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1.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204780

RESUMO

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br2 exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br2 exposure.


Assuntos
Comportamento Animal , Tronco Encefálico/patologia , Bromo/administração & dosagem , Bromo/efeitos adversos , Neurônios/patologia , Estresse Oxidativo , Administração por Inalação , Animais , Biomarcadores/metabolismo , Lesões Encefálicas/patologia , Catecolaminas/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Metaboloma , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208374

RESUMO

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1ß (IL-1ß) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1ß levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1ß induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.


Assuntos
Comportamento Animal , Encefalite/tratamento farmacológico , Mitocôndrias/patologia , Pioglitazona/uso terapêutico , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Encefalite/patologia , Feminino , Hipotermia Induzida , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Pioglitazona/farmacologia , Gravidez , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Perda de Peso/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
3.
Biochemistry (Mosc) ; 86(6): 761-772, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225597

RESUMO

According to the two-hit hypothesis of psychoneuropathology formation, infectious diseases and other pathological conditions occurring during the critical periods of early ontogenesis disrupt normal brain development and increase its susceptibility to stress experienced in adolescence and adulthood. It is believed that these disorders are associated with changes in the functional activity of the glutamatergic system in the hippocampus. Here, we studied expression of NMDA (GluN1, GluN2a, GluN2b) and AMPA (GluA1, GluA2) glutamate receptor subunits, as well as glutamate transporter EAAT2, in the ventral and dorsal regions of the hippocampus of rats injected with LPS during the third postnatal week and then subjected to predator stress (contact with a python) in adulthood. The tests were performed 25 days after the stress. It was found that stress altered protein expression in the ventral, but not in the dorsal hippocampus. Non-stressed LPS-treated rats displayed lower levels of the GluN2b protein in the ventral hippocampus vs. control animals. Stress significantly increased the content of GluN2b in the LPS-treated rats, but not in the control animals. Stress also affected differently the exploratory behavior of LPS-injected and control rats. Compared to the non-stressed animals, stressed control rats demonstrated a higher locomotor activity during the 1st min of the open field test, while the stressed LPS-injected rats displayed lower locomotor activity than the non-stressed rats. In addition, LPS-treated stressed and non-stressed rats spent more time in the open arms of the elevated plus maze and demonstrated reduced blood levels of corticosterone. To summarize the results of our study, exposure to bacterial LPS in the early postnatal ontogenesis affects the pattern of stress-induced changes in the behavior and hippocampal expression of genes coding for ionotropic glutamate receptor subunits after psychogenic trauma suffered in adulthood.


Assuntos
Comportamento Animal , Hipocampo/metabolismo , Lipopolissacarídeos/toxicidade , Receptores Ionotrópicos de Glutamato/genética , Estresse Psicológico/metabolismo , Animais , Animais Recém-Nascidos , Regulação da Expressão Gênica , Hipocampo/crescimento & desenvolvimento , Masculino , Ratos , Ratos Wistar , Estresse Psicológico/genética
4.
Nat Commun ; 12(1): 4095, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215734

RESUMO

Interhemispheric correlation between homotopic areas is a major hallmark of cortical physiology and is believed to emerge through the corpus callosum. However, how interhemispheric correlations and corpus callosum activity are affected by behavioral states remains unknown. We performed laminar extracellular and intracellular recordings simultaneously from both barrel cortices in awake mice. We find robust interhemispheric correlations of both spiking and synaptic activities that are reduced during whisking compared to quiet wakefulness. Accordingly, optogenetic inactivation of one hemisphere reveals that interhemispheric coupling occurs only during quiet wakefulness, and chemogenetic inactivation of callosal terminals reduces interhemispheric correlation especially during quiet wakefulness. Moreover, in contrast to the generally elevated firing rate observed during whisking epochs, we find a marked decrease in the activity of imaged callosal fibers. Our results indicate that the reduction in interhemispheric coupling and correlations during active behavior reflects the specific reduction in the activity of callosal neurons.


Assuntos
Corpo Caloso/fisiologia , Vias Neurais/fisiologia , Vibrissas/patologia , Animais , Comportamento Animal , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Percepção/fisiologia
6.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201014

RESUMO

The amygdala plays a critical role in the acquisition and consolidation of fear-related memories. Recent studies have demonstrated that ADP-ribosylation of histones, accelerated by PARPs, affects the chromatin structure and the binding of chromatin remodeling complexes with transcription factors. Inhibition of PARP-1 activity during the labile phase of re-consolidation may erase memory. Accordingly, we investigated the possibility of interfering with fear conditioning by PARP-1 inhibition. Herein, we demonstrate that injection of PARP-1 inhibitors, specifically into the CeA or i.p., in different time windows post-retrieval, attenuates freezing behavior. Moreover, the association of memory with pharmacokinetic timing of PARP inhibitor arrival to the brain enabled/achieved attenuation of a specific cue-associated memory of fear but did not hinder other memories (even traumatic events) associated with other cues. Our results suggest using PARP-1 inhibitors as a new avenue for future treatment of PTSD by disrupting specific traumatic memories in a broad time window, even long after the traumatic event. The safety of using these PARP inhibitors, that is, not interfering with other natural memories, is an added value.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Medo/fisiologia , Memória/fisiologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Tonsila do Cerebelo/patologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos/enzimologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/patologia
7.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201038

RESUMO

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague-Dawley pups during early postnatal development (p5-p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42-p44, p60-p62) and in early adulthood (p90-p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/patologia , Glutationa/deficiência , Hipocampo/patologia , Transtornos do Neurodesenvolvimento/patologia , Esquizofrenia/patologia , Animais , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Ratos , Ratos Sprague-Dawley , Esquizofrenia/etiologia , Esquizofrenia/metabolismo
8.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203675

RESUMO

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied whether or not EA has any anti-inflammatory and analgesic properties via TRPC4/5 in the carrageenan model of inflammation. We found that EA treatment in CD1 mice inhibited thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Furthermore, EA significantly reduced the volume of carrageenan-induced paw oedema and the mass of the treated paws. Additionally, in dorsal root ganglion (DRG) neurons cultured from WT 129S1/SvIm mice, EA induced a dose-dependent cobalt uptake that was surprisingly preserved in cultured DRG neurons from 129S1/SvIm TRPC5 KO mice. Likewise, EA-induced anti-inflammatory and analgesic effects were preserved in the carrageenan model in animals lacking TRPC5 expression or in mice treated with TRPC4/5 antagonist ML204.This study demonstrates that while EA activates a sub-population of DRG neurons, it induces a novel TRPC4/5-independent analgesic and anti-inflammatory effect in vivo. Future studies are needed to elucidate the molecular and cellular mechanisms underlying EA's anti-inflammatory and analgesic effects.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Sesquiterpenos de Guaiano/farmacologia , Canais de Cátion TRPC/metabolismo , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Carragenina , Células Cultivadas , Cobalto/metabolismo , Modelos Animais de Doenças , Edema/patologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos Knockout , Dor/complicações , Dor/tratamento farmacológico , Dor/patologia , Fenótipo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Sesquiterpenos de Guaiano/uso terapêutico
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203952

RESUMO

Endocannabinoids play a role in adaptation to stress and regulate the release of glucocorticoids in stressed and unstressed conditions. We recently found that basal corticosterone pulsatility may significantly impact the vulnerability for developing post-traumatic-stress-disorder (PTSD), suggesting that the endocannabinoid system may contribute to its development. To examine this, we exposed rats to predator scent stress (PSS). Behavioral reactions were recorded seven days post-PSS. Cerebrospinal fluid (CSF) was collected from anesthetized rats shortly after PSS exposure to determine the levels of 2-arachidonoyl glycerol (2-AG) and anandamide (AEA). To correlate between endocannabinoids and corticosterone levels, rats were placed in metabolic cages for urine collection. To assess the levels of endocannabinoids in specific brain regions, rats' brains were harvested one day after behavioral analysis for staining and fluorescence quantification. Moreover, 2-AG was elevated in the CSF of PTSD-phenotype rats as compared with other groups and was inversely correlated with corticosterone urinary secretion. Eight days post-PSS exposure, hippocampal and hypothalamic 2-AG levels and hippocampal AEA levels were significantly more reduced in the PTSD-phenotype group compared to other groups. We posit that maladaptation to stress, which is propagated by an abnormal activation of endocannabinoids, mediates the subsequent stress-induced behavioral disruption, which, later, reduces neuronal the expression of endocannabinoids, contributing to PTSD symptomology.


Assuntos
Endocanabinoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/patologia , Transtornos de Estresse Pós-Traumáticos/patologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Animais , Comportamento Animal , Corticosterona/urina , Endocanabinoides/líquido cefalorraquidiano , Masculino , Fenótipo , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos/urina , Estresse Psicológico/urina
10.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205191

RESUMO

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.


Assuntos
Encéfalo/metabolismo , Corticosterona/sangue , Angústia Psicológica , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Arginina Vasopressina/sangue , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Humanos , Metilprednisolona/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Glucocorticoides/sangue , Receptores de Mineralocorticoides/sangue , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/patologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Proteínas de Ligação a Tacrolimo/sangue
11.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207178

RESUMO

Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats. These data revealed that VPA-exposed male, but not female, rats exhibit reduced social responding in the three-chamber and olfactory habituation/dishabituation (OHD) test during adolescence. In comparison, VPA-exposed female, but not male, adolescent rats exhibited anxiety-like behaviour in the elevated plus maze (EPM) and open field test (OFT). In VPA-exposed female rats, increasing 2-AG levels augmented anxiety-like behaviour in the EPM and OFT, while increasing AEA levels reduced stress coping behaviour in the swim stress test. These data highlight sexual dimorphic behaviours in the VPA model and indicate that enhancing endocannabinoid levels may exacerbate negative affective behaviour in VPA-exposed females. Thus, considerations should be paid to the possible sex-specific effects of cannabinoids for the treatment of symptoms associated with autism.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Endocanabinoides/farmacologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Ácido Valproico/efeitos adversos , Animais , Transtorno Autístico/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Angústia Psicológica , Ratos , Ratos Sprague-Dawley
12.
Nat Commun ; 12(1): 4156, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230461

RESUMO

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction.


Assuntos
Núcleo Central da Amígdala/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Animais , Comportamento Animal , Condicionamento Clássico/fisiologia , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209274

RESUMO

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.


Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão , Transtornos do Espectro Alcoólico Fetal , Deficiências da Aprendizagem , Estresse Oxidativo/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/prevenção & controle , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Deficiências da Aprendizagem/prevenção & controle , Ratos , Ratos Wistar
14.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209318

RESUMO

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Fear-related behavior displayed during acquisition, extinction, and recovery, was measured through quantification of immobility and alarm 22-kHz ultrasonic vocalizations (USV). Trait-like inter-individual differences in novelty-seeking, anxiety-related behavior, habituation learning, cognitive performance, and pain sensitivity were examined for their predictive value in forecasting fear extinction. Our results show that SERT deficiency strongly affected the emission of 22-kHz USV during differential fear conditioning. During acquisition, extinction, and recovery, SERT deficiency consistently led to a reduction in 22-kHz USV emission. While SERT deficiency did not affect immobility during acquisition, genotype differences started to emerge during extinction, and during recovery rats lacking SERT showed higher levels of immobility than wildtype littermate controls. Recovery was reflected in increased levels of immobility but not 22-kHz USV emission. Prominent sex differences were evident. Among several measures for trait-like inter-individual differences, anxiety-related behavior had the best predictive quality.


Assuntos
Comportamento Animal , Medo , Locos de Características Quantitativas , Proteínas de Ligação a RNA/genética , Animais , Ratos , Ratos Mutantes
15.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208184

RESUMO

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.


Assuntos
Cloridrato de Duloxetina/farmacologia , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Neuralgia/tratamento farmacológico , Oxaliplatina/toxicidade , Limiar da Dor/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Antibacterianos/farmacologia , Antineoplásicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Masculino , Camundongos , Microglia/fisiologia , Neuralgia/induzido quimicamente , Neuralgia/patologia
16.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299078

RESUMO

The oxytocin system plays a role in stress responses and behavior modulation. However, the effects of oxytocin signaling on stress adaptation remain unclear. Here, we demonstrated the roles of oxytocin signaling as a biomarker under stress conditions in the peripheral tissues (the gills) and central nervous system (the brain). All the environmental stressors downregulated the expression of oxytocin receptors in the gills, and the alteration of the expression of oxytocin receptors was also found in the brain after the acidic (AC) and high-ammonia (HA) treatments. The number of oxytocin neurons was increased after double-deionized (DI) treatment. By transgenic line, Tg(oxtl:EGFP), we also investigated the projections of oxytocin neurons and found oxytocin axon innervations in various nuclei that might regulate the anxiety levels and aggressiveness of adult zebrafish under different environmental stresses. The oxytocin system integrates physiological responses and behavioral outcomes to ensure environmental adaptation in adult zebrafish. Our study provides insight into oxytocin signaling as a stress indicator upon environmental stressors.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Neurônios/patologia , Ocitócicos/farmacologia , Ocitocina/farmacologia , Estresse Fisiológico , Animais , Animais Geneticamente Modificados , Encéfalo/efeitos dos fármacos , Meio Ambiente , Neurônios/efeitos dos fármacos , Peixe-Zebra
17.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299103

RESUMO

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Citalopram/farmacologia , Depressão/tratamento farmacológico , Proteína 2 de Ligação a Metil-CpG/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/complicações , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 3/genética , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ratos , Ratos Wistar
18.
Nutrients ; 13(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201092

RESUMO

The influence of dietary choline availability on cognition is currently being suggested by animal and human studies which have focused mainly on the early developmental stages. The aim of this review is to systematically search through the available rodent (rats and mice) research published during the last two decades that has assessed the effect of dietary choline interventions on cognition and related attentional and emotional processes for the entire life span. The review has been conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines covering peer-reviewed studies included in PubMed and Scopus databases. After excluding duplicates and applying the inclusion/exclusion criteria we have reviewed a total of 44 articles published in 25 journals with the contribution of 146 authors. The results are analyzed based on the timing and duration of the dietary intervention and the behavioral tests applied, amongst other variables. Overall, the available results provide compelling support for the relevance of dietary choline in cognition. The beneficial effects of choline supplementation is more evident in recognition rather than in spatial memory tasks when assessing nonpathological samples whilst these effects extend to other relational memory tasks in neuropathological models. However, the limited number of studies that have evaluated other cognitive functions suggest a wider range of potential effects. More research is needed to draw conclusions about the critical variables and the nature of the impact on specific cognitive processes. The results are discussed on the terms of the theoretical framework underlying the relationship between the brain systems and cognition.


Assuntos
Colina/farmacologia , Cognição/efeitos dos fármacos , Dieta/psicologia , Animais , Ansiedade/psicologia , Autoria , Comportamento Animal/efeitos dos fármacos , Colina/administração & dosagem , Emoções/efeitos dos fármacos , Publicações
19.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281274

RESUMO

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.


Assuntos
Ginsenosídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Antagonistas da Serotonina/farmacologia , Síndrome da Serotonina/prevenção & controle , Acetofenonas/farmacologia , Anfetaminas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzopiranos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/fisiopatologia
20.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281288

RESUMO

PURPOSE: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), causing a dysfunctional visual (retinoid) cycle. METHODS: The introduced mutation was confirmed by DNA and RNA sequencing. The expression of Lrat was determined on both the RNA and protein level in wildtype and knockout animals using RT-PCR and immunohistochemistry. The retinal structure and function, as well as the visual behavior of the Lrat-/- and control rats, were characterized using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) and vision-based behavioral assays. RESULTS: Wildtype animals had high Lrat mRNA expression in multiple tissues, including the eye and liver. In contrast, hardly any expression was detected in Lrat-/- animals. LRAT protein was abundantly present in wildtype animals and absent in Lrat-/- animals. Lrat-/- animals showed progressively reduced ERG potentials compared to wildtype controls from two weeks of age onwards. Vison-based behavioral assays confirmed reduced vision. Structural abnormalities, such as overall retinal thinning, were observed in Lrat-/- animals. The retinal thickness in knockout rats was decreased to roughly 80% by four months of age. No functional or structural differences were observed between wildtype and heterozygote animals. CONCLUSIONS: Our Lrat-/- rat is a new animal model for retinal dystrophy, especially for the LRAT-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies.


Assuntos
Aciltransferases/deficiência , Aciltransferases/genética , Retinite Pigmentosa/genética , Animais , Comportamento Animal , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Oftalmoscopia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Transgênicos , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/fisiopatologia , Deleção de Sequência , Tomografia de Coerência Óptica , Visão Ocular
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