Corrigendum: Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.

[This corrects the article DOI: 10.3389/fnmol.2023.1107355.].

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.

Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice.

Mild behavioral impairment (MBI), which can include compulsive behavior, is an early sign of Alzheimer's disease (AD), but its underlying neural mechanisms remain unclear. Here, we show that 3-5-month-old APP/PS1 mice display obsessive-compulsive disorder (OCD)-like behavior. The number of parvalbumin-positive (PV) interneurons and level of high gamma (γhigh) oscillation are significantly decreased in the striatum of AD mice. This is accompanied by enhanced ß-γhigh coupling and firing rates of putative striatal projection neurons (SPNs), indicating decorrelation between PV interneurons and SPNs. Local field potentials (LFPs) simultaneously recorded in prefrontal cortex (PFC) and striatum (Str) demonstrate a decrease in γhigh-band coherent activity and spike-field coherence in corticostriatal circuits of APP/PS1 mice. Furthermore, levels of GABAB receptor (GABABR), but not GABAA receptor (GABAAR), and glutamatergic receptors, were markedly reduced, in line with presymptomatic AD-related behavioral changes. These findings suggest that MBI occurs as early as 3-5 months in APP/PS1 mice and that altered corticostriatal synchronization may play a role in mediating the behavioral phenotypes observed.

Optimized Golgi-Cox Staining Validated in the Hippocampus of Spared Nerve Injury Mouse Model.

Golgi-Cox staining has been used extensively in neuroscience. Despite its unique ability to identify neuronal interconnections and neural processes, its lack of consistency and time-consuming nature reduces its appeal to researchers. Here, using a spared nerve injury (SNI) mouse model and control mice, we present a modified Golgi-Cox staining protocol that can stain mouse hippocampal neurons within 8 days. In this improved procedure, the mouse brain was fixed with 4% paraformaldehyde and then stored in a modified Golgi-Cox solution at 37 ± 2°C. The impregnation period was reduced from 5-14 days to 36-48 h. Brain slices prepared in this way could be preserved long-term at -80°C for up to 8 weeks. In addition to minimizing frequently encountered problems and reducing the time required to conduct the method, our modified protocol maintained, and even improved, the quality of traditional Golgi-Cox staining as applied to hippocampal neuronal morphology in SNI mice.

The role of CA3-LS-VTA loop in the formation of conditioned place preference induced by context-associated reward memory for morphine.

Addiction-related behaviors, such as conditioned place preference (CPP), require animals to remember an association between environmental cue and drug treatment, and exposure to environmental cue is one of the key contributing factors to relapse. However, how central neural circuit participates in the formation of CPP induced by stimulus of morphine-paired environment remains unknown. In the present study, we found that reexposure to morphine-paired environment significantly increased the activity of hippocampal CA3 neurons, increased the excitability of GABAergic neurons and expression of glutamic acid decarboxylase 65/67 in the caudal lateral septum (LSc) and decreased the activity of GABAergic neurons and GAD65/67 expression in ventral tegmental area (VTA), leading to activation (disinhibition) of dopaminergic neurons. Inactivation of CA3 neurons attenuated GABAergic neurons activity and decreased the upregulation of GAD65/67 in LSc, prevented the dopaminergic neurons activation,and GAD65/67 downregulation in VTA and ameliorated the CPP behavior following exposure to morphine-paired context. Blockade of NMDA receptor in LSc also prevented the upregulation of GAD65/67 in LSc and formation of CPP induced by stimulus of morphine-paired environment. Suppression of GAD activity in LSc also remarkably attenuated the dopaminergic neurons activation and the GAD65/67 downregulation in VTA and prevented the formation of CPP induced by reexposure to morphine-associated context. Collectively, these results, for the first time, illustrated the involvement of neural circuitry of CA3-LSc-VTA, through integration of the contexts and reward information, participated in the reinstatement of CPP induced by exposure to morphine-associated context, which advanced our understanding on neurobiological basis for the context-associated memory and rewarding behavior.

[A sketch of the overlap in the neural circuitry underlying psychological- and physical-pain].

From the phenomenological point of view, pain can be classified into psychological-pain and physical-pain. Emerging evidence has shown that the psychological- and physical-pain recruit overlapping neural activity in regions associated with the affective component of pain, and share some common pain circuits, e.g., the dorsal anterior cingulate cortex (dACC) and the anterior insula (AI) play important roles in both psychological- and physical-pain. Therefore, understanding the way in which psychological- and physical-pain demonstrate either similarity or discrepancy may provide new insights into the relationship between the two types of experiences and potential targets for treating psychological suffering. This review summarizes research progress that has been obtained through experiments conducted in human and nonhuman animals to discuss the similarity, discrepancy and interaction between psychological- and physical-pain. The important next steps, e.g., uncovering the mechanisms underlying the overlap of psychological- and physical-pain; and whether chronic psychological-pain shapes brain plasticity as physical-pain does, are also discussed.

Activation of TLR4/STAT3 signaling in VTA contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3flox/flox mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction.

Orexin A-mediated AKT signaling in the dentate gyrus contributes to the acquisition, expression and reinstatement of morphine-induced conditioned place preference.

Accumulating evidence indicates that the hippocampal dentate gyrus (DG), a critical brain region contributing to learning and memory, is involved in the addiction and relapse to abused drugs. Emerging studies also suggest the role of orexin signaling in the rewarding behavior induced by repeated exposure to opiates. In the present study, we investigated the dynamic adaptation of orexin signaling in the DG and its functional significance in the acquisition, expression, maintenance of and relapse to rewarding behavior induced by morphine. Repeated place conditioning with morphine significantly increased the orexin A content released from the lateral hypothalamic area projecting neurons into the DG. Local infusions of orexin A into the DG sensitized the acquisition of and relapse to the conditioned place preference induced by morphine. The application of the orexin receptor type 1 (OXR1) antagonist SB334867 significantly abolished the acquisition, expression and maintenance of the conditioned place preference induced by repeated exposure to morphine. Furthermore, the significant increase of the phosphorylation of AKT in the DG was associated with preference for the morphine-paired chamber in rats, which was reversed by the local administration of an OXR1 antagonist. Thus, these findings suggested that the dynamic upregulation of orexin A signaling, via the AKT pathway in the DG, may promote the acquisition and maintenance of opioid-induced craving behaviors and may increase sensitivity to the rewarding effect of subsequent opioids.