Background and Purpose
Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the ...prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D1 and D2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain‐dependent. Conversely, the role of D1 receptors in the regulation of PPI across different rat strains remains unclear.
Experimental Approach
We tested the effects of selective D1 and D2 receptor agonists and antagonists on the startle reflex and PPI of Sprague‐Dawley, Wistar and Long–Evans rats.
Key Results
In contrast with Sprague‐Dawley and Wistar rats, the full D1 receptor agonist SKF82958 elicited significant PPI deficits in Long–Evans rats, an effect sensitive to the selective D1 antagonist SCH23390.
Conclusions and Implications
Our results suggest that, in Long–Evans rats, D1 receptor activation may be sufficient to significantly impair PPI. These data emphasize the role of D1 receptors in the pathophysiology of neuropsychiatric disorders featuring alterations in sensorimotor gating, and uphold the importance of the genetic background in shaping the role of dopamine receptors in the regulation of this key information‐processing function.
Linked Articles
This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc
Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological ...outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported.
A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters (
= 138 mTBI;
= 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into "good" and "poor" sleepers and cytokine levels compared between groups.
In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 ß (SE) = 0.11 (0.04),
= 0.01 and TNFα ß (SE) = 0.07 (0.03),
< 0.01. When divided according to "good" versus "poor" sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep ß (SE) = 0.12 (0.04),
< 0.01. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls.
These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.
Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive ...involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone. SD selectively enhanced 5αR expression and activity, as well as AP levels, in the prefrontal cortex; furthermore, finasteride (10-100 mg/kg, IP) dose-dependently ameliorated PPI deficits, hyperactivity, and risk-taking behaviors, in a fashion akin to the antipsychotic haloperidol and the mood stabilizer lithium carbonate. Finally, PPI deficits were exacerbated by allopregnanolone (10 mg/kg, IP) and attenuated by progesterone (30 mg/kg, IP) in SD-subjected, but not control rats. Collectively, these results provide the first-ever evidence that 5αR mediates a number of psychosis- and mania-like complications of SD through imbalances in cortical levels of neuroactive steroids.
e propone un acercamiento al estudio de las evidencias materiales de ocupación del espacio a fines del siglo XIX, en dos sitios ubicados en el sector sur del Área Ecotonal Húmedo Seca Pampeana ...(AEHSP). El primero, San Carlos, se encuentra en el predio de la estancia Santa Ana en el partido de Coronel Suarez, en el sudoeste de la provincia de Buenos Aires. El otro sitio es la casa del primer intendente de la localidad de Puan, Rómulo Franco, localizada en la isla de Puan en el partido homónimo, próxima a la cabecera del distrito bonaerense. Ambos sitios presentan estructuras habitacionales remanentes, donde se evaluaron las distintas fases constructivas de las estructuras que se observan en la actualidad, con el fin de contribuir a determinar la funcionalidad del sitio. Para el análisis se consideraron las posturas teóricas de la arqueología de la arquitectura, las cuales implican estudiar la relación del ser humano con las construcciones que usa o elabora. Se intenta identificar cómo el medio es modificado y cómo los espacios construidos son diseñados con el objetivo de favorecer ciertas percepciones. Si se determina cómo los espacios son pensados y organizados para propiciar cierta percepción respecto a su entorno y a la construcción en sí misma, se puede acceder a la racionalidad del grupo que la creó y usó.
Diverse types of dental adhesives exhibit different cytotoxic outcomes on cells in vitro. Currently, no standard adhesive application technique has so far been decisive for clinicians for better ...durability of resin-dentin bonds of adhesive systems. The purpose of this study was to systematically review the literature to evaluate the bonding performance of adhesive systems to dentin by using different application modalities. The systematic research strategy was conducted by two reviewers among multiple databases: PubMed, Scopus, Web of Science, Embase, and Scielo. In vitro studies reporting the effects of additional steps for the application of adhesive systems on the bond strength to dentin were selected. Meta-analysis was performed using Review Manager Software version 5.3.5 using the random effects model. The methodological quality of each in vitro study was assessed according to the parameters of a previous systematic review. The electronic research through different databases generated a total of 8318 references. After the examination of titles and abstracts, a total of 106 potentially relevant studies accessed the full-text evaluation phase. After full-text examination, 78 publications were included for the qualitative analysis, and 68 studies were included in the meta-analysis. Regarding the etch-and-rinse adhesive systems, the application modalities that improved the overall bond strength were the application of a hydrophobic resin layer (
= 0.005), an extended application time (
< 0.001), an application assisted by an electric current (
< 0.001), a double-layer application (
= 0.05), the agitation technique (
= 0.02), and the active application of the adhesive (
< 0.001). For self-etch adhesive systems, the techniques that improved the overall bond strength were the application of a hydrophobic resin layer (
< 0.001), an extended application time (
= 0.001), an application assisted by an electric current (
< 0.001), a double-layer application (
< 0.001), the agitation technique (
= 0.01), and the active application of the adhesive (
< 0.001). The in vitro evidence suggests that the application of adhesive systems using alternative techniques or additional strategies may be beneficial for improving their bond strength to dentin. The application modalities that favored the overall bond strength to dentin were an extended application time, a double-layer application, an application assisted by an electric current, the active application of the adhesive, and the application of a hydrophobic resin layer. Worth mentioning is that some techniques are intended to increase the degree of the conversion of the materials, and therefore, improvements in the biocompatibility of the materials can be expected.
A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22. Using a positional-cloning ...strategy, we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP).
ABSTRACT Cognitive impairment is a common and disabling problem in Parkinson’s disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD ...might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1,105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised HVLT-R), working memory/executive function (Letter-Number Sequencing and Trail Making Test TMT A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation JoLO), and global cognitive function (Montreal Cognitive Assessment). For common variants we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate corrected P -value ( PFDR ) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 x 10-4 ) for JoLO, PARP4 rs9318600 ( PFDR = 0.006) and rs9581094 ( PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 ( PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.
Neuronal trafficking dynamics and regulators Feole, Monica; Devoto, Victorio Martin Pozo; Carna, Maria ...
Alzheimer's & dementia,
12/2020, Letnik:
16, Številka:
S2
Journal Article
Recenzirano
Abstract
Background
Neurons are highly polarized cells continuously relying on intracellular transport, through which they communicate with the external world. Among the somatodendritic and axonal ...compartments many proteins with different functions are sorted to reach long distances. The relevance of neuronal transport in ensuring cell development and homeostasis maintenance raises a big interest on this topic. Moreover, several neurodegenerative diseases, such as Alzheimer’s or Amyotrophic Lateral Sclerosis, exhibit significant axonal pathology, where transport impairment seems to have a crucial influence. However, the role of this process in neurodegeneration, remains poorly understood. In this study we aim to characterize neuronal transport dynamics of specific proteins, and the molecular machinery regulating this process. Furthermore, we aim to explore transport from the pathological point of view, evaluating the effect that mutant proteins (e.g. TDP43‐related) may have on it.
Method
Human Neural Stem Cells derived neurons were differentiated for 30 DIV. Plasmids encoding for different GFP‐coupled proteins were designed to express those who are involved in main neuronal functions (e.g. synaptic activity) and transfected in neurons. Time‐lapse movies of cargoes were acquired to detect changes in movement. Data analysis was performed using object segmentation and tracking algorithms. Raw data were processed to describe the main motion parameters: average velocity, directionality, track length, and others. Post‐imaging Immunocytochemistry was performed to assess cargoes localization and discriminate between axonal and dendritic transport.
Result
Amyloid Precursor Protein (APP) cargoes with higher velocity in anterograde direction were observed compared with the retrograde one; meanwhile for Synaptophysin, a major population of stationary particles was found. Moreover, sorted data for axonal and dendritic transport description shown faster APP particles in axonal anterograde movement. Relying on the movement dynamics description, we decided to screen for protein‐protein interactions, using GFP‐trap and CoIP approaches followed by Mass Spectrometry analysis, which can shed light on possible partners involved in the transport regulation.
Conclusion
Our work describes an
in vitro
model for neuronal transport study and highlights the different behavior of proteins with various physiological functions. A complete view will elucidate details about transport regulation and will open a way to understand its role in neuropathological processes.
Background
Neurons are highly polarized cells continuously relying on intracellular transport, through which they communicate with the external world. Among the somatodendritic and axonal ...compartments many proteins with different functions are sorted to reach long distances. The relevance of neuronal transport in ensuring cell development and homeostasis maintenance raises a big interest on this topic. Moreover, several neurodegenerative diseases, such as Alzheimer’s or Amyotrophic Lateral Sclerosis, exhibit significant axonal pathology, where transport impairment seems to have a crucial influence. However, the role of this process in neurodegeneration, remains poorly understood. In this study we aim to characterize neuronal transport dynamics of specific proteins, and the molecular machinery regulating this process. Furthermore, we aim to explore transport from the pathological point of view, evaluating the effect that mutant proteins (e.g. TDP43‐related) may have on it.
Method
Human Neural Stem Cells derived neurons were differentiated for 30 DIV. Plasmids encoding for different GFP‐coupled proteins were designed to express those who are involved in main neuronal functions (e.g. synaptic activity) and transfected in neurons. Time‐lapse movies of cargoes were acquired to detect changes in movement. Data analysis was performed using object segmentation and tracking algorithms. Raw data were processed to describe the main motion parameters: average velocity, directionality, track length, and others. Post‐imaging Immunocytochemistry was performed to assess cargoes localization and discriminate between axonal and dendritic transport.
Result
Amyloid Precursor Protein (APP) cargoes with higher velocity in anterograde direction were observed compared with the retrograde one; meanwhile for Synaptophysin, a major population of stationary particles was found. Moreover, sorted data for axonal and dendritic transport description shown faster APP particles in axonal anterograde movement. Relying on the movement dynamics description, we decided to screen for protein‐protein interactions, using GFP‐trap and CoIP approaches followed by Mass Spectrometry analysis, which can shed light on possible partners involved in the transport regulation.
Conclusion
Our work describes an in vitro model for neuronal transport study and highlights the different behavior of proteins with various physiological functions. A complete view will elucidate details about transport regulation and will open a way to understand its role in neuropathological processes.
PDF
