexon Inc). Tracking of the animals position was made using MouseLabTracker (http://www.neuro.ufrn.br/incerebro/ mouselabtracker.php), an open-source MATLAB version of a previously described software.
Electrodes positions were confirmed by brain slices stained with cresyl violet. For complementary information see Caixeta et. al, 2013.
Data analysis
Local field potentials (LFPs) were analyzed through built-in functions from the Signal Processing Toolbox of MATLAB (MathWorks), and through specific routines made by our group. We analyzed LFPs from one electrode anatomically positioned in CA1 and one electrode in DG (Figure 1). Only the first ten minutes after saline and ketamine (25, 50 e 75 mg/kg) injections and in basal state were analyzed. To compare situations with similar behavioral conditions, we also selected LFPs intervals in which animals had locomotion speed lower than 5 cm/s. To obtain the instantaneous amplitude of the delta oscillations, we used the function “eegfilt” from the EEGLAB toolbox (http://sccn.ucsd.edu/eeglab/) in order to filter only signals in the 1-4 Hz range frequency, followed by the “hilbert” function to get the amplitude envelope of the signal (Signal Processing Toolbox). Since animals had different levels of basal amplitude, the envelope amplitude of each session was normalized by the mean amplitude measured during basal state of each animal. For statistical analysis, we used Student’s T-test and two-way ANOVA followed by Tukey-kramer post-hoc test. Alpha values lower than 0.05 were considered significant.
Figure 1 | Slice of the hippocampus shows the electrode position in the CA1 and DG subregions. Black arrows indicate the electrodes used in analysis. With permission Caixeta, et al., 2013.(A); raw LFP traces of CA1 (blue) and DG (black) and amplitude envelope of delta banda (red) (B).
Figure 2 | Group result (n=4) of the mean delta amplitude in the first 10 minutes after the injection of ketamine at doses of 25, 50 and 75 mg/kg in CA1 (A) and DG (B); Mean of delta amplitude in CA1 (C) and DG (D) along the first ten minutes after each dose of ketamine (p < 10-23).
Results
Initially, we compared the amplitude of CA1 and DG delta oscillations in response to tree different doses of ketamine. Figure 2 shows the mean delta amplitude in CA1 (A) and DG (B) during the 10 minutes after the I.P. injection of 25, 50, and 75 mg/kg. We found progressive increases in the amplitude of delta oscillations according to the dose of ketamine in both areas. By averaging the amplitude of delta oscillations in a minute-by-minute scale, it was also possible to see a progressive increase in amplitude along the first 10 minutes after ketamine injection in both sub-regions (Figure 2, C-D). These results corroborate the idea that modulation in delta oscillations during schizophrenic episodes may be related to a disorder in glutamatergic neurotransmission.
We then analyzed the average amplitude of delta oscillations in CA1 and DG minute-to-minute, along the first ten minutes after treatments with saline and each of the three doses of ketamine. The comparison between saline and ketamine treatments showed a progressive, dose-dependent increase in delta amplitude of both areas following ketamine injection in doses of 50 and 75 mg/kg (p <10-23) but not in 25 mg/kg (figure 3 - A, B). Considering the internal circuitry within the hippocampus and their connections with other cortical regions, we also sought to investigate whether ketamine affects the amplitude of the delta oscillations differently in CA1 and DG. We found that CA1 sub-region has an average amplitude greater than DG at doses of 50 and 75 mg/kg (p <10-23, n = 4, figure 3-C).
Since delta oscillations in the rat hippocampus are negatively modulated by locomotion and as there are reports that in schizophrenic episodes or mimetic conditions, induced by NMDAr antagonism, animals show an increase in the amplitude of delta oscillations at awake states (Zhang et al., 2012), we then investigated delta amplitude at moments wherein the animals had lower locomotion speed. For this, we analyzed subsets of intervals in which the locomotion speed of the animals were lower than 5 cm/s. We found that delta amplitude in CA1 area was significantly higher in ketamine (75 mg/kg) than in saline treatments. However, the same was not observed in DG, in which delta amplitude did not differ between saline and ketamine. The direct comparison between CA1 and DG showed no statistical difference in none of the three doses of ketamine (Figure 4)
Figure 3 | Mean delta amplitude in the first 10 minutes after saline (blue) and ketamine (red) injection in CA1 (A) and DG (B). Direct comparison between delta amplitude in CA1 (blue) and DG (red) areas along the 10 minutes after injection. Circles denote mean and colored shadows denote SEM.
Discussion
In accordance with previous evidence showing modulation of hippocampal delta oscillations during schizophrenic episodes (Siekmeier and Stufflebeam, 2010) and during mimetic conditions induced by NMDA receptor antagonist, ketamine (Lahti et al., 2001; Becker and Grecksch, 2004), our results showed a modulation in the amplitude of delta oscillations in CA1 and DG hippocampal areas (Figure 2).
The increase of amplitude of delta oscillations in CA1 and in DG under different doses of ketamine indicates that schizophrenic-like symptoms induced by this experimental model occur in a dose-dependent manner. It agreed with previous reports showing that small doses of ketamine (<25 mg/kg) were not sufficient to elicit behavioral changes similar to those observed in
Figure 4 | Group comparison of the mean delta amplitude in the first 10 minutes after injection of saline and ketamine with locomotion speed lower than 5 cm/s in CA1 (A) and DG (B), respectively; Direct group comparison between delta amplitude in CA1 and DG sub-regions 10 minutes after injection with locomotion speed lower than 5 cm/s (C).
Schizophrenia (Zhang et al., 2012). In addition to this result, the comparison among delta oscillations after saline and ketamine treatments supports evidence of the relationship modulation that occurs in delta oscillations by locomotion in natural states, and in accordance with previous results that this oscillations at CA1 are positively affected by during acute blockade of NMDAr between systemic administration of NMDA antagonists and delta amplitude in CA1 and DG areas of the hippocampus (Hunt et al., 2017). Moreover, the higher normalized amplitude of delta oscillation in CA1 in direct comparison with DG indicates a differential modulation between these sub-regions under the effect of ketamine. These results support the idea that delta oscillations are affected by hippocampal glutamatergic hypofunction induced by NMDA antagonism (Zhang et al., 2012) and suggest, yet, that CA1 and DG areas are affected differentially at moments of free locomotion speed.
However, analysis performed in subsets of intervals in which locomotion speed of the animals was lower than 5 cm/s presents statistical difference only in delta oscillations amplitude of CA1 sub-region under dose of 75 mg/kg in comparison with saline state (Figure 4). However the amplitude of delta oscillations in CA1 showed no statistical difference from DG sub-region. The results yet present by analysis with free locomotion speed DG sub-region exhibit statistical difference in delta oscillations amplitude among saline and ketamine states in all doses. Since the analysis of subsets of intervals with controlled locomotion speed revealed no statistical difference in the direct comparison between delta amplitude in CA1 and DG, the differences observed in Figure 3 may thus be caused by state transitions between locomotion and still behaviors.
In summary, our results suggest a dose-dependent and temporally progressive modulation of hippocampal delta oscillations in an animal model of schizophrenia induced by ketamine. Specifically, ketamine increased delta oscillations in CA1 and DG areas of the hippocampus, which may indicate that both hippocampal structures are similarly affected in schizophenic episodes. These findings strengthen the hypothesis that glutamatergic hypofunction may mediate some dysfunctional changes observed in the hippocampus of schizophrenic patients.
Data Availability
The data that support the findings of this study are available upon request
Ethics Statement
The studies involving this animal model were reviewed and approved by the Edmond and Lily Safra International Institute of Neuroscience of Natal Committee for Ethics in Animal
Experimentation (permit 02/2011).
Author Contributions
IP, HAB wrote analysis routines and manuscript, FC with data collect and ABLT wrote.
Conflict of Interest Statement
The authors declare that no have conflict of interest.
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