Journal of Neuroscience Research

doi: 10.1002/jnr.25116pmid: N/A

doi: 10.1002/jnr.24888pmid: N/A

Valli, Mikaeel; Uribe, Carme; Mihaescu, Alexander; Strafella, Antonio P.

doi: 10.1002/jnr.25099pmid: 35790021

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by polysomnography‐confirmed REM sleep without atonia and dream‐enacting behaviors. This disorder is considered a prodromal syndrome of alpha‐synucleinopathies like Parkinson's disease (PD), where it affects more than 50% of PD patients. The underlying pathology of RBD has been generally understood to involve the pontine nuclei within the brainstem. However, the complete pathophysiology beyond the brainstem remains unclear as does its relationship with PD pathology. Therefore, this review aims to survey the neuroimaging literature involving PET, SPECT, and MR imaging techniques to provide an updated understanding of the neuro‐chemical, structural, and functional changes in both RBD and PD patients comorbid with RBD. This review found neuroimaging evidence that indicate alterations to the dopaminergic and cholinergic system, blood perfusion, and glucose metabolism in both RBD patients and PD patients with RBD. Beyond the brainstem, structural and functional changes were found to involve the nigrostriatal system, limbic system, and the cortex—suggesting that RBD is a multi‐systemic neurodegenerative process. Future investigations are encouraged to follow RBD patients longitudinally using multimodal imaging techniques to enhance our understanding of this parasomnia disorder. Uncovering which individuals are most likely to develop an alpha‐synuclein disorder in the prodromal phase will improve patient outcomes and potentially aid in the development of novel treatments for patients affected by RBD.

K, Amrutha; Mishra, Amit; Singh, Sarika

doi: 10.1002/jnr.25101pmid: 35819247

Parkinson's disease (PD) pathology is the most common motor neurodegenerative disease that occurs due to the progressive degeneration of dopaminergic neurons of the nigrostriatal pathway of the brain. The histopathological hallmark of the disease is fibrillary aggregate called Lewy bodies which majorly contain α‐synuclein, suggesting the critical implication of diminished protein degradation mechanisms in disease pathogenesis. This α‐synuclein‐containing Lewy bodies are evident in both experimental models as well as in postmortem PD brain and are speculated to be pathogenic but still, the lineal association between these aggregates and the complexity of disease pathology is not yet well established and needs further attention. However, it has been reported that α‐synuclein aggregates have consorted with the declined proteasome and lysosome activities. Therefore, in this review, we reappraise intracellular protein degradation mechanisms during PD pathology. This article focused on the findings of the last two decades suggesting the implications of protein degradation mechanisms in disease pathogenesis and based on shreds of evidence, some of the approaches are also suggested which may be adopted to find out the novel therapeutic targets for the management of PD patients.

Maurya, Shashank Kumar; Gupta, Suchi; Bakshi, Amrita; Kaur, Harpreet; Jain, Arushi; Senapati, Sabyasachi; Baghel, Meghraj Singh

doi: 10.1002/jnr.25110pmid: 35856508

Mitochondria are one of the essential cellular organelles. Apart from being considered as the powerhouse of the cell, mitochondria have been widely known to regulate redox reaction, inflammation, cell survival, cell death, metabolism, etc., and are implicated in the progression of numerous disease conditions including neurodegenerative diseases. Since brain is an energy‐demanding organ, mitochondria and their functions are important for maintaining normal brain homeostasis. Alterations in mitochondrial gene expression, mutations, and epigenetic modification contribute to inflammation and neurodegeneration. Dysregulation of reactive oxygen species production by mitochondria and aggregation of proteins in neurons leads to alteration in mitochondria functions which further causes neuronal death and progression of neurodegeneration. Pharmacological studies have prioritized mitochondria as a possible drug target in the regulation of neurodegenerative diseases. Therefore, the present review article has been intended to provide a comprehensive understanding of mitochondrial role in the development and progression of neurodegenerative diseases mainly Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis followed by possible intervention and future treatment strategies to combat mitochondrial‐mediated neurodegeneration.

Sirisi, Sònia; Querol‐Vilaseca, Marta; Dols‐Icardo, Oriol; Pegueroles, Jordi; Montal, Victor; Muñoz, Laia; Torres, Soraya; Ferrer‐Raventós, Paula; Iulita, Maria Florencia; Sánchez‐Aced, Érika; Blesa, Rafael; Illán‐Gala, Ignacio; Molina‐Porcel, Laura; Borrego‐Ecija, Sergi;

Spelta, Lidia Emmanuela Wiazowski; Real, Caroline Cristiano; Buchpiguel, Carlos Alberto; Paula Faria, Daniele; Marcourakis, Tania

doi: 10.1002/jnr.25102pmid: 35779255

We verified if cocaine‐induced peripheral activation might disrupt [18F]FDG brain uptake after a cocaine challenge and suggested an optimal protocol to measure cocaine‐induced brain metabolic alterations in mice. C57Bl/6 male mice were injected with [18F]FDG and randomly separated into three groups. Groups 1 and 2 were kept conscious after [18F]FDG administration and after 5 min received saline or cocaine (20 mg/kg). The animals in group 1 (n = 5) were then evaluated in the open field for 30 min and those from group 2 (n = 6) were kept alone in a home cage for the same period. Forty‐five minutes after [18F]FDG administration, images were acquired for 30 min. Group 3 (n = 6) was kept anesthetized and image acquisition started immediately after tracer injection, for 75 min. Saline (Day 1) or cocaine (Day 2) was injected 5 min after starting acquisition. Another set of animals (n = 5) were treated with cocaine every other day for 10 days or saline (n = 6) and were scanned with the dynamic protocol to verify its efficacy. [18F]FDG uptake increased after cocaine administration when compared to baseline only in animals kept under anesthesia. No brain effect of cocaine was observed in animals submitted to the open field or kept in the home cage. The use of anesthesia is essential to visualize cocaine‐induced changes in brain metabolism by [18F]FDG PET, providing an interesting preclinical approach to investigate naïve subjects and enabling a bidirectional translational science approach for better understanding of cocaine use disorder.

Boorman, Damien C.; Keay, Kevin A.

doi: 10.1002/jnr.25103pmid: 35853016

Chronic pain is more prevalent and reported to be more severe in women. Opioid analgesics are less effective in women and result in stronger nauseant effects. The neurobiological mechanisms underlying these sex differences have yet to be clearly defined, though recent research has suggested neuronal–glial interactions are likely involved. We have previously shown that similar to people, morphine is less effective at reducing pain behaviors in female rats. In this study, we used the immunohistochemical detection of glial fibrillary acidic protein (GFAP) expression to investigate sex differences in astrocyte density and morphology in six medullary regions known to be modulated by pain and/or opioids. Morphine administration had small sex‐dependent effects on overall GFAP expression, but not on astrocyte morphology, in the rostral ventromedial medulla, the subnucleus reticularis dorsalis, and the area postrema. Significant sex differences in the density and morphology of GFAP immunopositive astrocytes were detected in all six regions. In general, GFAP‐positive cells in females showed smaller volumes and reduced complexity than those observed in males. Furthermore, females showed lower overall GFAP expression in all regions except for the area postrema, the critical medullary region responsible for opioid‐induced nausea and emesis. These data support the possibility that differences in astrocyte activity might underlie the sex differences seen in the processing of opioids in the context of chronic neuropathic pain.

Wang, Guo‐Qiang; Wang, Fei‐Xiang; He, Yi‐Na; Lin, Jing‐Yan

doi: 10.1002/jnr.25104pmid: 35796387

The glymphatic system is a recently discovered glial‐dependent macroscopic interstitial waste clearance system that promotes the efficient elimination of soluble proteins and metabolites from the central nervous system. Its anatomic foundation is the astrocytes and aquaporin‐4 (AQP4) water channels on the endfeet of astrocytes. The aim of this study is to evaluate the plasticity of the spinal glymphatic system in male SD rats with painful diabetic neuropathy (PDN) induced by type 2 diabetes mellitus. PDN rats were modeled under a high‐fat and high‐glucose diet with a low dose of streptozotocin. MRI was applied to observe the infiltration and clearance of contrast to indicate the functional variability of the glymphatic system at the spinal cord level. The paw withdrawal threshold was used to represent mechanical allodynia. The numerical change of glial fibrillary acidic protein (GFAP) positive astrocytes was assessed and the polarity reversal of AQP4 protein was measured by immunofluorescence. As a result, deceased contrast infiltration and clearance, enhanced mechanical allodynia, increased number of GFAP positive astrocytes, and reversed polarity of AQP4 protein were found in the PDN rats. The above molecular level changes may contribute to the impairment of the spinal glymphatic system in PDN rats. This study revealed the molecular and functional variations of the spinal glymphatic system in PDN rats and for the first time indicated that there might be a correlation between the impaired spinal glymphatic system and PDN rats.

Gøtzsche, Casper R.; Woldbye, David P. D.; Hundahl, Christian Ansgar; Hay‐Schmidt, Anders

doi: 10.1002/jnr.25105pmid: 35822521

Neuroglobin (Ngb) is found in the neurones of several different brain areas and is known to bind oxygen and other gaseous molecules and reactive oxygen species (ROS) in vitro, but it does not seem to act as a respiratory molecule for neurones. Using male and female Ngb‐knockout (KO) mice, we addressed the role of Ngb in neuronal brain activity using behavioral tests but found no differences in general behaviors, memory processes, and anxiety−/depression‐like behaviors. Oxidative stress and ROS play key roles in epileptogenesis, and oxidative injury produced by an excessive production of free radicals is involved in the initiation and progression of epilepsy. The ROS binding properties led us to hypothesize that lack of Ngb could affect central coping with excitatory stimuli. We consequently explored whether exposure to the excitatory molecule kainate (KA) would increase severity of seizures in mice lacking Ngb. We found that the duration and severity of seizures were increased, while the latency time to develop seizures was shortened in Ngb‐KO compared to wildtype adult female mice. Consistently, c‐fos expression after KA was significantly increased in Ngb‐KO mice in the amygdala and piriform cortex, regions rich in Ngb and known to be centrally involved in seizure generation. Moreover, the measured c‐fos expression levels were correlated with seizure susceptibility. With these new findings combined with previous studies we propose that Ngb could constitute an intrinsic defense mechanism against neuronal hyperexcitability and oxidative stress by buffering of ROS in amygdala and other Ngb‐containing brain regions.