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Incomplete recovery of the loss of mature OLs in CTX after CPZ withdrawal. (A) An image showing GST-pi positive cells in CTX of a mouse of the control (CNT) group. (B) An image from a mouse of the CPZ group in which only a few GST-pi positive cells left in CTX after CPZ treatment. (C) An image showing GST-pi positive cells in CTX of a mouse treated with VEH during the 3-week recovery period after CPZ withdrawal. (D) The quantitative data (mean ± SEM; n = 5/group). The dotted line indicates the value of the CNT group, which was significantly higher than all other groups. **p < 0.01, compared to the CPZ group. The scale bar in image (C) represents about 25 μm.
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Recent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine possible effects of antipsychotic drugs on the recovery pro...
Citations
... Redox imbalance causes myelination deficits in the PFC of a rat SZ model [202] as well as decreased structural integrity of the anterior commissure and fornix WM in mice [234], suggesting that oxidative stress has a direct effect on myelination and WM tracts. In line with this, NAC antioxidant treatment can ameliorate myelin abnormalities not only in a rat model of SZ associated with redox imbalance [202] but also in demyelination mouse models induced by cuprizone [235] that exhibit SZ-like features including reduced social interactions [236][237][238][239]. Interestingly, NAC also reversed social deficit in these demyelination models, further highlighting a possible contribution of oxidative stress-induced myelin defects to SZ social deficits [235]. ...
Schizophrenia (SZ) is a devastating psychiatric disorder affecting about 1% of the world's population. Social-cognitive impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social-cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the whole-brain level, an abnormal activation of social brain regions and interregional dysconnectivity within social-cognitive brain networks have been identified as major contributors to these symptoms. At the cellular and subcellular levels, an interplay between oxidative stress, neuroinflammation and N-methyl-D-aspartate receptor hypofunction is thought to underly SZ pathology. However, it is not clear how these molecular processes are linked with interregional dysconnectivity in the genesis of social-cognitive symptoms. Here, we aim to bridge the gap between macroscale (connectivity analyses) and microscale (molecular and cellular mechanistic) knowledge by proposing impaired myelination and the disinhibition of local microcircuits as possible causative biological pathways leading to dysconnectivity and abnormal activity of the social brain. Furthermore, we recommend electroencephalography as a promising translational technique that can foster pre-clinical drug development and discuss attractive drug targets for the treatment of social-cognitive symptoms in SZ.
... Redox imbalance causes myelination deficits in the PFC of a rat SZ model [202] as well as decreased structural integrity of the anterior commissure and fornix WM in mice [234], suggesting that oxidative stress has a direct effect on myelination and WM tracts. In line with this, NAC antioxidant treatment can ameliorate myelin abnormalities not only in a rat model of SZ associated with redox imbalance [202] but also in demyelination mouse models induced by cuprizone [235] that exhibit SZ-like features including reduced social interactions [236][237][238][239]. Interestingly, NAC also reversed social deficit in these demyelination models, further highlighting a possible contribution of oxidative stress-induced myelin defects to SZ social deficits [235]. ...
Schizophrenia (SZ) is a devastating psychiatric disorder affecting 1% of the world population. Social cognition impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the cellular level, an interplay between oxidative stress, inflammation and N-methyl-D-aspartate (NMDA) receptor hypofunction is thought to underly SZ pathology. At the whole-brain level, a reduced activation of social brain regions and a decrease in inter-regional connectivity within the social brain have been identified as major contributors to social cognition impairment in SZ. However, it is not clear how these pathological processes at the cellular level lead to whole-brain dysconnectivity in the origin of social cognition impairments. Aiming at bridging the gap between microscale (molecular and cellular mechanisms) and macroscale (whole-brain) knowledge, in this review, we propose impaired myelination and glial cell death in white matter tracts as possible intermediate biological pathways. Furthermore, we recommend electroencephalography as a promising translational technique that could revolutionize pre-clinical drug development research and discuss promising drug targets for the treatment of SZ social cognition impairment.
... In support of the interaction between mitochondrial defects and abnormal DA metabolism in the pathogenesis of schizophrenia, antipsychotic drugs protected against the cuprizone-induced changes or promoted the recovery processes of the changes in mice. Specifically, haloperidol improved PPI deficit, clozapine and quetiapine improved more behavioral abnormalities while ameliorated the cuprizone-induced white matter damage [171][172][173]. The additional therapeutic effects of clozapine and quetiapine were attributed to the antioxidant and anti-inflammatory actions of the atypical antipsychotics as demonstrated in animal and cell culture studies [167,170,[174][175][176][177]. ...
Dopamine (DA) is a major monoamine neurotransmitter in the brain and has essential roles in higher functions of the brain. Malfunctions of dopaminergic signaling have been implicated in various mental disorders such as addiction, attention deficit/hyperactivity disorder, Huntington’s disease, Parkinson’s disease (PD), and schizophrenia. The pathogenesis of PD and schizophrenia involves the interplay of mitochondrial defect and DA metabolism abnormalities. This article focuses on this issue in schizophrenia. It started with the introduction of metabolism, behavioral action, and physiology of DA, followed by reviewing evidence for malfunctions of dopaminergic signaling in patients with schizophrenia. Then it provided an overview of multiple facets of mitochondrial physiology before summarizing mitochondrial defects reported in clinical studies with schizophrenia patients. Finally, it discussed the interplay between DA metabolism abnormalities and mitochondrial defects and outlined some clinical studies showing effects of combination therapy of antipsychotics and antioxidants in treating patients with schizophrenia. The update and integration of these lines of information may advance our understanding of the etiology, pathogenesis, phenomenology, and treatment of schizophrenia.
... Y-maze spontaneous alternation test. The Y-Maze is widely used to evaluate spatial working memory (39) and has been previously used to detect memory deficits in CPZ models in numerous studies (18,30,40,41). Mice exhibiting normal behavior remember the arm they have already explored and will enter one of the other arms of the maze (19). ...
Depression is a common and disabling comorbidity of multiple sclerosis (MS), with currently no clear guidelines for treatment. Low-field magnetic stimulation (LFMS), a novel non-invasive neuromodulation intervention, has been previously demonstrated to rapidly alleviate mood disorders. The aim of the present study was to investigate the effects of LFMS on depression-like behaviors and demyelination in a well-established mouse model of MS. C57BL/6 female mice were fed a 0.2% cuprizone (CPZ) diet for 3 or 6 weeks to induce acute demyelination. During this time, the mice were treated with either sham or LFMS for 20 min/day, 5 days/week. After 3 or 6 weeks of treatment, behavior was assessed with the open field task, Y-maze and the forced swim test. The prefrontal cortex and hippocampus were then collected to perform immunohistochemistry and western blot analysis to verify myelination status. The CPZ diet did not cause significant locomotor deficits; however, working memory, measured using the Y maze, depression-like behavior and adaptive learning, assayed using the forced swim test, were significantly impaired in these animals. LFMS treatment demonstrated a significant antidepressant-like effect and markedly attenuated the CPZ-induced demyelination in the prefrontal cortex after 3- and 6-weeks of treatment, as observed by changes in myelin basic protein immunostaining and western blot analysis. Therefore, the results of the present study indicated that LFMS may be a promising therapy for demyelinating diseases due to the improvement of depressive symptoms via regulation of myelination in cortical areas.
... Further, we found that the higher copper levels had a significantly inverse association with NAA/Cr ratios in the left LN of patients with MDD. Studies have suggested that the cuprizone (CPZ, a copper chelator) may damage oligodendrocytes by causing demyelinating insult and leading to the appearance of abnormal mental functions, such as schizophrenia symptoms (51). Rats on the CPZ diet showed decreased expression of mRNA transcripts encoding oligodendroglia proteins and displayed a specific deficit in the ability to shift between perceptual dimensions in the attentional set-shifting task, similar to WCST deficits observed in schizophrenia (52). ...
Objective: The mechanism of executive function (EF) impairment in major depressive disorder (MDD) remains unclear. Previous studies have demonstrated that altered serum copper levels and neurometabolic alterations may be associated with the psychopathology and cognitive impairment of MDD. While, their inter-relationships in MDD remain uncertain. The present study aims to assess whether the interaction between serum copper levels and neurometabolic alterations is involved in the deficit of executive function (EF) in patients with unmedicated MDD.
Methods: Serum copper levels and EFs were measured in 41 MDD patients and 50 control subjects. EFs were evaluated by Trail Making Test, Part-B (TMT-B), Digit Symbol Substitution Test (DSST), Wisconsin Card Sorting Task (WCST), and Semantic Verbal Fluency testing (SVFT). Additionally, 41 patients and 41 healthy controls underwent proton magnetic resonance spectroscopy (¹H-MRS) to obtain ratios of N-acetyl aspartate to creatine (NAA/Cr) and choline-containing compounds to creatine (Cho/Cr) in the lenticular nucleus (LN) of basal ganglia (BG). Finally, association and interaction analysis were conducted to investigate their inter-relationships.
Results: The results showed that patients performed worse in the DSST, WCST, TMT-B time and SVFT. Moreover, patients had higher serum copper levels, but lower NAA/Cr ratios in left LN of BG than healthy controls. In patients, serum copper levels were found to significantly negative associated with Categories Completed (CC) number of WCST (r = −0.408, p = 0.008), and positive associated with the Total Errors (TE) and Nonperseverative Errors (PE) number of WCST (r = 0.356, p = 0.023; r = −0.356, p = 0.022). In addition, the NAA/Cr ratios of left LN were found to significantly negative associated with VFS (r = −0.401, p = 0.009), as well as negative associated with serum copper levels (r = −0.365, p = 0.019). Finally, the interaction between copper and NAA may as influencing factors for SVFT and CC number of WCST in patients.
Conclusion: Our results indicated that the interaction of abnormal copper levels and NAA/Cr neurometabolic disruption of the LN may impact executive dysfunction, and this may relevant to the pathophysiology of executive impairment in MDD patients.
... 61,69 Observations that were compatible with this notion included impaired spatial working memory in the Y-maze test, decreased paired-pulse inhibition and lower intensity of social interactions observed in mice that received 0.2% to 0.4% cuprizone in the diet for short periods. 59,60,67,70 Furthermore, the sensitivity of these phenotypes to antipsychotic drugs such as quetiapine or clozapine, 52,54,55,66,70,71 as well as increased levels of brain dopamine in cuprizone-treated mice 57,60,70 It should be noted that the ability to emit vigorous and accurate responding in touchscreen tasks depends on good eyesight: to be able to discriminate windows with and without visual stimuli and to differentiate between stimuli in discrimination paradigms. 34 Good sense of hearing is also essential as sound is used as a reinforcing signal of reward dispensation in touchscreen tests. ...
Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9–10‐week‐old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared to that of vehicle‐treated mice. Cuprizone‐treated animals demonstrated multiple deficits in short touchscreen‐based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule‐learning task. In contextual/cued fear conditioning experiments, cuprizone‐treated mice demonstrated significantly lower levels of contextual freezing than vehicle‐treated mice. Diffusion tensor imaging revealed treatment‐dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone‐treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results demonstrate that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.
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... Cognitive behaviour in animals can be assessed using the Y-maze, novel object recognition, social interaction, Morris water maze and fear conditioning tests (Table 3; Campos et al., 2013;Karl et al., 2003;Taylor et al., 2010;Webster et al., 2014;Zhang et al., 2012;Zieba et al., 2015). CPZ-fed animals showed decreased memory functions and impaired social interaction as assessed by these tests (Abakumova et al., 2015;Adilijiang et al., 2015;Aryanpour et al., 2017;Chang et al., 2017;Cui et al., 2018;Dutta et al., 2013;Hibbits et al., 2009;Kondo et al., 2016;Li et al., 2015;Makinodan et al., 2009;Murakami et al., 2017;Omotoso et al., 2018;Ray et al., 2017;Serra-de-Oliveira et al., 2015;Shao et al., 2015;Sun et al., 2017;Tezuka et al., 2013;Valeiras et al., 2014;Wang et al., 2015;Xiao et al., 2008;Xu et al., 2010Xu et al., , 2011Xu et al., 2009). ...
... Animals are placed at the end of the 'start' arm and allowed to explore the new environment. Reduced exploration/alteration frequency, but increase frequency of entry into the other arms indicates declining cognitive function and this has been observed in CPZ-fed animals (Adilijiang et al., 2015;Kondo et al., 2016;Li et al., 2015;Makinodan et al., 2009;Murakami et al., 2017;Omotoso et al., 2018;Sun et al., 2017;Tezuka et al., 2013;Wang et al., 2015;Xiao et al., 2008;Xu et al., 2010Xu et al., , 2011. In contrast, two studies reported no changes compared to naïve controls using the Y-maze test after 0.4% CPZ-feeding for 3 weeks or 0.2% CPZ for 1 week (Chang et al., 2017;Shao et al., 2015) and correlative histological examination showed no demyelination in the hippocampus (Shao et al., 2015), suggesting that short term (1-3 week) exposure to CPZ did not evoke memory dysregulation; complete demyelination of this region takes 5-6 weeks Norkute et al., 2009). ...
... The number of close contacts (e.g.˜5 cm, 0.2 s) are scored as a measure of social interaction for rodents (Thanos et al., 2017;Wilson and Koenig, 2014). Less interaction with another animal has been documented in CPZ-fed animals, indicating impaired social interaction (Abakumova et al., 2015;Adilijiang et al., 2015;Hibbits et al., 2009;Makinodan et al., 2009;Mierzwa et al., 2013;Valeiras et al., 2014;Wang et al., 2015;Xu et al., 2010Xu et al., , 2011Xu et al., 2009). ...
... 76 Conversely, OLZ, an atypical antipsychotic, has been shown to increase expression of myelination-related genes. 77 In cuprizone-fed mice (a model of demyelination and oligodendrocyte loss 78 ), atypical antipsychotics (quetiapine and clozapine) but not haloperidol protected against myelin sheath loss 79 with concurrent administration of cuprizone but none of the 3 antipsychotics were effective in repairing WM damage when given later during the recovery phase, 80 suggesting that that they yield better outcomes when taken earlier. Therefore, we are reminded that antipsychotics have different therapeutic mechanisms (eg, via antioxidative, anti-inflammatory, and antidopaminergic actions), resulting in different clinical and neurobiological outcomes. ...
Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as “disconnection syndromes,” with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from postmortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labeling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal, and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory, and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.
... In addition to alterations in myelination, chronic CUP treatment has been used to model other neurological disorders such schizophrenia and epilepsy (Praet, et al., 2014). Mice on CUP diet exhibit a loss of mossy neurons in the hippocampus, impaired spatial memory, decreased social behavior, and neurotransmitter dysregulation in the prefrontal cortex (Hoffmann, Lindner, Gröticke, Stangel, & Löscher, 2008;Makinodan et al., 2009;Xu, Yang, Rose, & Li, 2011; Page 17 of 57 ...
Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia. Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelination in vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.
... Cuprizone is a copper chelating agent that when included in the rodent diet for weeks will result in mice developing widespread demyelination, oligodendrocyte loss and myelin breakdown which is similar to changes seen in post-mortem brains of individuals who had schizophrenia (Gudi et al., 2014;Walker et al., 2018). This model was used to test the effects of haloperidol, clozapine, quetiapine on WM recovery and remyelination (Xu et al., 2011). This study examined WM recovery by histological examination using myelin basic protein and anti-glutathione-transferase-pi immunostaining. ...
... This study examined WM recovery by histological examination using myelin basic protein and anti-glutathione-transferase-pi immunostaining. They found that recovery of WM was still impaired after all three antipsychotic drug treatments with none of the three treatments promoting WM recovery, suggesting that typical and atypical antipsychotics do not act on WM (Xu et al., 2011). This is not surprising given what we know about the mechanism of action of these three drugs and further affirms that an alternative approach to promoting WM recovery is needed. ...
Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter.
