scholarly journals Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudia Villani ◽  
Mirjana Carli ◽  
Anna Maria Castaldo ◽  
Giuseppina Sacchetti ◽  
Roberto William Invernizzi
Keyword(s):  
Prefrontal Cortex ◽  
Rett Syndrome ◽  
Motor Coordination ◽  
Antidepressant Drug ◽  
Brain Regions ◽  
Loss Of Function ◽  
Heterozygous Mouse ◽  
Skill Deficit ◽  
Second Year ◽  
The Brain

AbstractMotor skill deficit is a common and invalidating symptom of Rett syndrome (RTT), a rare disease almost exclusively affecting girls during the first/second year of life. Loss-of-function mutations of the methyl-CpG-binding protein2 (MECP2; Mecp2 in rodents) gene is the cause in most patients. We recently found that fluoxetine, a selective serotonin (5-HT) reuptake inhibitor and antidepressant drug, fully rescued motor coordination deficits in Mecp2 heterozygous (Mecp2 HET) mice acting through brain 5-HT. Here, we asked whether fluoxetine could increase MeCP2 expression in the brain of Mecp2 HET mice, under the same schedule of treatment improving motor coordination. Fluoxetine increased the number of MeCP2 immuno-positive (MeCP2+) cells in the prefrontal cortex, M1 and M2 motor cortices, and in dorsal, ventral and lateral striatum. Fluoxetine had no effect in the CA3 region of the hippocampus or in any of the brain regions of WT mice. Inhibition of 5-HT synthesis abolished the fluoxetine-induced rise of MeCP2+ cells. These findings suggest that boosting 5-HT transmission is sufficient to enhance the expression of MeCP2 in several brain regions of Mecp2 HET mice. Fluoxetine-induced rise of MeCP2 could potentially rescue motor coordination and other deficits of RTT.

scholarly journals Sex in the brain: hormones and sex differences

2016 ◽  
Vol 18 (4) ◽  
pp. 373-383 ◽  
Keyword(s):  
Sex Differences ◽  
Sex Hormones ◽  
Genetic Factors ◽  
Motor Coordination ◽  
Brain Regions ◽  
New Era ◽  
Brain Functions ◽  
Opioid Sensitivity ◽  
Males And Females ◽  
The Brain

Contrary to popular belief, sex hormones act throughout the entire brain of both males and females via both genomic and nongenomic receptors. Many neural and behavioral functions are affected by estrogens, including mood, cognitive function, blood pressure regulation, motor coordination, pain, and opioid sensitivity. Subtle sex differences exist for many of these functions that are developmentally programmed by hormones and by not yet precisely defined genetic factors, including the mitochondrial genome. These sex differences, and responses to sex hormones in brain regions and upon functions not previously regarded as subject to such differences, indicate that we are entering a new era in our ability to understand and appreciate the diversity of gender-related behaviors and brain functions.

scholarly journals The Effects of Tryptamine Psychedelics in the Brain: A meta-Analysis of Functional and Review of Molecular Imaging Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
João Castelhano ◽  
Gisela Lima ◽  
Marta Teixeira ◽  
Carla Soares ◽  
Marta Pais ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Theory Of Mind ◽  
Molecular Mimicry ◽  
Meta Analysis ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Imaging Studies ◽  
Activation Patterns ◽  
Therapeutic Benefits ◽  
The Brain

There is an increasing interest in the neural effects of psychoactive drugs, in particular tryptamine psychedelics, which has been incremented by the proposal that they have potential therapeutic benefits, based on their molecular mimicry of serotonin. It is widely believed that they act mainly through 5HT2A receptors but their effects on neural activation of distinct brain systems are not fully understood. We performed a quantitative meta-analysis of brain imaging studies to investigate the effects of substances within this class (e.g., LSD, Psilocybin, DMT, Ayahuasca) in the brain from a molecular and functional point of view. We investigated the question whether the changes in activation patterns and connectivity map into regions with larger 5HT1A/5HT2A receptor binding, as expected from indolaemine hallucinogens (in spite of the often reported emphasis only on 5HT2AR). We did indeed find that regions with changed connectivity and/or activation patterns match regions with high density of 5HT2A receptors, namely visual BA19, visual fusiform regions in BA37, dorsal anterior and posterior cingulate cortex, medial prefrontal cortex, and regions involved in theory of mind such as the surpramarginal gyrus, and temporal cortex (rich in 5HT1A receptors). However, we also found relevant patterns in other brain regions such as dorsolateral prefrontal cortex. Moreover, many of the above-mentioned regions also have a significant density of both 5HT1A/5HT2A receptors, and available PET studies on the effects of psychedelics on receptor occupancy are still quite scarce, precluding a metanalytic approach. Finally, we found a robust neuromodulatory effect in the right amygdala. In sum, the available evidence points towards strong neuromodulatory effects of tryptamine psychedelics in key brain regions involved in mental imagery, theory of mind and affective regulation, pointing to potential therapeutic applications of this class of substances.

scholarly journals Integrating memories: Congruency and reactivation aid memory integration through reinstatement of prior knowledge

2019 ◽  
Author(s):  
Marlieke T.R. van Kesteren ◽  
Paul Rignanese ◽  
Pierre G. Gianferrara ◽  
Lydia Krabbendam ◽  
Martijn Meeter
Keyword(s):  
Prefrontal Cortex ◽  
Prior Knowledge ◽  
Medial Prefrontal Cortex ◽  
Medial Temporal Lobe ◽  
Knowledge Building ◽  
Activity Patterns ◽  
Brain Regions ◽  
Memory Integration ◽  
The Brain ◽  
Parahippocampal Place Area

AbstractBuilding consistent knowledge schemas that organize information and guide future learning is of great importance in everyday life. Such knowledge building is suggested to occur through reinstatement of prior knowledge during new learning in stimulus-specific brain regions. This process is proposed to yield integration of new with old memories, supported by the medial prefrontal cortex (mPFC) and medial temporal lobe (MTL). Possibly as a consequence, congruency of new information with prior knowledge is known to enhance subsequent memory. Yet, it is unknown how reactivation and congruency interact to optimize memory integration processes that lead to knowledge schemas. To investigate this question, we here used an adapted AB-AC inference paradigm in combination with functional Magnetic Resonance Imaging (fMRI). Participants first studied an AB-association followed by an AC-association, so B (a scene) and C (an object) were indirectly linked through their common association with A (an unknown pseudoword). BC-associations were either congruent or incongruent with prior knowledge (e.g. a bathduck or a hammer in a bathroom), and participants were asked to report subjective reactivation strength for B while learning AC. Behaviorally, both the congruency and reactivation measures enhanced memory integration. In the brain, these behavioral effects related to univariate and multivariate parametric effects of congruency and reactivation on activity patterns in the MTL, mPFC, and Parahippocampal Place Area (PPA). Moreover, mPFC exhibited larger connectivity with the PPA for more congruent associations. These outcomes provide insights into the neural mechanisms underlying memory integration enhancement, which can be important for educational learning.Significance statementHow does our brain build knowledge through integrating information that is learned at different periods in time? This question is important in everyday learning situations such as educational settings. Using an inference paradigm, we here set out to investigate how congruency with, and active reactivation of previously learned information affects memory integration processes in the brain. Both these factors were found to relate to activity in memory-related regions such as the medial prefrontal cortex (mPFC) and the hippocampus. Moreover, activity in the parahippocampal place area (PPA), assumed to reflect reinstatement of the previously learned associate, was found to predict subjective reactivation strength. These results show how we can moderate memory integration processes to enhance subsequent knowledge building.

scholarly journals In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

2021 ◽  
Author(s):  
Marjo K Hytönen ◽  
Riika Sarviaho ◽  
Christopher B Jackson ◽  
Pernilla Syrjä ◽  
Tarja Jokinen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Motor Coordination ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Brain Disorder ◽  
Clinical Genetic ◽  
The Brain

Abstract We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6 to 12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.

Memory Engrams in the Neocortex

2020 ◽  
pp. 107385842094152
Author(s):  
Svenja Brodt ◽  
Steffen Gais
Keyword(s):  
Posterior Parietal Cortex ◽  
Brain Regions ◽  
Loss Of Function ◽  
Noninvasive Methods ◽  
New Era ◽  
Parallel Memory ◽  
Memory Representations ◽  
Posterior Parietal ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

While in the past much of our knowledge about memory representations in the brain has relied on loss-of-function studies in which whole brain regions were temporarily inactivated or permanently lesioned, the recent development of new methods has ushered in a new era of downright “engram excitement.” Animal research is now able to specifically label, track, and manipulate engram cells in the brain. While early studies have mostly focused on single brain regions like the hippocampus, recently more and more evidence for brain-wide distributed engram networks is emerging. Memory research in humans has also picked up pace, fueled by promising magnetic resonance imaging (MRI)-based methods like diffusion-weighted MRI (DW-MRI) and brain decoding. In this review, we will outline recent advancements in engram research, with a focus on human data and neocortical representations. We will illustrate the available noninvasive methods for the detection of engrams in different neocortical regions like the medial prefrontal cortex and the posterior parietal cortex and discuss evidence for systems consolidation and parallel memory encoding. Finally, we will explore how reactivation and prior knowledge can lead to and enhance engram formation in the neocortex.

scholarly journals Concept generation techniques change patterns of brain activation during engineering design

2020 ◽  
Vol 6 ◽  
Author(s):  
Tripp Shealy ◽  
John Gero ◽  
Mo Hu ◽  
Julie Milovanovic
Keyword(s):  
Prefrontal Cortex ◽  
Morphological Analysis ◽  
Engineering Students ◽  
Near Infrared ◽  
Brain Activation ◽  
Brain Regions ◽  
Concept Generation ◽  
Functional Near Infrared Spectroscopy ◽  
Cognitive Activation ◽  
The Brain

Abstract This paper presents the results of studying the brain activations of 30 engineering students when using three different design concept generation techniques: brainstorming, morphological analysis, and TRIZ. Changes in students’ brain activation in the prefrontal cortex were measured using functional near-infrared spectroscopy. The results are based on the area under the curve analysis of oxygenated hemodynamic response as well as an assessment of functional connectivity using Pearson’s correlation to compare students’ cognitive brain activations using these three different ideation techniques. The results indicate that brainstorming and morphological analysis demand more cognitive activation across the prefrontal cortex (PFC) compared to TRIZ. The highest cognitive activation when brainstorming and using morphological analysis is in the right dorsolateral PFC (DLPFC) and ventrolateral PFC. These regions are associated with divergent thinking and ill-defined problem-solving. TRIZ produces more cognitive activation in the left DLPFC. This region is associated with convergent thinking and making judgments. Morphological analysis and TRIZ also enable greater coordination (i.e., synchronized activation) between brain regions. These findings offer new evidence that structured techniques like TRIZ reduce cognitive activation, change patterns of activation and increase coordination between regions in the brain.

The Neuroscience of Learning Agility

2021 ◽  
pp. 118-142
Author(s):  
Kim E. Ruyle
Keyword(s):  
Emotional Intelligence ◽  
Prefrontal Cortex ◽  
Executive Function ◽  
Limbic System ◽  
Brain Regions ◽  
Learning Agility ◽  
Attention Networks ◽  
The Relationship ◽  
The Brain

“The Neuroscience of Learning Agility” explores the relationship between neurobiology and learning agility. It provides an overview of the organization of the brain, focusing on the roles of the limbic system and the prefrontal cortex and how these particular brain regions relate to personality, executive function, and the metacompetencies of emotional intelligence and learning agility. The neuroscience of learning is discussed, including the brain’s attention networks, neuroplasticity, and biological underpinnings of memory. An argument is posited that the brain’s perceptions of threats directly impacts one’s personality and, by extension, influences one’s level of learning agility. The chapter concludes by providing neuroscience-based suggestions for developing learning agility.

scholarly journals Fluoxetine rescues rotarod motor deficits in Mecp2 heterozygous mouse model of Rett syndrome via brain serotonin

2020 ◽  
Author(s):  
Claudia Villani ◽  
Giuseppina Sacchetti ◽  
Mirjana Carli ◽  
Roberto W. Invernizzi
Keyword(s):  
Rett Syndrome ◽  
Motor Skill ◽  
Motor Coordination ◽  
Protein A ◽  
Specific Area ◽  
Repeated Administration ◽  
Skill Learning ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Beneficial Effects

AbstractMotor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linked methyl-CpG-binding protein2 (MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients and Mecp2 mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity.In the present study, we used heterozygous (Het) Mecp2 female and Mecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits. Repeated administration of 10 mg/kg fluoxetine fully rescued rotarod deficit in Mecp2 Het mice regardless of age, route of administration or pre-training to rotarod. The motor improvement was confirmed in the beam walking test while no effect was observed in the hanging-wire test, suggesting a preferential action of fluoxetine on motor coordination. Citalopram mimicked the effects of fluoxetine, while the inhibition of 5-HT synthesis abolished the fluoxetine-induced improvement of motor coordination. Mecp2 null mice, which responded poorly to fluoxetine in the rotarod, showed reduced 5-HT synthesis in the prefrontal cortex, hippocampus and striatum, and reduced efficacy of fluoxetine in raising extracellular 5-HT as compared to female mutants. No sex differences were observed in the ability of fluoxetine to desensitize 5-HT1A autoreceptors upon repeated administration. These findings indicate that fluoxetine rescues motor coordination in Mecp2 Het mice through its ability to enhance brain 5-HT and suggest that drugs enhancing 5-HT neurotransmission may have beneficial effects on motor symptoms of RTT.

scholarly journals Representational organization of novel task sets during proactive encoding

2019 ◽  
Author(s):  
Ana F. Palenciano ◽  
Carlos González-García ◽  
Juan E. Arco ◽  
Luiz Pessoa ◽  
María Ruz
Keyword(s):  
Prefrontal Cortex ◽  
Neural Coding ◽  
Brain Regions ◽  
Stimulus Category ◽  
General Effect ◽  
Lateral Prefrontal Cortex ◽  
Representational Space ◽  
Task Encoding ◽  
Brain Data ◽  
The Brain

AbstractRecent multivariate analyses of brain data have boosted our understanding of the organizational principles that shape neural coding. However, most of this progress has focused on perceptual visual regions (Connolly et al., 2012), whereas far less is known about the organization of more abstract, action-oriented representations. In this study, we focused on humans’ remarkable ability to turn novel instructions into actions. While previous research shows that instruction encoding is tightly linked to proactive activations in fronto-parietal brain regions, little is known about the structure that orchestrates such anticipatory representation. We collected fMRI data while participants (both males and females) followed novel complex verbal rules that varied across control-related variables (integrating within/across stimuli dimensions, response complexity, target category) and reward expectations. Using Representational Similarity Analysis (Kriegeskorte et al., 2008) we explored where in the brain these variables explained the organization of novel task encoding, and whether motivation modulated these representational spaces. Instruction representations in the lateral prefrontal cortex were structured by the three control-related variables, while intraparietal sulcus encoded response complexity and the fusiform gyrus and precuneus organized its activity according to the relevant stimulus category. Reward exerted a general effect, increasing the representational similarity among different instructions, which was robustly correlated with behavioral improvements. Overall, our results highlight the flexibility of proactive task encoding, governed by distinct representational organizations in specific brain regions. They also stress the variability of motivation-control interactions, which appear to be highly dependent on task attributes such as complexity or novelty.Significance StatementIn comparison with other primates, humans display a remarkable success in novel task contexts thanks to our ability to transform instructions into effective actions. This skill is associated with proactive task-set reconfigurations in fronto-parietal cortices. It remains yet unknown, however, how the brain encodes in anticipation the flexible, rich repertoire of novel tasks that we can achieve. Here we explored cognitive control and motivation-related variables that might orchestrate the representational space for novel instructions. Our results showed that different dimensions become relevant for task prospective encoding depending on the brain region, and that the lateral prefrontal cortex simultaneously organized task representations following different control-related variables. Motivation exerted a general modulation upon this process, diminishing rather than increasing distances among instruction representations.

scholarly journals Tracking prototype and exemplar representations in the brain across learning

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Caitlin R Bowman ◽  
Takako Iwashita ◽  
Dagmar Zeithamova
Keyword(s):  
Prefrontal Cortex ◽  
Inferior Frontal Gyrus ◽  
Brain Regions ◽  
Ventromedial Prefrontal Cortex ◽  
Central Tendency ◽  
Final Test ◽  
Single Task ◽  
Multiple Levels ◽  
The Right ◽  
The Brain

There is a long-standing debate about whether categories are represented by individual category members (exemplars) or by the central tendency abstracted from individual members (prototypes). Neuroimaging studies have shown neural evidence for either exemplar representations or prototype representations, but not both. Presently, we asked whether it is possible for multiple types of category representations to exist within a single task. We designed a categorization task to promote both exemplar and prototype representations and tracked their formation across learning. We found only prototype correlates during the final test. However, interim tests interspersed throughout learning showed prototype and exemplar representations across distinct brain regions that aligned with previous studies: prototypes in ventromedial prefrontal cortex and anterior hippocampus and exemplars in inferior frontal gyrus and lateral parietal cortex. These findings indicate that, under the right circumstances, individuals may form representations at multiple levels of specificity, potentially facilitating a broad range of future decisions.

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