The Nucleus Accumbens CRH-CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse / 神经科学通报·英文版

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.

O-GlcNAcylation in Ventral Tegmental Area Dopaminergic Neurons Regulates Motor Learning and the Response to Natural Reward / 神经科学通报·英文版

Protein O-GlcNAcylation is a post-translational modification that links environmental stimuli with changes in intracellular signal pathways, and its disturbance has been found in neurodegenerative diseases and metabolic disorders. However, its role in the mesolimbic dopamine (DA) system, especially in the ventral tegmental area (VTA), needs to be elucidated. Here, we found that injection of Thiamet G, an O-GlcNAcase (OGA) inhibitor, in the VTA and nucleus accumbens (NAc) of mice, facilitated neuronal O-GlcNAcylation and decreased the operant response to sucrose as well as the latency to fall in rotarod test. Mice with DAergic neuron-specific knockout of O-GlcNAc transferase (OGT) displayed severe metabolic abnormalities and died within 4-8 weeks after birth. Furthermore, mice specifically overexpressing OGT in DAergic neurons in the VTA had learning defects in the operant response to sucrose, and impaired motor learning in the rotarod test. Instead, overexpression of OGT in GABAergic neurons in the VTA had no effect on these behaviors. These results suggest that protein O-GlcNAcylation of DAergic neurons in the VTA plays an important role in regulating the response to natural reward and motor learning in mice.

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice / 神经科学通报·英文版

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N

Comparative proteomic analysis of the nucleus accumbens during extinction and reinstatement of morphine dependence / Análisis proteómico comparativo del núcleo accumbens durante laextinción y recaída de la dependencia a la morfina

BACKGROUND: The aim of this study was to detect differentially expressed proteins in the nucleus accumbens between the states of extinction and reinstatement of morphine addiction. Numerous studies on the neurobiological mechanisms concerning drug craving and relapse have been reported to date, but data on their relationship with the underlying key molecular mechanisms involved remain limited. METHODS: In this study, 40 male SpragueDawley rats were equally randomized into a saline group and a morphine group. Both groups received drug selfadministration training, after which extinction models were established naturally. The groups were further divided into two subgroups for extinction and reinstatement tests. Cerebral nucleus accumbens masses were measured for total protein extraction. Twodimensional electrophoresis was performed to determine differential protein spots. These differential proteins were then enzymolysed and identified using mass spectrography. RESULTS: The proteins were classified as fatty acidbinding protein, serine/threonine protein phosphatase 2A catalytic subunit beta isoform, serine/threonine protein phosphatase 2A catalytic subunit alpha isoform, serine/threonine protein phosphatase 2A regulatory subunit B² subunit gamma or heat shock protein 90 cochaperone CDC37. CONCLUSION: Significant changes in five proteins were detected between extinction and reinstatement. These proteins are correlated with phosphorylation and the tricarboxylic acid cycle.

ANTECEDENTES: El objetivo de este estudio fue detectar las proteínas diferencialmente expresadas en el núcleo accumbens entre los estados de extinción y recaída de la adicción a la morfina. Hasta la fecha se han reportado numerosos estudios en relación con los mecanismos neurobiológicos del deseo incontenible y recaída en el consumo de drogas, pero los datos sobre su relación con los mecanismos moleculares fundamentales subyacentes implicados, siguen siendo limitados. MÉTODO: En este estudio, 40 ratas machos SpragueDawley fueron por igual asignadas de manera aleatoria a un grupo salino y un grupo de morfina. Ambos grupos recibieron entrenamiento de autoadministración de drogas, después de lo cual se establecieron modelos de extinción de manera natural. A su vez, los grupos fueron luego subdivididos en dos subgrupos para realizar pruebas de extinción y recaída. Se procedió a medir las masas cerebrales del núcleo accumbens para la extracción total de proteína. Se realizó una electroforesis bidimensional para determinar manchas proteicas diferenciales. Estas proteínas diferenciales fueron entonces sometidas a enzimólisis e identificadas mediante espectrografía de masa. RESULTADOS: Las proteínas fueron clasificadas como proteína de unión a ácidos grasos, isoforma beta de la subunidad catalítica serinatreonina proteína fosfatasa 2A, isoforma alfa de la subunidad catalítica serinatreonina proteína fosfatasa 2A, subunidad gamma subunidad B" de la serinatreonina proteína fosfatasa 2A, o la proteína CDC37 cochaperona 90 de choque térmico. CONCLUSIÓN: Se detectaron cambios significativos en cinco proteínas entre la extinción y la recaída. Estas proteínas están correlacionadas con la fosforilación y el ciclo del ácido tricarboxílico.

Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test

It has been demonstrated that exposure to a variety of stressful experiences enhances fearful reactions when behavior is tested in current animal models of anxiety. Until now, no study has examined the neurochemical changes during the test and retest sessions of rats submitted to the elevated plus maze (EPM). The present study uses a new approach (HPLC) by looking at the changes in dopamine and serotonin levels in the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens in animals upon single or double exposure to the EPM (one-trial tolerance). The study involved two experiments: i) saline or midazolam (0.5 mg/kg) before the first trial, and ii) saline or midazolam before the second trial. For the biochemical analysis a control group injected with saline and not tested in the EPM was included. Stressful stimuli in the EPM were able to elicit one-trial tolerance to midazolam on re-exposure (61.01 percent). Significant decreases in serotonin contents occurred in the prefrontal cortex (38.74 percent), amygdala (78.96 percent), dorsal hippocampus (70.33 percent), and nucleus accumbens (73.58 percent) of the animals tested in the EPM (P < 0.05 in all cases in relation to controls not exposed to the EPM). A significant decrease in dopamine content was also observed in the amygdala (54.74 percent, P < 0.05). These changes were maintained across trials. There was no change in the turnover rates of these monoamines. We suggest that exposure to the EPM causes reduced monoaminergic neurotransmission activity in limbic structures, which appears to underlie the "one-trial tolerance" phenomenon.

Thyrotropin releasing hormone injected into the nucleus accumbens septi selectively increases face grooming in rats

The effect of unilateral injection of peptides into the nucleus accumbens septi (NAS) on subcategories of grooming behavior was studied in male rats. The peptides used were: thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LHRH) and corticotropin releasing hormone (CRH). Male rats (Holtzman strain, 240-270 g body weight) injected with progressive doses of TRH (100, 200 and 400 ng) at 5-day intervals were compared with the control state (injection of artificial cerebrospinal fluid CSF). A selective increase in face grooming was observed with the 100 ng (49.78 + 6.11, N = 18) and 200 ng (50.29 + 7.72, N = 17) doses of TRH (P<0.05 vs CSF injection 26.94 + 3.64, N = 18). Face grooming increased further with the 400 ng dose (55.19 + 8.26, N = 16, P<0.01), but a dose-response curve could not be obtained at the dose range used. Flank scratching, head, body and genital grooming were not altered by the TRH injection, but the rearing behavior was inhibited (10.33 + 1.56; N = 18; 10.76 + 1.77, N = 17; 12 + 2.06, N = 16) (P<0.05 for all doses vs controls, 20.61 + 2.81, N = 18). The rats that received LHRH (75 ng, N = 16) and CRH (100 ng, N = 14) did not show behavioral changes when compared with their control states. The results show that injection on TRH into the NAS, but not the injection of LHRH or CRH, selectively increases face grooming without affecting other subcategories of grooming at the doses used, and appears to link this peptide with the neural substrate of stereotyped behavior.