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.
Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Nucleus Accumbens/metabolism* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Sleep ; Sleep Wake Disorders ; Stress, Psychological/complications*

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.
Animals ; Dopaminergic Neurons/physiology* ; GABAergic Neurons/physiology* ; Mice ; Nucleus Accumbens/metabolism* ; Reward ; Ventral Tegmental Area/metabolism*

As a kind of mental illness, depression produces great difficulties in clinical diagnosis and treatment, and has a high disability rate. It is urgent to clarify the mechanism of depression to find potential therapeutic targets and effective clinical treatment methods. As a deacetylase, silent mating type information regulator 2 homolog 1 (SIRT1) is involved in many biological processes such as cell aging, cancer, and cardiovascular disease. In recent years, more and more studies have found that SIRT1 gene plays an important role in the pathogenesis of depression, but the mechanism is still unclear. Therefore, this review mainly summarizes the relevant research progress on the role and mechanism of SIRT1 gene in the hippocampus, prefrontal cortex, amygdala, hypothalamic suprachiasmatic nucleus, and nucleus accumbens in depression, in order to provide new ideas for exploring the mechanism and prevention of depression.
Cellular Senescence ; Depression/genetics* ; Hippocampus/metabolism* ; Humans ; Nucleus Accumbens ; Sirtuin 1/metabolism*

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
Animals ; Interneurons/metabolism* ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/metabolism* ; Neurons/metabolism* ; Nucleus Accumbens/metabolism* ; Parvalbumins/metabolism*

Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABA receptor agonist, is the only specific GABA receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABA receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 μL/side or 0.12 nmol/0.2 μL/side), rather than vehicle or BLF (0.01 nmol/0.2 μL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABA receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.
Animals ; Baclofen ; administration & dosage ; Conditioning, Classical ; GABA-B Receptor Agonists ; administration & dosage ; Locomotion ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Morphine ; Nucleus Accumbens ; drug effects ; Opioid-Related Disorders ; Reward

OBJECTIVE: To investigate the potential neural pathway connecting the nucleus accumbens (NAc) and the rostral ventrolateral medulla (RVLM), and whether the pathway participates in the regulation of cardiovascular function in a model rat of anorexia nervosa (AN). METHODS: Rat models of AN were established by allowing voluntary activity in a running wheel with restricted feeding, with the rats having free access to normal chow without exercise as the control group. FluoroGold (FG) retrograde tracing method and multi-channel simultaneous recording technique were used to explore the possible pathway between the NAc and the RVLM. RESULTS: The rats in AN group exhibited significantly reduced systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) with significantly increased discharge frequency of RVLM neurons in comparison with the control rats. After the injection of FG into the RVLM, retrograde labeled neurons were observed in the NAc of the rats in both the normal control and AN groups. In both groups, SBP and HR were significantly decreased in response to 400 μA electrical stimulation of the NAc accompanied by an obvious increase in the discharge frequency of the RVLM neurons; the diastolic blood pressure (DBP) and MAP were significantly lower in AN model rats than in the normal rats in response to the stimulation. CONCLUSIONS We successfully established a rat model of AN via hyperactivity and restricted feeding and confirm the presence of a neural pathway connecting the NAc and the RVLM. This pathway might participate in the regulation of cardiovascular function in AN model rats.
Animals ; Anorexia Nervosa ; Blood Pressure ; Disease Models, Animal ; Medulla Oblongata ; Neural Pathways ; Nucleus Accumbens ; Rats ; Rats, Sprague-Dawley

The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins known to play roles in cell-shape determination as well as in signaling pathways. We have previously shown that amphetamine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important neuronal substrate mediating rewarding effects of drugs of abuse. In the present study, we further examined what molecular pathways may be involved in this process. By direct microinjection of LY294002, a PI3 kinase inhibitor, or of S9 peptide, a proposed GSK3β activator, into the NAcc core, we found that phosphorylation levels of ERM as well as of GSK3β in this site are simultaneously decreased. These results indicate that ERM proteins are under the regulation of Akt-GSK3β signaling pathway in the NAcc core. The present findings have a significant implication to a novel signal pathway possibly leading to structural plasticity in relation with drug addiction.
Amphetamine ; Animals ; Glycogen Synthase Kinases ; Humans ; Membrane Proteins ; Microinjections ; Negotiating ; Neurons ; Nucleus Accumbens ; Phosphorylation ; Phosphotransferases ; Plastics ; Proto-Oncogene Proteins c-akt ; Rats ; Reward ; Signal Transduction ; Street Drugs ; Substance-Related Disorders

µ-opioid receptor (MOR) is a class of opioid receptors with a high affinity for enkephalins and beta-endorphin. In hippocampus, activation of MOR is known to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons. In contrast, the potential role of MOR in hippocampal astrocytes, the most abundant cell type in the brain, has remained unexplored. Here, we determine the cellular and subcellular distribution of MOR in different cell types of the hippocampus by utilizing MOR-mCherry mice and two different antibodies against MOR. Consistent with previous findings, we demonstrate that MOR expression in the CA1 pyramidal layer is co-localized with axon terminals from GABAergic inhibitory neurons but not with soma of pyramidal neurons. More importantly, we demonstrate that MOR is highly expressed in CA1 hippocampal astrocytes. The ultrastructural analysis further demonstrates that the astrocytic MOR is localized in soma and processes, but not in microdomains near synapses. Lastly, we demonstrate that astrocytes in ventral tegmental area and nucleus accumbens also express MOR. Our results provide the unprecedented evidence for the presence of MOR in astrocytes, implicating potential roles of astrocytic MOR in addictive behaviors.
Animals ; Antibodies ; Astrocytes* ; Behavior, Addictive ; beta-Endorphin ; Brain ; Carisoprodol ; Enkephalins ; gamma-Aminobutyric Acid ; Hippocampus ; Interneurons ; Mice ; Microscopy, Electron ; Neurons ; Nucleus Accumbens ; Presynaptic Terminals ; Pyramidal Cells ; Receptors, Opioid ; Synapses ; Ventral Tegmental Area

BACKGROUND AND PURPOSE: Apathy is one of the most common neuropsychiatric symptoms in patients with Alzheimer's disease (AD). It may have adverse impacts on the progression of AD. However, its neurobiological underpinnings remain unclear. The objective of this study was to investigate differences in regional cerebral blood flow (rCBF) between AD patients with apathy and those without apathy. METHODS: Sixty-six apathetic AD patients and 66 AD patients without apathy completed Neuropsychiatric Inventory (NPI) and underwent technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT) scans. Voxel-wise differences in rCBF between the 2 groups were examined. Association between rCBF and levels of apathy in the apathetic group was also assessed. RESULTS: AD patients with apathy showed lower rCBF in the bilateral orbitofrontal cortex, left putamen, left nucleus accumbens, left thalamus, and bilateral insula than those without (all p < 0.005). Mean perfusion across all significant clusters showed a negative linear correlation with NPI apathy score in AD patients with apathy (β = −0.25; p = 0.04). CONCLUSIONS: Hypoperfusion in the prefrontal, striatal, and insular areas may be neural correlates of apathy in AD patients.
Alzheimer Disease* ; Apathy* ; Brain* ; Cerebrovascular Circulation ; Humans ; Nucleus Accumbens ; Perfusion* ; Prefrontal Cortex ; Putamen ; Regional Blood Flow ; Thalamus ; Tomography, Emission-Computed ; Tomography, Emission-Computed, Single-Photon

The nucleus accumbens (NAc) is the major component of the ventral striatum that regulates stress-induced depression. The NAc receives dopaminergic inputs from the ventral tegmental area (VTA), and the role of VTA-NAc neurons in stress response has been recently characterized. The NAc also receives glutamatergic inputs from various forebrain structures including the prelimbic cortex (PL), basolateral amygdala (BLA), and ventral hippocampus (vHIP), whereas the role of those glutamatergic afferents in stress response remains underscored. In the present study, we investigated the extent to which descending glutamatergic neurons activated by stress in the PL, BLA, and vHIP project to the NAc. To specifically label the input neurons into the NAc, fluorescent-tagged cholera toxin subunit B (CTB), which can be used as a retrograde neuronal tracer, was injected into the NAc. After two weeks, the mice were placed under restraint for 1 h. Subsequent histological analyses indicated that CTB-positive cells were detected in 170~680 cells/mm² in the PL, BLA, and vHIP, and those CTB-positive cells were mostly glutamatergic. In the PL, BLA, and vHIP regions analyzed, stress-induced c-Fos expression was found in 20~100 cells/mm². Among the CTB-positive cells, 2.6% in the PL, 4.2% in the BLA, and 1.1% in the vHIP were co-labeled by c-Fos, whereas among c-Fos-positive cells, 7.7% in the PL, 19.8% in the BLA, and 8.5% in the vHIP were co-labeled with CTB. These results suggest that the NAc receives a significant but differing proportion of glutamatergic inputs from the PL, BLA, and vHIP in stress response.
Animals ; Basolateral Nuclear Complex ; Cholera Toxin ; Depression ; Hippocampus ; Mice ; Neurons* ; Nucleus Accumbens* ; Prosencephalon ; Ventral Striatum ; Ventral Tegmental Area