Since psychiatric disorders are associated with changes in the development of the nervous system,... more Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.
Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage... more Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage) are important characteristics of mitochondrial dysfunction; features that are often correlated with neurodegeneration. The measurement of oxygen consumption rate (OCR) is thus essential to evaluate cellular metabolism, survival, and neuroprotective strategies. In the present chapter, we describe the oxygen consumption assay using a Clark-type oxygen electrode in different types of samples named cells suspension (from primary and established cell culture), brain slices (ex vivo), and fresh brain tissues. In addition, we demonstrate herein how the program Oxygraph can be used in order to analyze the data and different approaches to normalize it.
Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease... more Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS’s unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS’s main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altoge...
Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, inc... more Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive defici...
Background The neurodevelopment refers to the process that generates and shapes the nervous syste... more Background The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schizophrenia. Results of our research group showed that a mitochondria dysfunction during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the b...
SIRS 2020 Abstracts S106 Poster Session I investigate sex-specific effects. A significant differe... more SIRS 2020 Abstracts S106 Poster Session I investigate sex-specific effects. A significant difference in schizophrenia pol-ygenic risk was observed between males and females, which indicated that males with SAD have lower schizophrenia polygenic risk scores than females with SAD (OR= 0.46, 95% CI= 0.28-0.74, R2= 0.143, p=1.5x10-3). Sex-specific effects were not observed for depression PRS or phenotypes. Discussion: Our results indicate a number of differences between individuals with schizophrenia and SAD. Primarily, the results demonstrate a greater burden of depression in those with SAD, both phenotypically and genotypically. Our results also suggest that the genetic contribution to SAD may differ between males and females. The findings indicate that schizophrenia research, particularly genetic research, needs to consider the impacts of sex-specific effects and comorbid depression before combining patient samples for analysis. Background: The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schiz-ophrenia. Results of our research group showed that a mitochondria dys-function during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the behavioral deficits in an early age (prodromal phase) and if the behavioral deficits presented at young adulthood could be attenuated or reverted by antipsychotic (Haldol-Hal) or psychostimulant (Metilphenidate-MPD). Notwithstanding, draw a parallel between this animal model and a neuropsychiatric disorder. Methods: To reach this goal, we treated intraperitoneally wistar puppies (P) with Rotenone 0.1mg/kg (Rot), Saline (Sal) or Vehicle (Veh) (DMSO) during P5-P11. To verify the prodromal phase, we performed behavioral tests (open field, social interaction and contextual fear conditioning) at P35. Therefore, in order to analyze the behavior during the young adult-hood (P60), each animal previously treated with Sal, Veh or Rot was then treated intraperitoneally, 30 min before the behavioral tests (open field, social interaction and contextual fear conditioning), with either Saline (Sal-Sal, Veh-Sal, Rot-Sal), Hal (Sal-Hal, Veh-Hal, Rot-Hal) or MPD (Sal-MPD, Veh-MPD, Rot-MPD). Results: Results showed mean±SEM (n=8 for each group) and analyzed by One-Way Anova and Duncan post-hoc compared to control group (Sal-Sal 100%). At P35, we verified: i) no significant changes in locomotor activity between Rot and Sal; ii) decrease in social interaction after treatment with Rot (68.40%±3.077; p<0.05 in relation to Sal); iii) a reduction in freezing time in contextual fear conditioning task to Rot group (45.20±8.03; p<0.05 when compared to Sal). At P60, we noticed i) an increase in locomotor activity after treatment with Rot-Sal (134.88%±3.95; p<0.05 when compared to Sal-Sal) that was decreased by treatment with Rot-Hal (94.76%±15.74; p<0.05 when compared to Rot-Sal), but not with Rot-MPD (compared to Rot-Sal); ii) a decrease in social interaction at P60 after treatment with Rot-Sal (68.35%±5.87; p<0.05 when compared to Sal-Sal) that was reverted
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenera... more Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.
Since psychiatric disorders are associated with changes in the development of the nervous system,... more Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism , we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adult-hood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behav-ioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.
Since psychiatric disorders are associated with changes in the development of the nervous system,... more Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.
Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage... more Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage) are important characteristics of mitochondrial dysfunction; features that are often correlated with neurodegeneration. The measurement of oxygen consumption rate (OCR) is thus essential to evaluate cellular metabolism, survival, and neuroprotective strategies. In the present chapter, we describe the oxygen consumption assay using a Clark-type oxygen electrode in different types of samples named cells suspension (from primary and established cell culture), brain slices (ex vivo), and fresh brain tissues. In addition, we demonstrate herein how the program Oxygraph can be used in order to analyze the data and different approaches to normalize it.
Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease... more Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS’s unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS’s main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altoge...
Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, inc... more Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive defici...
Background The neurodevelopment refers to the process that generates and shapes the nervous syste... more Background The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schizophrenia. Results of our research group showed that a mitochondria dysfunction during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the b...
SIRS 2020 Abstracts S106 Poster Session I investigate sex-specific effects. A significant differe... more SIRS 2020 Abstracts S106 Poster Session I investigate sex-specific effects. A significant difference in schizophrenia pol-ygenic risk was observed between males and females, which indicated that males with SAD have lower schizophrenia polygenic risk scores than females with SAD (OR= 0.46, 95% CI= 0.28-0.74, R2= 0.143, p=1.5x10-3). Sex-specific effects were not observed for depression PRS or phenotypes. Discussion: Our results indicate a number of differences between individuals with schizophrenia and SAD. Primarily, the results demonstrate a greater burden of depression in those with SAD, both phenotypically and genotypically. Our results also suggest that the genetic contribution to SAD may differ between males and females. The findings indicate that schizophrenia research, particularly genetic research, needs to consider the impacts of sex-specific effects and comorbid depression before combining patient samples for analysis. Background: The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schiz-ophrenia. Results of our research group showed that a mitochondria dys-function during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the behavioral deficits in an early age (prodromal phase) and if the behavioral deficits presented at young adulthood could be attenuated or reverted by antipsychotic (Haldol-Hal) or psychostimulant (Metilphenidate-MPD). Notwithstanding, draw a parallel between this animal model and a neuropsychiatric disorder. Methods: To reach this goal, we treated intraperitoneally wistar puppies (P) with Rotenone 0.1mg/kg (Rot), Saline (Sal) or Vehicle (Veh) (DMSO) during P5-P11. To verify the prodromal phase, we performed behavioral tests (open field, social interaction and contextual fear conditioning) at P35. Therefore, in order to analyze the behavior during the young adult-hood (P60), each animal previously treated with Sal, Veh or Rot was then treated intraperitoneally, 30 min before the behavioral tests (open field, social interaction and contextual fear conditioning), with either Saline (Sal-Sal, Veh-Sal, Rot-Sal), Hal (Sal-Hal, Veh-Hal, Rot-Hal) or MPD (Sal-MPD, Veh-MPD, Rot-MPD). Results: Results showed mean±SEM (n=8 for each group) and analyzed by One-Way Anova and Duncan post-hoc compared to control group (Sal-Sal 100%). At P35, we verified: i) no significant changes in locomotor activity between Rot and Sal; ii) decrease in social interaction after treatment with Rot (68.40%±3.077; p<0.05 in relation to Sal); iii) a reduction in freezing time in contextual fear conditioning task to Rot group (45.20±8.03; p<0.05 when compared to Sal). At P60, we noticed i) an increase in locomotor activity after treatment with Rot-Sal (134.88%±3.95; p<0.05 when compared to Sal-Sal) that was decreased by treatment with Rot-Hal (94.76%±15.74; p<0.05 when compared to Rot-Sal), but not with Rot-MPD (compared to Rot-Sal); ii) a decrease in social interaction at P60 after treatment with Rot-Sal (68.35%±5.87; p<0.05 when compared to Sal-Sal) that was reverted
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenera... more Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.
Since psychiatric disorders are associated with changes in the development of the nervous system,... more Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism , we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adult-hood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behav-ioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.
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