Os modelos experimentais da pilocarpina e do acido cainico, em diversos aspectos mimetizam a epil... more Os modelos experimentais da pilocarpina e do acido cainico, em diversos aspectos mimetizam a epilepsia de lobo temporal de humanos. Utilizando este dois modelos, decidimos avaliar a lesao neuronal nas diversas fases do processo epileptico. A identificacao de neuronios lesados apos status epilepticus (SE) ou crises espontaneas recorrentes (CERs) foi estudada predominantemente atraves da utilizacao de uma tecnica de impregnacao pela prata que permite a visualizacao de tais neuronios, corados em marrom, contra um fundo amarelo-caramelo, constituido pelos demais elementos (nao lesados) do tecido nervoso. O SE e consequentes CERs foram induzidos pela administracao sistemica de pilocarpina (320 mg/kg) ou de acido cainico (1O mg/kg). Parte do nosso objetivo foi avaliar a lesao neuronal frente a diferentes duracoes de SE induzido pela pilocarpina. Nossos resultados indicam que mesmo um SE de curtissima duracao determina lesao neuronal. Tambem avaliamos a lesao neuronal que sucede ao SE indu...
In the present study, we investigated the possible additive effects of epilepsy and aging on the ... more In the present study, we investigated the possible additive effects of epilepsy and aging on the expression of m1 muscarinic acetylcholine receptors (AChR) in the rat hippocampus. Young (3 months) and Aged (20 months) male, Wistar rats were treated with pilocarpine to induce status epilepticus (SE). Immunohistochemical procedure for m1 AChR detection was performed 2 months after pilocarpine-induced SE. In the CA1 pyramidal region m1 AChR staining was significantly decreased in aged epileptic animals when compared to young epileptic and aged control rats, indicating that the aging effect is worsened by the epileptic condition. However, the Nissl-stained cell analysis indicated that the number of pyramidal CA1 neurons was similarly reduced in both epileptic groups, young and aged animals. Therefore, our data suggest that the progressive reduction of m1 AChR expression in CA1 pyramidal cells of aged epileptic rats might bear relevance to the associated progressive cognitive impairment.
Apoptosis 24Â h after pilocarpine-induced status epilepticus. No significant differences were fou... more Apoptosis 24Â h after pilocarpine-induced status epilepticus. No significant differences were found in hippocampal caspase 3 activity when animals who developed pilocarpine-induced SE with or without DBS were compared to controls. (TIFF 94 kb)
ABSTRACT: In the present study, we investigated the possible additive effects of epilepsy and agi... more ABSTRACT: In the present study, we investigated the possible additive effects of epilepsy and aging on the expression of m1 muscarinic acetylcholine receptors (AChR) in the rat hippocampus. Young (3 months) and Aged (20 months) male, Wistar rats were treated with pilocarpine to induce status epilepticus (SE). Immunohistochemical procedure for m1 AChR detection was performed 2 months after pilocarpine-induced SE. In the CA1 pyramidal region m1 AChR staining was significantly decreased in aged epileptic animals when compared to young epileptic and aged control rats, indicating that the aging effect is worsened by the epileptic condition. However, the Nissl-stained cell analysis indicated that the number of pyramidal CA1 neurons was similarly reduced in both epileptic groups, young and aged animals. Therefore, our data suggest that the progressive reduction of m1 AChR expression in CA1 pyramidal cells of aged epileptic rats might bear relevance to the associated progressive cognitive i...
The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these... more The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these changes, however, is still under debate. The high complexity of neural systems justifies the use of computational simulation to investigate mechanisms that are possibly involved. Simulated neuronal activity includes non-synaptic epileptiform events (NEA) induced in hippocampal slices perfused with high-K(+) and zero-Ca(2+), therefore in the absence of the synaptic circuitry. A network of functional units composes the NEA model. Each functional unit represents one interface of neuronal/extracellular space/glial segments. Each interface contains transmembrane ionic transports, such as ionic channels, cotransporters, exchangers and pumps. Neuronal interconnections are mediated by gap-junctions, electric field effects and extracellular ionic fluctuations modulated by extracellular electrodiffusion. Mechanisms investigated are those that change intracellular and extracellular ionic concentrations and are able to affect [H(+)]. Our simulations suggest that the intense fluctuations in intra and extracellular concentrations of Na(+), K(+) and Cl(-) that accompany NEA are able to affect the combined action of the Na(+)/H(+) exchanger (NHE), [HCO(-)(3)]/Cl(-) exchanger (HCE), H(+) pump and the catalytic activity of intra and extracellular carbonic anhydrase. Cellular volume changes and extracellular electrodiffusion are responsible for modulating pH.
It is still a question of much debate whether single epileptic seizures can cause cell loss. Desp... more It is still a question of much debate whether single epileptic seizures can cause cell loss. Despite the clinical impression that epilepsy in general is a progressive disorder, experimental evidence is not conclusive on this point. Recently, it has been shown that electrically-induced afterdischarges of less than 2 min may induce structural impairments in neurons. Here we evaluated whether spontaneous seizures would lead to similar impairments. Chronic spontaneous recurrent seizures were induced with pilocarpine (320 mg/kg, i.p.). Animals were sacrificed from 1 to 6 h either after single or multiple seizures. A Golgi-like sensitive silver-impregnation procedure was used to reveal injured neurons. Silver-impregnated dark neurons were never found in control animals nor in epileptic animals that had no behavioral seizures in the 8 h prior to sacrifice. After spontaneous seizures (injured) dark neurons were mostly interneurons and were present in hippocampus (CA1 stratum radiatum), amygdala, piriform cortex and other limbic structures. Animals with multiple seizures had a higher number of dark cells than animals with single seizures. Our findings suggest that even single generalized spontaneous tonic-clonic seizures can induce long-lasting morphological changes. Our results favor the idea that epilepsy is a progressive disorder where one seizure begets the next.
Recent studies in patients with treatment-resistant depression have shown similar results with th... more Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. ...
Magnetic resonance images are useful in the study of experimental models of temporal lobe epileps... more Magnetic resonance images are useful in the study of experimental models of temporal lobe epilepsy. The manganese-enhanced MRI (MEMRI) technique is of interest since it combines the effects caused by manganese on the increased contrast in activated cell populations, when competing with calcium in synaptic transmission. Thus, the purpose of this study was to investigate the temporal evolution of the contrast related to manganese in the acute phase of temporal lobe epilepsy induced by systemic pilocarpine and compare it to the expression of the c-Fos protein. During this phase, the intensity of the MEMRI signal was analyzed at three different time points (5, 15 or 30 minutes) after the onset of status epilepticus (SE). The group that was maintained in status epilepticus for 30 minutes showed a decrease in intensity of the signal in CA1 and the dentate gyrus (DG). There were no differences between the control group and the other groups treated with pilocarpine. The expression of the pr...
Although it is known that nociceptive stimulation in the first postnatal week in rats is useful t... more Although it is known that nociceptive stimulation in the first postnatal week in rats is useful to model preterm pain, resulting in activation of specific brain areas, as assessed in vivo using manganese‐enhanced magnetic resonance imaging (MEMRI), little is known about its long‐term effects and sex specificity. Here we aimed to investigate whether inflammatory pain induced in male and female adult rats modify the pattern of brain activation between animals subjected or not to neonatal pain. For this, Complete Freund's adjuvant (CFA) was injected into the left hind paw of rat pups on postnatal day 1 (P1) or P8 to induce inflammatory response. During adulthood, CFA‐treated and control animals were injected with CFA 1 hr prior MRI. MEMRI has the ability to enhance the contrast of selective brain structures in response to a specific stimulus, as the pain. MEMRI responses were consistent with activation of nociceptive pathways and these responses were reduced in animals treated with CFA on P1, but increased in animals treated on P8, mainly in the female group. In agreement, P8 female group showed exacerbated responses in the thermal nociceptive test. Using MEMRI, we conclude that the natural ability of adult rats to recognize and react to pain exposition is modified by neonatal painful exposition, mainly among females.
The dopaminergic system is implicated in several cognitive processes including memory, attention ... more The dopaminergic system is implicated in several cognitive processes including memory, attention and executive functions. This study was a double-blind, placebo-randomized trial designed to investigate the effect of dopamine D2receptor blockade on episodic and working memory and particularly the relationship between executive functions, working memory capacity and long-term memory (LTM). Subjects ingested a single oral dose (4 mg) of haloperidol, a dopamine D2receptor antagonist or placebo. Multiple linear regression using generalized linear models and a generalized estimating equation were used for statistical analyses. The results demonstrated that haloperidol impaired episodic memory (free recall of words and prose recall), working memory capacity-WMC (operation span task-OSPAN) and highly demanding executive functions (random number generation - RNG). In addition, it demonstrated that despite the large impairment in the RNG task performance in the haloperidol group, it did not a...
Os modelos experimentais da pilocarpina e do acido cainico, em diversos aspectos mimetizam a epil... more Os modelos experimentais da pilocarpina e do acido cainico, em diversos aspectos mimetizam a epilepsia de lobo temporal de humanos. Utilizando este dois modelos, decidimos avaliar a lesao neuronal nas diversas fases do processo epileptico. A identificacao de neuronios lesados apos status epilepticus (SE) ou crises espontaneas recorrentes (CERs) foi estudada predominantemente atraves da utilizacao de uma tecnica de impregnacao pela prata que permite a visualizacao de tais neuronios, corados em marrom, contra um fundo amarelo-caramelo, constituido pelos demais elementos (nao lesados) do tecido nervoso. O SE e consequentes CERs foram induzidos pela administracao sistemica de pilocarpina (320 mg/kg) ou de acido cainico (1O mg/kg). Parte do nosso objetivo foi avaliar a lesao neuronal frente a diferentes duracoes de SE induzido pela pilocarpina. Nossos resultados indicam que mesmo um SE de curtissima duracao determina lesao neuronal. Tambem avaliamos a lesao neuronal que sucede ao SE indu...
In the present study, we investigated the possible additive effects of epilepsy and aging on the ... more In the present study, we investigated the possible additive effects of epilepsy and aging on the expression of m1 muscarinic acetylcholine receptors (AChR) in the rat hippocampus. Young (3 months) and Aged (20 months) male, Wistar rats were treated with pilocarpine to induce status epilepticus (SE). Immunohistochemical procedure for m1 AChR detection was performed 2 months after pilocarpine-induced SE. In the CA1 pyramidal region m1 AChR staining was significantly decreased in aged epileptic animals when compared to young epileptic and aged control rats, indicating that the aging effect is worsened by the epileptic condition. However, the Nissl-stained cell analysis indicated that the number of pyramidal CA1 neurons was similarly reduced in both epileptic groups, young and aged animals. Therefore, our data suggest that the progressive reduction of m1 AChR expression in CA1 pyramidal cells of aged epileptic rats might bear relevance to the associated progressive cognitive impairment.
Apoptosis 24Â h after pilocarpine-induced status epilepticus. No significant differences were fou... more Apoptosis 24Â h after pilocarpine-induced status epilepticus. No significant differences were found in hippocampal caspase 3 activity when animals who developed pilocarpine-induced SE with or without DBS were compared to controls. (TIFF 94 kb)
ABSTRACT: In the present study, we investigated the possible additive effects of epilepsy and agi... more ABSTRACT: In the present study, we investigated the possible additive effects of epilepsy and aging on the expression of m1 muscarinic acetylcholine receptors (AChR) in the rat hippocampus. Young (3 months) and Aged (20 months) male, Wistar rats were treated with pilocarpine to induce status epilepticus (SE). Immunohistochemical procedure for m1 AChR detection was performed 2 months after pilocarpine-induced SE. In the CA1 pyramidal region m1 AChR staining was significantly decreased in aged epileptic animals when compared to young epileptic and aged control rats, indicating that the aging effect is worsened by the epileptic condition. However, the Nissl-stained cell analysis indicated that the number of pyramidal CA1 neurons was similarly reduced in both epileptic groups, young and aged animals. Therefore, our data suggest that the progressive reduction of m1 AChR expression in CA1 pyramidal cells of aged epileptic rats might bear relevance to the associated progressive cognitive i...
The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these... more The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these changes, however, is still under debate. The high complexity of neural systems justifies the use of computational simulation to investigate mechanisms that are possibly involved. Simulated neuronal activity includes non-synaptic epileptiform events (NEA) induced in hippocampal slices perfused with high-K(+) and zero-Ca(2+), therefore in the absence of the synaptic circuitry. A network of functional units composes the NEA model. Each functional unit represents one interface of neuronal/extracellular space/glial segments. Each interface contains transmembrane ionic transports, such as ionic channels, cotransporters, exchangers and pumps. Neuronal interconnections are mediated by gap-junctions, electric field effects and extracellular ionic fluctuations modulated by extracellular electrodiffusion. Mechanisms investigated are those that change intracellular and extracellular ionic concentrations and are able to affect [H(+)]. Our simulations suggest that the intense fluctuations in intra and extracellular concentrations of Na(+), K(+) and Cl(-) that accompany NEA are able to affect the combined action of the Na(+)/H(+) exchanger (NHE), [HCO(-)(3)]/Cl(-) exchanger (HCE), H(+) pump and the catalytic activity of intra and extracellular carbonic anhydrase. Cellular volume changes and extracellular electrodiffusion are responsible for modulating pH.
It is still a question of much debate whether single epileptic seizures can cause cell loss. Desp... more It is still a question of much debate whether single epileptic seizures can cause cell loss. Despite the clinical impression that epilepsy in general is a progressive disorder, experimental evidence is not conclusive on this point. Recently, it has been shown that electrically-induced afterdischarges of less than 2 min may induce structural impairments in neurons. Here we evaluated whether spontaneous seizures would lead to similar impairments. Chronic spontaneous recurrent seizures were induced with pilocarpine (320 mg/kg, i.p.). Animals were sacrificed from 1 to 6 h either after single or multiple seizures. A Golgi-like sensitive silver-impregnation procedure was used to reveal injured neurons. Silver-impregnated dark neurons were never found in control animals nor in epileptic animals that had no behavioral seizures in the 8 h prior to sacrifice. After spontaneous seizures (injured) dark neurons were mostly interneurons and were present in hippocampus (CA1 stratum radiatum), amygdala, piriform cortex and other limbic structures. Animals with multiple seizures had a higher number of dark cells than animals with single seizures. Our findings suggest that even single generalized spontaneous tonic-clonic seizures can induce long-lasting morphological changes. Our results favor the idea that epilepsy is a progressive disorder where one seizure begets the next.
Recent studies in patients with treatment-resistant depression have shown similar results with th... more Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. ...
Magnetic resonance images are useful in the study of experimental models of temporal lobe epileps... more Magnetic resonance images are useful in the study of experimental models of temporal lobe epilepsy. The manganese-enhanced MRI (MEMRI) technique is of interest since it combines the effects caused by manganese on the increased contrast in activated cell populations, when competing with calcium in synaptic transmission. Thus, the purpose of this study was to investigate the temporal evolution of the contrast related to manganese in the acute phase of temporal lobe epilepsy induced by systemic pilocarpine and compare it to the expression of the c-Fos protein. During this phase, the intensity of the MEMRI signal was analyzed at three different time points (5, 15 or 30 minutes) after the onset of status epilepticus (SE). The group that was maintained in status epilepticus for 30 minutes showed a decrease in intensity of the signal in CA1 and the dentate gyrus (DG). There were no differences between the control group and the other groups treated with pilocarpine. The expression of the pr...
Although it is known that nociceptive stimulation in the first postnatal week in rats is useful t... more Although it is known that nociceptive stimulation in the first postnatal week in rats is useful to model preterm pain, resulting in activation of specific brain areas, as assessed in vivo using manganese‐enhanced magnetic resonance imaging (MEMRI), little is known about its long‐term effects and sex specificity. Here we aimed to investigate whether inflammatory pain induced in male and female adult rats modify the pattern of brain activation between animals subjected or not to neonatal pain. For this, Complete Freund's adjuvant (CFA) was injected into the left hind paw of rat pups on postnatal day 1 (P1) or P8 to induce inflammatory response. During adulthood, CFA‐treated and control animals were injected with CFA 1 hr prior MRI. MEMRI has the ability to enhance the contrast of selective brain structures in response to a specific stimulus, as the pain. MEMRI responses were consistent with activation of nociceptive pathways and these responses were reduced in animals treated with CFA on P1, but increased in animals treated on P8, mainly in the female group. In agreement, P8 female group showed exacerbated responses in the thermal nociceptive test. Using MEMRI, we conclude that the natural ability of adult rats to recognize and react to pain exposition is modified by neonatal painful exposition, mainly among females.
The dopaminergic system is implicated in several cognitive processes including memory, attention ... more The dopaminergic system is implicated in several cognitive processes including memory, attention and executive functions. This study was a double-blind, placebo-randomized trial designed to investigate the effect of dopamine D2receptor blockade on episodic and working memory and particularly the relationship between executive functions, working memory capacity and long-term memory (LTM). Subjects ingested a single oral dose (4 mg) of haloperidol, a dopamine D2receptor antagonist or placebo. Multiple linear regression using generalized linear models and a generalized estimating equation were used for statistical analyses. The results demonstrated that haloperidol impaired episodic memory (free recall of words and prose recall), working memory capacity-WMC (operation span task-OSPAN) and highly demanding executive functions (random number generation - RNG). In addition, it demonstrated that despite the large impairment in the RNG task performance in the haloperidol group, it did not a...
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