scholarly journals The emergence of molecular systems neuroscience

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Yang Shen ◽  
Alessandro Luchetti ◽  
Giselle Fernandes ◽  
Won Do Heo ◽  
Alcino J. Silva
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Spatial And Temporal Patterns ◽  
Molecular Systems ◽  
Systems Neuroscience ◽  
Molecular Approaches ◽  
Electrophysiological Recordings ◽  
Brain States ◽  
And Behavior ◽  
The Brain

AbstractSystems neuroscience is focused on how ensemble properties in the brain, such as the activity of neuronal circuits, gives rise to internal brain states and behavior. Many of the studies in this field have traditionally involved electrophysiological recordings and computational approaches that attempt to decode how the brain transforms inputs into functional outputs. More recently, systems neuroscience has received an infusion of approaches and techniques that allow the manipulation (e.g., optogenetics, chemogenetics) and imaging (e.g., two-photon imaging, head mounted fluorescent microscopes) of neurons, neurocircuits, their inputs and outputs. Here, we will review novel approaches that allow the manipulation and imaging of specific molecular mechanisms in specific cells (not just neurons), cell ensembles and brain regions. These molecular approaches, with the specificity and temporal resolution appropriate for systems studies, promise to infuse the field with novel ideas, emphases and directions, and are motivating the emergence of a molecularly oriented systems neuroscience, a new discipline that studies how the spatial and temporal patterns of molecular systems modulate circuits and brain networks, and consequently shape the properties of brain states and behavior.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

Insights into the molecular basis of host behaviour manipulation by Toxoplasma gondii infection

2017 ◽  
Vol 1 (6) ◽  
pp. 563-572 ◽  
Author(s):  
Pierre-Mehdi Hammoudi ◽  
Dominique Soldati-Favre
Keyword(s):  
Toxoplasma Gondii ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Intermediate Hosts ◽  
Toxoplasma Gondii Infection ◽  
Host Parasite ◽  
Host Behaviour ◽  
The Brain ◽  
Brain Homeostasis

Typically illustrating the ‘manipulation hypothesis’, Toxoplasma gondii is widely known to trigger sustainable behavioural changes during chronic infection of intermediate hosts to enhance transmission to its feline definitive hosts, ensuring survival and dissemination. During the chronic stage of infection in rodents, a variety of neurological dysfunctions have been unravelled and correlated with the loss of cat fear, among other phenotypic impacts. However, the underlying neurological alteration(s) driving these behavioural modifications is only partially understood, which makes it difficult to draw more than a correlation between T. gondii infection and changes in brain homeostasis. Moreover, it is barely known which among the brain regions governing fear and stress responses are preferentially affected during T. gondii infection. Studies aiming at an in-depth dissection of underlying molecular mechanisms occurring at the host and parasite levels will be discussed in this review. Addressing this reminiscent topic in the light of recent technical progress and new discoveries regarding fear response, olfaction and neuromodulator mechanisms could contribute to a better understanding of this complex host–parasite interaction.

scholarly journals Increased sensitivity to strong perturbations in a whole-brain model of LSD

2021 ◽  
Author(s):  
Beatrice M. Jobst ◽  
Selen Atasoy ◽  
Adrián Ponce-Alvarez ◽  
Ana Sanjuán ◽  
Leor Roseman ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
External Perturbation ◽  
Brain Regions ◽  
Lysergic Acid ◽  
Functional Magnetic Resonance ◽  
Resonance Imaging ◽  
Whole Brain ◽  
Response Diversity ◽  
Brain States ◽  
The Brain

AbstractLysergic acid diethylamide (LSD) is a potent psychedelic drug, which has seen a revival in clinical and pharmacological research within recent years. Human neuroimaging studies have shown fundamental changes in brain-wide functional connectivity and an expansion of dynamical brain states, thus raising the question about a mechanistic explanation of the dynamics underlying these alterations. Here, we applied a novel perturbational approach based on a whole-brain computational model, which opens up the possibility to externally perturb different brain regions in silico and investigate differences in dynamical stability of different brain states, i.e. the dynamical response of a certain brain region to an external perturbation. After adjusting the whole-brain model parameters to reflect the dynamics of functional magnetic resonance imaging (fMRI) BOLD signals recorded under the influence of LSD or placebo, perturbations of different brain areas were simulated by either promoting or disrupting synchronization in the regarding brain region. After perturbation offset, we quantified the recovery characteristics of the brain area to its basal dynamical state with the Perturbational Integration Latency Index (PILI) and used this measure to distinguish between the two brain states. We found significant changes in dynamical complexity with consistently higher PILI values after LSD intake on a global level, which indicates a shift of the brain’s global working point further away from a stable equilibrium as compared to normal conditions. On a local level, we found that the largest differences were measured within the limbic network, the visual network and the default mode network. Additionally, we found a higher variability of PILI values across different brain regions after LSD intake, indicating higher response diversity under LSD after an external perturbation. Our results provide important new insights into the brain-wide dynamical changes underlying the psychedelic state - here provoked by LSD intake - and underline possible future clinical applications of psychedelic drugs in particular psychiatric disorders.HighlightsNovel offline perturbational method applied on functional magnetic resonance imaging (fMRI) data under the effect of lysergic acid diethylamide (LSD)Shift of brain’s global working point to more complex dynamics after LSD intakeConsistently longer recovery time after model perturbation under LSD influenceStrongest effects in resting state networks relevant for psychedelic experienceHigher response diversity across brain regions under LSD influence after an external in silico perturbation

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceicao Bettencourt ◽  
Tammaryn Lashley ◽  
Pietro Fratta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Lobar Degeneration ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Temporal Cortex ◽  
Neuronal Loss ◽  
Underlying Disease ◽  
Brain Regions ◽  
Neuronal Markers ◽  
The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

scholarly journals The Maternal Brain: An Organ with Peripartal Plasticity

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Katharina Maria Hillerer ◽  
Volker Rudolf Jacobs ◽  
Thorsten Fischer ◽  
Ludwig Aigner
Keyword(s):  
Mental Health ◽  
Synaptic Plasticity ◽  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Tight Control ◽  
Maternal Brain ◽  
Pregnancy And Lactation ◽  
Underlying Mechanisms ◽  
And Behavior

The time of pregnancy, birth, and lactation, is characterized by numerous specific alterations in several systems of the maternal body. Peripartum-associated changes in physiology and behavior, as well as their underlying molecular mechanisms, have been the focus of research since decades, but are still far from being entirely understood. Also, there is growing evidence that pregnancy and lactation are associated with a variety of alterations in neural plasticity, including adult neurogenesis, functional and structural synaptic plasticity, and dendritic remodeling in different brain regions. All of the mentioned changes are not only believed to be a prerequisite for the proper fetal and neonatal development, but moreover to be crucial for the physiological and mental health of the mother. The underlying mechanisms apparently need to be under tight control, since in cases of dysregulation, a certain percentage of women develop disorders like preeclampsia or postpartum mood and anxiety disorders during the course of pregnancy and lactation. This review describes common peripartum adaptations in physiology and behavior. Moreover, it concentrates on different forms of peripartum-associated plasticity including changes in neurogenesis and their possible underlying molecular mechanisms. Finally, consequences of malfunction in those systems are discussed.

scholarly journals Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

2020 ◽  
Author(s):  
Li Niu ◽  
Shiming Yang ◽  
Weixi Wang ◽  
Cui-fang Ye ◽  
He Li
Keyword(s):  
Molecular Mechanisms ◽  
Early Stage ◽  
Brain Regions ◽  
Zinc Level ◽  
Significant Loss ◽  
Zinc Homeostasis ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Bhk Cells ◽  
The Brain

Abstract Background Synaptic dysfunction caused by mutant huntingtin greatly contributes to Huntington’s disease (HD) pathogenesis. HD patients show cognitive impairment as well as uncontrolled movements. Vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. However, whether does mutant huntingtin affect zinc homeostasis in the brain or not? This will be of great significance for further revealing the pathogenesis of HD. Methods N171-HD82Q transgenic mice and cultured BHK cells expressing N-terminal mutant huntingtin fragment containing 160 glutamines (160Q BHK cells) were used to investigate the effect of mutant huntingtin on zinc homeostasis and its molecular mechanisms. Results Herein, we have demonstrated that the density of synaptic vesicular zinc decreases in the cortex, striatum and hippocampus of N171-82Q mice. Given that vesicular zinc concentration depends on the abundance of zinc transporter 3 (ZnT3) on the membrane of synaptic vesicles, ZnT3 expression is detected in the brain of N171-82Q mice and 160Q BHK cells. Mutant huntingtin leads to a dramatical decrease in ZnT3 mRNA and protein levels in the three brain regions of these mice aged from 14 to 20 weeks. Significantly, Sp1 activates ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Nevertheless, mutant huntingtin inhibits the binding of Sp1 to the promoter of ZnT3 gene and down-regulates ZnT3 expression. Furthermore, the overexpression of Sp1 ameliorates inhibition of ZnT3 gene transcription by mutant huntingtin. Conclusions Collectively, this first study to reveal a significant loss of synaptic vesicular zinc and ZnT3 expression caused by mutant huntingtin in the early stage of HD. Our findings have revealed the molecular mechanism underlying this change. Mutant huntingtin inhibits the binding of Sp1 to ZnT3 gene promoter to reduce ZnT3 expression. The imbalance of vesicular zinc homeostasis may be closely associated with synaptic dysfunction and cognitive deficits in HD. This work sheds novel mechanistic insights into the pathogenesis of HD and promises a potential therapeutic strategy for HD.

scholarly journals Drosophila as a Model for Microbiota Studies of Neurodegeneration

2021 ◽  
pp. 1-12
Author(s):  
Fukiko Kitani-Morii ◽  
Robert P. Friedland ◽  
Hideki Yoshida ◽  
Toshiki Mizuno
Keyword(s):  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
Environmental Changes ◽  
Fruit Fly ◽  
Endocrine Regulation ◽  
Nutrient Metabolism ◽  
Host Health ◽  
And Behavior ◽  
The Brain ◽  
Lateral Sclerosis

Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly’s gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.

scholarly journals Macroscopic quantities of collective brain activity during wakefulness and anesthesia

2021 ◽  
Author(s):  
Adrián Ponce-Alvarez ◽  
Lynn Uhrig ◽  
Nikolas Deco ◽  
Camilo M. Signorelli ◽  
Morten L. Kringelbach ◽  
...  
Keyword(s):  
Brain Activity ◽  
Brain Regions ◽  
Brain State ◽  
Loss Of Consciousness ◽  
Information Theoretic ◽  
Maximum Entropy Models ◽  
Information Theoretic Measures ◽  
Brain States ◽  
Parietal Cortices ◽  
The Brain

AbstractThe study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. Using maximum entropy models, we derived collective, macroscopic properties that quantify the system’s capabilities to produce work, to contain information and to transmit it, and that indicate a phase transition from critical awake dynamics to supercritical anesthetized states. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in brain state and in state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.

The somatic error hypothesis of anxiety

2018 ◽  
Author(s):  
Sahib S. Khalsa ◽  
Justin S. Feinstein
Keyword(s):  
Central Nervous System ◽  
Physiological State ◽  
Brain Regions ◽  
Novel Therapies ◽  
Body State ◽  
Long Term Changes ◽  
The Central Nervous System ◽  
And Behavior ◽  
The Brain

A regulatory battle for control ensues in the central nervous system following a mismatch between the current physiological state of an organism as mapped in viscerosensory brain regions and the predicted body state as computed in visceromotor control regions. The discrepancy between the predicted and current body state (i.e. the “somatic error”) signals a need for corrective action, motivating changes in both cognition and behavior. This chapter argues that anxiety disorders are fundamentally driven by somatic errors that fail to be adaptively regulated, leaving the organism in a state of dissonance where the predicted body state is perpetually out of line with the current body state. Repeated failures to quell somatic error can result in long-term changes to interoceptive circuitry within the brain. This chapter explores the neuropsychiatric sequelae that can emerge following chronic allostatic dysregulation of somatic errors and discusses novel therapies that might help to correct this dysregulation.

How Stress Physically Re-shapes the Brain: Impact on Brain Cell Shapes, Numbers and Connections in Psychiatric Disorders

2019 ◽  
Author(s):  
Dominic Kaul ◽  
Sibylle Schwab ◽  
Naguib Mechawar ◽  
Natalie Matosin
Keyword(s):  
Psychiatric Disorders ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Brain Cell ◽  
Intervention Strategies ◽  
Traumatic Experiences ◽  
Brain Pathology ◽  
Cell Shapes ◽  
Brain Circuitry ◽  
The Brain

Exposure to stressful or traumatic experiences is one of the most robust risk factors for severe psychiatric disorders and has been shown to reshape entire brain regions, especially those involved in processing the stress response. This is likely underpinned by alterations to brain cell shapes, numbers and their connections, thus changing brain circuitry to enable coping with the current and future stress. In this review, we present a model for how stress re-shapes the brain, consolidating evidence of morphometric changes and the cellular and molecular mechanisms that underlie them. We illustrate how the temporal effects of stress can cause persistent remodelling of brain cells, highlighting that an individual's stress history is important for understanding psychiatric disorder risk and development. Understanding how stress re-shapes the brain is a critical step for understanding stress as a risk factor for brain pathology, and to develop appropriate biomarkers, treatments and intervention strategies.

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