An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT2A-receptor mediated head-twitch response in mice

Background Methamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT2A/C receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT2A receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.g., cocaine) suppress the DOI-evoked HTR via indirect stimulation of serotonergic 5-HT1A- and adrenergic ɑ2-receptors. Since the induction of HTR by DOI is age-dependent, we investigated whether: (1) during development MA can evoke the HTR by itself, and (2) acute pretreatment with either the selective 5-HT2A receptor antagonist EMD 281014 or low-doses of MA can: (i) modulate the DOI-induced HTR in mice across postnatal days 20, 30 and 60, and (ii) alter the DOI-induced c-fos expression in mice prefrontal cortex (PFC). To further explore the possible modulatory effect of MA on DOI-induced HTR, we investigated whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors by corresponding selective antagonists (WAY 100635 or RS 79948, respectively), can prevent the effect of MA on DOI-induced HTR during aging. Results Although neither EMD 281014 nor MA by themselves could evoke the HTR, acute pretreatment with either EMD 281014 (0.01, 0.05 and 0.1 mg/kg, i.p.) or MA (1, 2.5, 5 mg/kg, i.p.), dose-dependently suppressed the DOI-induced HTR across ages. While WAY 100635 significantly reversed the inhibitory effect of MA in 20- and 30-day old mice, RS 79948 failed to significantly counter MA’s inhibitory effect. Moreover, DOI significantly increased c-fos expressions in several PFC regions. EMD 281014 prevented the DOI-induced increases in c-fos expression. Despite the inhibitory effect of MA on DOI-induced HTR, MA alone or in combination with DOI, significantly increased c-fos expression in several regions of the PFC. Conclusion The suppressive effect of MA on the DOI-evoked HTR appears to be mainly due to functional interactions between the HTR-inducing 5-HT2A receptor and the inhibitory 5-HT1A receptor. The MA-induced increase in c-fos expression in different PFC regions may be due to MA-evoked increases in synaptic concentrations of 5-HT, NE and/or DA.

Observing errors in a combination of error and correct models favors observational motor learning

Background Imitative learning is highly effective from infancy to old age; however, little is known about the effects of observing errors during imitative learning. This study aimed to examine how observing errors affected imitative learning performance to maximize its effect. Methods In the pre-training session, participants were instructed to pinch at a target force (8 N) with auditory feedback regarding generated force while they watched videos of someone pinching a sponge at the target force. In the pre-test, participants pinched at the target force and did not view a model or receive auditory feedback. In Experiment 1, in the main training session, participants imitated models while they watched videos of pinching at either the incorrect force (error-mixed condition) or target force (correct condition). Then, the exact force generated was measured without receiving auditory feedback or viewing a model. In Experiment 2, using the same procedures, newly recruited participants watched videos of pinching at incorrect forces (4 and 24 N) as the error condition and the correct force as the correct condition. Results In Experiment 1, the average force was closer to the target force in the error-mixed condition than in the correct condition. In Experiment 2, the average force in the correct condition was closer to the target force than in the error condition. Conclusion Our findings indicated that observing error actions combined with correct actions affected imitation motor learning positively as error actions contained information on things to avoid in the target action. It provides further information to enhance imitative learning in mixed conditions compared to that with correct action alone.

Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies

Background Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer’s disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. Methods Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. Results We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. Conclusions Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

Analysis of risk factors and preventive strategies for intracranial infection after neuroendoscopic transnasal pituitary adenoma resection

Objective To analyse the risk factors for intracranial infection after neuroendoscopic transnasal pituitary adenoma resection (NTPAR) to provide a reference for the prevention and treatment of postoperative intracranial infection. Methods The clinical data of 387 patients who underwent NTPAR in the Department of Neurosurgery of the First People’s Hospital of Yichang from March 2013 to March 2021 were retrospectively analysed. The patients were divided into an infected group and a noninfected group according to the occurrence of intracranial infection. The detailed clinical data of the two groups were collected. Univariate and multivariate logistic regression was used to analyse the risk factors for intracranial infection after NTPAR. Results Among the 387 surgical patients, 32 patients (8.27%) were in the intracranially infected group and 355 patients (91.73%) were in the noninfected group. The results of the univariate analysis suggested that age > 45 years, tumour size > 1 cm, operation time > 240 min, blood loss > 400 ml, Kelly Grade of cerebrospinal fluid (CSF) leakage > Grade 2, postoperative CSF leakage, lumbar cistern drainage and blood transfusion were the influencing factors for postoperative intracranial infection, while the results of multivariate logistic regression analysis implied that intraoperative CSF leakage (Kelly Grade > 2) and postoperative CSF leakage were independent influencing factors for intracranial infection after NTPAR, and perioperative use of antibiotics was an independent protective factor for postoperative intracranial infection. Conclusions There are a variety of risk factors for intracranial infection after NTPAR, which indicates that it is necessary to develop different repair strategies for CSF leakage according to the Kelly Grade, timely treatment of postoperative CSF leakage and perioperative use of antibiotics. These measures have been shown to effectively reduce the probability of intracranial infection after NTPAR.

Cascade process mediated by left hippocampus and left superior frontal gyrus affects relationship between aging and cognitive dysfunction

Background Cognitive function declines with age and has been shown to be associated with atrophy in some brain regions, including the prefrontal cortex. However, the details of the relationship between aging and cognitive dysfunction are not well understood. Methods Across a wide range of ages (24- to 85-years-old), this research measured the gray matter volume of structural magnetic resonance imaging data in 39 participants, while some brain regions were set as mediator variables to assess the cascade process between aging and cognitive dysfunction in a path analysis. Results Path analysis showed that age affected the left hippocampus, thereby directly affecting the left superior frontal gyrus. Furthermore, the gyrus directly affected higher order flexibility and maintenance abilities calculated as in the Wisconsin card sorting test, and the two abilities affected the assessment of general cognitive function. Conclusion Our finding suggests that a cascade process mediated by the left hippocampus and left superior frontal gyrus is involved in the relationship between aging and cognitive dysfunction.

Metformin attenuates sepsis-induced neuronal injury and cognitive impairment

Background Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures. Methods Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments. Results Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats. Conclusion These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.

Longitudinal alterations of the cisternal segment of trigeminal nerve and brain pain-matrix regions in patients with trigeminal neuralgia before and after treatment

Background Trigeminal neuralgia (TN) is the most common type of chronic neuropathic facial pain, but the etiology and pathophysiological mechanisms after treatment are still not well understood. The purpose of this study was to investigate the longitudinal changes of the cisternal segment of the trigeminal nerve and brain pain-related regions in patients with TN before and after treatment using readout segmentation of long variable echo-train (RESOLVE) diffusion tensor imaging (DTI) and transverse relaxation (T2)-weighted sampling perfection with application-optimized contrast at different flip angle evolutions (T2-SPACE). Methods Twelve patients with TN and four healthy controls were enrolled in this study. All patients underwent assessment of the visual analog scale (VAS), and acquisition of RESOLVE DTI and T2-SPACE images before and at 1, 6, and 12 months after treatments. Regions-of-interest were placed on the bilateral anterior, middle, and posterior parts of the cisternal segment of the trigeminal nerve, the bilateral root entry zone (REZ), bilateral nuclear zone, and the center of pontocerebellar tracts, respectively. Voxel-based morphometry (VBM) analysis was conducted with T2-SPACE images, and gray matter volumes (GMV) were measured from brain pain-matrix regions. Results The results demonstrated that the VAS scores, the axial diffusivity of the middle part of the affected cisternal trigeminal nerve, the fractional anisotropy of the bilateral nuclear zones, and the mean diffusivity of the center of pontocerebellar tract significantly changed over time before and after treatment. The changes of GMV in the pain-matrix regions exhibited similar trends to the VAS before and after treatment. Conclusion We conclude that magnetic resonance imaging with RESOLVE DTI and VBM with T2-SPACE images were helpful in the understanding of the pathophysiological mechanisms in patients with TN before and after treatment.

Overt speech critically changes lateralization index and did not allow determination of hemispheric dominance for language: an fMRI study

Background Pre-surgical mapping of language using functional MRI aimed principally to determine the dominant hemisphere. This mapping is currently performed using covert linguistic task in way to avoid motion artefacts potentially biasing the results. However, overt task is closer to natural speaking, allows a control on the performance of the task, and may be easier to perform for stressed patients and children. However, overt task, by activating phonological areas on both hemispheres and areas involved in pitch prosody control in the non-dominant hemisphere, is expected to modify the determination of the dominant hemisphere by the calculation of the lateralization index (LI). Objective Here, we analyzed the modifications in the LI and the interactions between cognitive networks during covert and overt speech task. Methods Thirty-three volunteers participated in this study, all but four were right-handed. They performed three functional sessions consisting of (1) covert and (2) overt generation of a short sentence semantically linked with an audibly presented word, from which we estimated the “Covert” and “Overt” contrasts, and a (3) resting-state session. The resting-state session was submitted to spatial independent component analysis to identify language network at rest (LANG), cingulo-opercular network (CO), and ventral attention network (VAN). The LI was calculated using the bootstrapping method. Results The LI of the LANG was the most left-lateralized (0.66 ± 0.38). The LI shifted from a moderate leftward lateralization for the Covert contrast (0.32 ± 0.38) to a right lateralization for the Overt contrast (− 0.13 ± 0.30). The LI significantly differed from each other. This rightward shift was due to the recruitment of right hemispheric temporal areas together with the nodes of the CO. Conclusion Analyzing the overt speech by fMRI allowed improvement in the physiological knowledge regarding the coordinated activity of the intrinsic connectivity networks. However, the rightward shift of the LI in this condition did not provide the basic information on the hemispheric language dominance. Overt linguistic task cannot be recommended for clinical purpose when determining hemispheric dominance for language.

Saccharomyces boulardii improves the behaviour and emotions of spastic cerebral palsy rats through the gut-brain axis pathway

Background Cerebral palsy (CP) is a kind of disability that influences motion, and children with CP also exhibit depression-like behaviour. Inflammation has been recognized as a contributor to CP and depression, and some studies suggest that the gut-brain axis may be a contributing factor. Our team observed that Saccharomyces boulardii (S. boulardii) could reduce the inflammatory level of rats with hyperbilirubinemia and improve abnormal behaviour. Both CP and depression are related to inflammation, and probiotics can improve depression by reducing inflammation. Therefore, we hypothesize that S. boulardii may improve the behaviour and emotions of spastic CP rats through the gut-brain axis pathway. Methods Our new rat model was produced by resecting the cortex and subcortical white matter. Seventeen-day-old CP rats were exposed to S. boulardii or vehicle control by gastric gavage for 9 days, and different behavioural domains and general conditions were tested. Inflammation was assessed by measuring the inflammatory markers IL-6 and TNF-α. Hypothalamic–pituitary–adrenal (HPA) axis activity was assessed by measuring adrenocorticotropic hormone and corticosterone in the serum. Changes in the gut microbiome were detected by 16S rRNA. Results The hemiplegic spastic CP rats we made with typical spastic paralysis exhibited depression-like behaviour. S. boulardii treatment of hemiplegic spastic CP rats improves behaviour and general conditions and significantly reduces the level of inflammation, decreases HPA axis activity, and increases gut microbiota diversity. Conclusions The model developed in this study mimics a hemiplegic spastic cerebral palsy. Damage to the cortex and subcortical white matter of 17-day-old Sprague–Dawley (SD) rats led to spastic CP-like behaviour, and the rats exhibited symptoms of depression-like behaviour. Our results indicate that S. boulardii might have potential in treating hemiplegic spastic CP rat models or as an add-on therapy via the gut-brain axis pathway.