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Social eavesdropping is a low-cost learning mechanism by which individuals extract relevant social information from social interactions between conspecifics, thereby gaining subsequent advantages in information gathering and usage. The aim of this study was to take advantage of a new hamster model of social eavesdropping to investigate behavioral consequences and neural activity in male hamsters during social eavesdropping. Bystander hamsters with a defeat experience were exposed to either a fighting interaction, a neutral encounter, or control conditions for 3 days of social eavesdropping. In Experiment 1, bystanders in the fight and neutral groups displayed more information gathering behaviors and less nonsocial behavior than control hamsters. The fight group displayed significant increases in c-Fos-positive neurons in the anterior mid-cingulate cortex (aMCC) and the piriform cortex. A slight but not significant group difference was found in their serum cortisol levels. In vivo local field potential oscillation recordings in Experiment 2 revealed that bystanders in the fight group had more delta oscillations in the aMCC during information gathering across 3-day social eavesdropping than those in the other 2 groups. Experiment 3 confirmed that 20 min of social eavesdropping on Day 1 was sufficient to evoke differential behavioral outcomes, and the behavioral responses became more prominent after 3 days of social eavesdropping. Collectively, our study confirmed that male golden hamsters are capable of social eavesdropping and indicated the involvement of aMCC delta oscillations in social eavesdropping.
Assuntos
Mesocricetus/fisiologia , Sistema Nervoso/anatomia & histologia , Comportamento Social , Estimulação Acústica/psicologia , Animais , Comportamento Animal/fisiologia , Cricetinae , Hidrocortisona/metabolismo , Masculino , Motivação/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Aprendizado Social/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.
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Astrócitos/fisiologia , Disfunção Cognitiva/fisiopatologia , Esquizofrenia/fisiopatologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismoRESUMO
BACKGROUND: A newly defined Cordyceps species, Ophiocordyceps formosana (O. formosana) has been implicated in multitudinous bioactivities, including lowering glucose and cholesterol levels and modulating the immune system. However, few literatures demonstrate sufficient evidence to support these proposed functions. Although the use of Cordyceps spp. has been previously addressed to improve insulin insensitivity and improve the detrimental symptoms of depression; its mechanistic nature remains unsettled. Herein, we reveal the effects of O. formosana in ameliorating hyperglycemia accompanied with depression. METHODS: Diabetes was induced in mice by employing streptozotocin(STZ), a chemical that is toxic to insulin-producing ß cells of the pancreas. These streptozotocin (STZ)-induced diabetic mice showed combined symptoms of hyperglycemia and depressive behaviors. Twenty-four STZ-induced mice were randomly divided into 3 groups subjected to oral gavage with 100 µL solution of either PBS or 25 mg/mL Ophiocordyceps formosana extract (OFE) or 2 mg/mL rosiglitazone (Rosi, positive control group). Treatments were administered once per day for 28 days. An additional 6 mice without STZ induction were treated with PBS to serve as the control group. Insulin sensitivity was measured by a glucose tolerance test and levels of adiponectin in plasma and adipose tissue were also quantified. Behavioral tests were conducted and levels of monoamines in various brain regions relating to depression were evaluated. RESULTS: HPLC analysis uncovered three major constituents, adenosine, D-mannitol and cordycepin, within O. formosana similar to other prestigious medicinal Cordyceps spp.. STZ-induced diabetic mice demonstrated decreased body weight and subcutaneous adipose tissue, while these symptoms were recovered in mice receiving OFE treatment. Moreover, the OFE group displayed improved insulin sensitivity and elevated adiponectin within the plasma and adipose tissue. The anti-depressive effect of OFE was observed in various depression-related behavior tests. Concurrently, neurotransmitters, like 5-HT and dopamine in the frontal cortex, striatum and hippocampus were found to be up-regulated in OFE-treated mice. CONCLUSIONS: Our findings illustrated, for the first time, the medicinal merits of O. formosana on Type I diabetes and hyperglycemia-induced depression. OFE were found to promote the expression of adiponectin, which is an adipokine involved in insulin sensitivity and hold anti-depressive effects. In addition, OFE administration also displayed altered levels of neurotransmitters in certain brain regions that may have contributed to its anti-depressive effect. Collectively, this current study provided insights to the potential therapeutic effects of O. formosana extracts in regards to hyperglycemia and its depressive complications.
Assuntos
Comportamento Animal/efeitos dos fármacos , Produtos Biológicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental , Hiperglicemia/sangue , Hypocreales/química , Adiponectina , Animais , Peso Corporal/efeitos dos fármacos , Depressão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , EstreptozocinaRESUMO
BACKGROUND AND OBJECTIVE: Current methods for imaging reconstruction from high-ratio expansion microscopy (ExM) data are limited by anisotropic optical resolution and the requirement for extensive manual annotation, creating a significant bottleneck in the analysis of complex neuronal structures. METHODS: We devised an innovative approach called the IsoGAN model, which utilizes a contrastive unsupervised generative adversarial network to sidestep these constraints. This model leverages multi-scale and isotropic neuron/protein/blood vessel morphology data to generate high-fidelity 3D representations of these structures, eliminating the need for rigorous manual annotation and supervision. The IsoGAN model introduces simplified structures with idealized morphologies as shape priors to ensure high consistency in the generated neuronal profiles across all points in space and scalability for arbitrarily large volumes. RESULTS: The efficacy of the IsoGAN model in accurately reconstructing complex neuronal structures was quantitatively assessed by examining the consistency between the axial and lateral views and identifying a reduction in erroneous imaging artifacts. The IsoGAN model accurately reconstructed complex neuronal structures, as evidenced by the consistency between the axial and lateral views and a reduction in erroneous imaging artifacts, and can be further applied to various biological samples. CONCLUSION: With its ability to generate detailed 3D neurons/proteins/blood vessel structures using significantly fewer axial view images, IsoGAN can streamline the process of imaging reconstruction while maintaining the necessary detail, offering a transformative solution to the existing limitations in high-throughput morphology analysis across different structures.
Assuntos
Microscopia , Neurônios , Anisotropia , Processamento de Imagem Assistida por ComputadorRESUMO
Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with susceptibilit to schizophrenia, we previously identified two subregions that were consistently associated with the disease. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.
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Aciltransferases/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Esquizofrenia/genética , Aciltransferases/química , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA , Maleato de Dizocilpina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Éxons , Proteínas de Membrana/química , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
We used 18F-fluorodeoxyglucose small-animal positron-emission tomography to determine whether different styles of coping with stress are associated with different patterns of neuronal activity in the hypothalamus. Adult rats were subjected to immobilization (IMO)-stress or to a non-immobilized condition for 30 min, in random order on separate days, each of which was followed by brain-scanning. Some rats in the immobilized condition were allowed to actively cope with the stress by chewing a wooden stick during IMO, while the other immobilized rats were given nothing to chew on. Voxel-based statistical analysis of the brain imaging data shows that chewing counteracted the stress-induced increased glucose uptake in the hypothalamus to the level of the non-immobilized condition. Region-of-interest analysis of the glucose uptake values further showed that chewing significantly suppressed stress-induced increased glucose uptake in the paraventricular hypothalamic nucleus and the anterior hypothalamic area but not in the lateral hypothalamus. Together with the finding that the mean plasma corticosterone concentration at the termination of the IMO was also significantly suppressed when rats had an opportunity to chew a wooden stick, our results showed that active coping by chewing inhibited the activation of the hypothalamic-pituitary-adrenal axis to reduce the endocrine stress response.
Assuntos
Adaptação Psicológica , Glucose/metabolismo , Hipotálamo/metabolismo , Estresse Fisiológico/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Animais , Corticosterona/sangue , Corticosterona/metabolismo , Regulação para Baixo/fisiologia , Fluordesoxiglucose F18/metabolismo , Imobilização , Masculino , Neuroimagem , Núcleo Hipotalâmico Paraventricular/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-DawleyRESUMO
Schizophrenia is a chronic and severe mental disorder. Dysregulated decision-making and affective processing have been implicated in patients with schizophrenia (SZ) and have significant impacts on their cognitive and social functions. However, little is known about how affective arousal influences reward-based decision-making in SZ. Taking advantage of a two-choice probabilistic gambling task and utilizing three facial expressions as affective primes (i.e., neutral, angry, and happy conditions) in each trial, we investigated how affective arousal influences reward-related choice based on behavioral, model fitting, and feedback-related negativity (FRN) data in 38 SZ and 26 healthy controls (CTRL). We also correlated our measurements with patients' symptom severity. Compared with the CTRL group, SZ expressed blunted responses to angry facial primes. They had lower total game scores and displayed more maladaptive choice strategies (i.e., less win-stay and more lose-shift) and errors in monitoring rewards. Model fitting results revealed that the SZ group had a higher learning rate and lower choice consistency, especially in the happy condition. Brain activity data further indicated that SZ had smaller amplitudes of FRN than their controls in the angry and happy conditions. Importantly, the SZ group exhibited attenuated affective influence on decision-making, and their impairments in decision-making were only correlated with their clinical symptoms in the angry condition. Our findings imply the affective processing is dysregulated in SZ and it is selectively involved in the regulation of choice strategies, choice behaviors, and FRN in SZ, which lead to impairments in reward-related decision-making, especially in the angry condition.
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Monitoring fecal outputs and fecal cortisol metabolites (FCM), a noninvasive technique, has been used to investigate physiological responses to stress and relationships between hormones and behavior in an increasing number of species. The aim of this study was to investigate whether measurements of fecal outputs and FCM can be used as indexes to repeatedly and precisely monitor stress levels in male Syrian hamsters using a social defeat as a biological validation method. The feces voided by each animal were collected every 3 h for at least 1 day before and after experiencing a single fighting interaction, and the extracted FCM during the pre- and post-fight phases was quantified by enzyme immunoassays. During the pre-fight baseline phase, both the number of fecal pellets and the FCM levels fluctuated throughout the whole day. Although the number of fecal pellets did not differ between the dark and light cycles, the levels of FCM were significantly higher during the dark cycle than during the light cycle. During the post-fight phase, the experience of fighting did not result in a significant difference in the number of fecal pellets per hour between the winner and loser groups, but did considerably increase the total amount of fecal outputs in both groups. The level of FCM was significantly higher in the loser group than in the winner group during the 1st and 7th 3-h collection periods after the fight, which indicated that the experience of defect affected the behavioral and physiological responses of the losers. Our findings suggest that measurement of FCM is sensitive enough to distinguish the stress levels between winners and losers after experiencing a fight. The measurements of fecal outputs and FCM levels provide new opportunities to longitudinally and frequently monitor behavioral and hormonal responses to stress in hamsters and other small laboratory animals.
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Fezes/química , Hidrocortisona/metabolismo , Animais , Cricetinae , Masculino , MesocricetusRESUMO
Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.
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A reconfigurable differential-to-single-ended autonomous current adaptation buffer amplifier (ACABA) is proposed. The ACABA, based on floating-gate technologies, is a capacitive circuit, of which output DC level and bandwidth can be adjusted by programming charges on floating nodes. The gain is variable by switching different amounts of capacitors without altering the output DC level. Without extra sensing and control circuitries, the current consumption of the proposed ACABA increases spontaneously when the input signal is fast or large, achieving a high slew rate. The supply current dwindles back to the low quiescent level autonomously when the output voltage reaches equilibrium. Therefore, the proposed ACABA is power-efficient and suitable for processing physiological signals. A prototype ACABA has been designed and fabricated in a [Formula: see text] CMOS process occupying an area of [Formula: see text]. When loaded by a [Formula: see text] capacitor, it consumes [Formula: see text] to achieve a unity-gain bandwidth of [Formula: see text] with a measured IIP2 value of [Formula: see text] and a slew rate of [Formula: see text].
Assuntos
Amplificadores Eletrônicos , EletrodosRESUMO
BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. METHODS: Heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/-p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. RESULTS: On slice electrophysiology, LC-NE neurons of Ndntm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndntm1ky mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. CONCLUSIONS: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.
Assuntos
Neurônios Adrenérgicos/metabolismo , Locus Cerúleo/metabolismo , Proteínas do Tecido Nervoso , Proteínas Nucleares , Síndrome de Prader-Willi/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , CamundongosRESUMO
BACKGROUND: Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli during information processing, and sensory gating deficits may contribute to the symptoms of schizophrenia. Among the three components of auditory event-related potentials reflecting sensory gating, P50 implies pre-attentional filtering of sensory information and N100/P200 reflects attention triggering and allocation processes. Although diminished P50 gating has been extensively documented in patients with schizophrenia, previous studies on N100 were inconclusive, and P200 has been rarely examined. This study aimed to investigate whether patients with schizophrenia have P50, N100, and P200 gating deficits compared with control subjects. METHODS: Control subjects and clinically stable schizophrenia patients were recruited. The mid-latency auditory evoked responses, comprising P50, N100, and P200, were measured using the auditory-paired click paradigm without manipulation of attention. Sensory gating parameters included S1 amplitude, S2 amplitude, amplitude difference (S1-S2), and gating ratio (S2/S1). We also evaluated schizophrenia patients with PANSS to be correlated with sensory gating indices. RESULTS: One hundred four patients and 102 control subjects were examined. Compared to the control group, schizophrenia patients had significant sensory gating deficits in P50, N100, and P200, reflected by larger gating ratios and smaller amplitude differences. Further analysis revealed that the S2 amplitude of P50 was larger, while the S1 amplitude of N100/P200 was smaller, in schizophrenia patients than in the controls. We found no correlations between sensory gating indices and schizophrenia positive or negative symptom clusters. However, we found a negative correlation between the P200 S2 amplitude and Bell's emotional discomfort factor/Wallwork's depressed factor. CONCLUSION: Till date, this study has the largest sample size to analyze P50, N100, and P200 collectively by adopting the passive auditory paired-click paradigm without distractors. With covariates controlled for possible confounds, such as age, education, smoking amount and retained pairs, we found that schizophrenia patients had significant sensory gating deficits in P50-N100-P200. The schizophrenia patients had demonstrated a unique pattern of sensory gating deficits, including repetition suppression deficits in P50 and stimulus registration deficits in N100/200. These results suggest that sensory gating is a pervasive cognitive abnormality in schizophrenia patients that is not limited to the pre-attentive phase of information processing. Since P200 exhibited a large effect size and did not require additional time during recruitment, future studies of P50-N100-P200 collectively are highly recommended.
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Accumulating evidence suggests AKT1 and DRD2-AKT-GSK3 signaling involvement in schizophrenia. AKT1 activity is also required for lithium, a GSK3 inhibitor, to modulate mood-related behaviors. Notably, GSK3 inhibitor significantly alleviates behavioral deficits in Akt1-/- female mice, whereas typical/atypical antipsychotics have no effect. In agreement with adjunctive therapy with lithium in treating schizophrenia, our data mining indicated that the average utilization rates of lithium in the Taiwan National Health Insurance Research Database from 2002 to 2013 are 10.9% and 6.63% in inpatients and outpatients with schizophrenia, respectively. Given that lithium is commonly used in clinical practice, it is of great interest to evaluate the effect of lithium on alleviating Akt1-related deficits. Taking advantage of Akt1+/- mice to mimic genetic deficiency in patients, behavioral impairments were replicated in female Akt1+/- mice but were alleviated by subchronic lithium treatment for 13 days. Lithium also effectively alleviated the observed reduction in phosphorylated GSK3α/ß expression in the brains of Akt1+/- mice. Furthermore, inhibition of Akt expression using an Akt1/2 inhibitor significantly reduced neurite length in P19 cells and primary hippocampal cell cultures, which was also ameliorated by lithium. Collectively, our findings implied the therapeutic potential of lithium and the importance of the AKT1-GSK3 signaling pathway.
Assuntos
Bases de Dados Factuais , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Seguro Saúde , Compostos de Lítio/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Transdução de Sinais , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Compostos de Lítio/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Taiwan , Adulto JovemRESUMO
Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.
Assuntos
Cromossomos de Mamíferos/fisiologia , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Ativação Transcricional , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cromossomos Humanos Par 22 , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Humanos , Aprendizagem em Labirinto/fisiologia , Camundongos , Fenótipo , Prolina Oxidase/genética , Esquizofrenia/metabolismoRESUMO
BACKGROUND: Compelling animal and clinical studies support the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia and suggest promising pharmacological agents to ameliorate negative and cognitive symptoms of schizophrenia, including sarcosine, a glycine transporter-1 inhibitor. AIMS AND METHODS: It is imperative to evaluate the therapeutic potential of sarcosine in animal models, which provide indispensable tools for testing drug effects in detail and elucidating the underlying mechanisms. In this study, a series of seven experiments was conducted to investigate the effect of sarcosine in ameliorating behavioral deficits and the underlying mechanism in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase-null mutant (SR-/-) mice) NMDAR hypofunction models. RESULTS: In Experiment 1, the acute administration of 500/1000 mg/kg sarcosine (i.p.) had no adverse effects on motor function and serum biochemical responses. In Experiments 2-4, sarcosine significantly alleviated MK-801-induced (0.2 mg/kg) brain abnormalities and behavioral deficits in MK-801-induced and SR-/- mouse models. In Experiment 5, the injection of sarcosine enhanced CSF levels of glycine and serine in rat brain. In Experiments 6-7, we show for the first time that sarcosine facilitated NMDAR-mediated hippocampal field excitatory postsynaptic potentials and influenced the movement of surface NMDARs at extrasynaptic sites. CONCLUSIONS: Sarcosine effectively regulated the surface trafficking of NMDARs, NMDAR-evoked electrophysiological activity, brain glycine levels and MK-801-induced abnormalities in the brain, which contributed to the amelioration of behavioral deficits in mouse models of NMDAR hypofunction.
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Sintomas Comportamentais/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina/agonistas , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Sarcosina/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Sintomas Comportamentais/induzido quimicamente , Encefalopatias/induzido quimicamente , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Racemases e Epimerases/genética , Sarcosina/administração & dosagem , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Esquizofrenia/fisiopatologiaRESUMO
Fairness perception and equality during social interactions frequently elicit affective arousal and affect decision making. By integrating the dictator game and a probabilistic gambling task, this study aimed to investigate the effects of a negative experience induced by perceived unfairness on decision making using behavioral, model fitting, and electrophysiological approaches. Participants were randomly assigned to the neutral, harsh, or kind groups, which consisted of various asset allocation scenarios to induce different levels of perceived unfairness. The monetary gain was subsequently considered the initial asset in a negatively rewarded, probabilistic gambling task in which the participants were instructed to maintain as much asset as possible. Our behavioral results indicated that the participants in the harsh group exhibited increased levels of negative emotions but retained greater total game scores than the participants in the other two groups. Parameter estimation of a reinforcement learning model using a Bayesian approach indicated that these participants were more loss aversive and consistent in decision making. Data from simultaneous ERP recordings further demonstrated that these participants exhibited larger feedback-related negativity to unexpected outcomes in the gambling task, which suggests enhanced reward sensitivity and signaling of reward prediction error. Collectively, our study suggests that a negative experience may be an advantage in the modulation of reward-based decision making.
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Córtex Cerebral/fisiologia , Tomada de Decisões/fisiologia , Emoções/fisiologia , Potenciais Evocados/fisiologia , Percepção , Reforço Psicológico , Eletroencefalografia , Feminino , Jogos Experimentais , Humanos , Masculino , Adulto JovemRESUMO
The ability to recognize individuals is essential for many aspects of social interaction and social organization, yet we know relatively little about the neural mechanisms underlying this ability. Most laboratory studies of individual recognition in rodents have studied differential responses to familiar versus unfamiliar individuals rather than differential responses to equally well known individuals having different significance for the subject. In experiment 1, we use a new method for studying true individual recognition in which male hamsters first had different experiences with two stimulus males (exposures to one male across a wire-mesh barrier and fights with another male). One day later, losers of fights were tested in a Y-maze for reactions to one of the two familiar males. Subjects tested with the familiar winner avoided this stimulus male, but subjects tested with the familiar, neutral male were attracted to him. Immunohistochemistry for c-Fos and Egr-1 implicate several areas of the brain in individual recognition, particularly the anterior piriform cortex, the CA1 and CA3 regions of anterior dorsal hippocampus, anterior and posterior dentate gyrus, and perirhinal cortex. In experiment 2, temporary inactivation of the CA1 region of anterior dorsal hippocampus by microinfusion of lidocaine eliminated the avoidance of the familiar winner, but a saline control injection had no effect. These results are the first to use a rodent model to characterize neural circuits involved in the recognition of equally well known individuals and the corresponding emotional responses to them.
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Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Rede Nervosa/anatomia & histologia , Rede Nervosa/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Cricetinae , Discriminação Psicológica/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Mesocricetus , OdorantesRESUMO
The developing brain is vulnerable to social defeat during the juvenile period. As complements of human studies, animal models of social defeat provide a straightforward approach to investigating the functional and neurobiological consequences of social defeats. Taking advantage of agonist behavior and social defeat in male golden hamster, a set of 6 experiments was conducted to investigate the consequences at multiple levels in young adulthood resulting from repeated, intermittent social defeats or "social threats" across the entire juvenile period. Male hamsters at postnatal day 28 (P28) were randomly assigned to either the social defeat, "social threat", or arena control group, and they correspondingly received a series of nine social interaction trials (i.e., either social defeat, "social threat", or arena control conditions) from P33 to P66. At the behavioral level (Experiment 1), we found that repeated social defeats (but not "social threats") significantly impacted locomotor activity in the familiar context and social interaction in the familiar/unfamiliar social contexts. At the physiological and hormonal levels (Experiments 2 and 3), repeated social defeat significantly enhanced the cortisol and norepinephrine concentrations in blood. Enlargement of the spleen was also found in the social defeat and "social threat" groups. At the immunological level (Experiment 4), the social defeat group showed lower levels of pro-inflammatory cytokines in the hypothalamus and hippocampus but higher concentration of IL-6 in the striatum compared to the other two groups. At the neurochemical level (Experiment 5), the socially defeated hamsters mainly displayed reductions of dopamine, dopamine metabolites, and 5-HT levels in the striatum and decreased level of 5-HT in the hippocampus. In Experiment 6, an increase in the spine density of hippocampal CA1 pyramidal neurons was specifically observed in the "social threat" group. Collectively, our findings indicate that repeated, intermittent social defeats throughout entire adolescence in hamsters impact their adult responses at multiple levels. Our results also suggest that the "social threat" group may serve as an appropriate control. This study further suggest that the alterations of behavioral responses and neurobiological functions in the body and brain might provide potential markers to measure the negative consequences of chronic social defeats.
RESUMO
Accumulating evidence implies that both AKT1 and GABAA receptor (GABAAR) subunit genes are involved in schizophrenia pathogenesis. Activated Akt promotes GABAergic neuron differentiation and increases GABAAR expression on the plasma membrane. To elucidate the role of Akt1 in modulating GABAergic functions and schizophrenia-related cognitive deficits, a set of 6 in vitro and in vivo experiments was conducted. First, an Akt1/2 inhibitor was applied to evaluate its effect on GABAergic neuron-like cell formation from P19 cells. Inhibiting Akt resulted in a reduction in parvalbumin-positive neuron-like cells. In Akt1(-/-) and wild-type mice, seizures induced using pentylenetetrazol (a GABAAR antagonist) were measured, and GABAAR expression and GABAergic interneuron abundance in the brain were examined. Female Akt1(-/-) mice, but not male Akt1(-/-) mice, exhibited less pentylenetetrazol-induced convulsive activity than their corresponding wild-type controls. Reduced parvalbumin-positive interneuron abundance and GABAAR subunit expression, especially in the hippocampus, were also observed in female Akt1(-/-) mice compared to female wild-type mice. Neuromorphometric analyses revealed significantly reduced neurite complexity in hippocampal pyramidal neurons. Additionally, female Akt1(-/-) mice displayed increased hippocampal oscillation power and impaired spatial memory compared to female wild-type mice. Our findings suggest that Akt1 deficiency modulates GABAergic interneurons and GABAAR expression, contributing to hippocampus-dependent cognitive functional impairment.
Assuntos
Neurônios GABAérgicos/fisiologia , Hipocampo/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores de GABA-A/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Animais , Ondas Encefálicas , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Convulsivantes/administração & dosagem , Feminino , Antagonistas GABAérgicos/administração & dosagem , Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Interneurônios/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos Knockout , Parvalbuminas/metabolismo , Pentilenotetrazol/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Piramidais/patologia , Receptores de GABA-A/metabolismo , Esquizofrenia/metabolismo , Convulsões/induzido quimicamenteRESUMO
Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.