scholarly journals Epigenetic signaling in psychiatric disorders: stress and depression

2014 ◽  
Vol 16 (3) ◽  
pp. 281-295 ◽  
Keyword(s):  
Environmental Factors ◽  
Psychiatric Disorders ◽  
Neural Circuit ◽  
Brain Regions ◽  
Transcriptional Dysregulation ◽  
Epigenetic Machinery ◽  
Multifactorial Disorders ◽  
As Stress ◽  
And Function ◽  
Circuit Function

Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. Insults at the developmental stage and in adulthood appear to induce distinct maladaptations. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. Understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.

Epigenetic basis of psychiatric disorders: a narrative review

2021 ◽  
Vol 20 ◽  
Author(s):  
Fabio Panariello ◽  
Giuseppe Fanelli ◽  
Chiara Fabbri ◽  
Anna Rita Atti ◽  
Diana De Ronchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Environmental Factors ◽  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Neural Circuit ◽  
Expression Patterns ◽  
Brain Regions ◽  
Epigenetic Modifications ◽  
Cochrane Library ◽  
Specific Gene

Background: Psychiatric disorders are complex, multifactorial illnesses with a demonstrated biological component in their etiopathogenesis. Epigenetic modifications, through the modulation of DNA methylation, histone modifications and RNA interference, tune tissue-specific gene expression patterns and play a relevant role in the etiology of psychiatric illnesses. Objective: This review aims to discuss the epigenetic mechanisms involved in psychiatric disorders, their modulation by environmental factors and their interactions with genetic variants, in order to provide a comprehensive picture of their mutual crosstalk. Methods: In accordance with the PRISMA guidelines, systematic searches of Medline, EMBASE, PsycINFO, Web of Science, Scopus, and the Cochrane Library were conducted. Results: Exposure to environmental factors, such as poor socio-economic status, obstetric complications, migration, and early life stressors, may lead to stable changes in gene expression and neural circuit function, playing a role in the risk of psychiatric diseases. The most replicated genes involved by studies using different techniques are discussed. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions and they interact with genetic variants in determining the risk of psychiatric disorders. Conclusion: An increasing amount of evidence suggests that epigenetics plays a pivotal role in the etiopathogenesis of psychiatric disorders. New therapeutic approaches may work by reversing detrimental epigenetic changes that occurred during the lifespan.

scholarly journals Zebrafish Dscaml1 is Essential for Retinal Patterning and Function of Oculomotor Subcircuits

2019 ◽  
Author(s):  
Manxiu Ma ◽  
Alexandro D. Ramirez ◽  
Tong Wang ◽  
Rachel L. Roberts ◽  
Katherine E. Harmon ◽  
...  
Keyword(s):  
Animal Model ◽  
Light Adaptation ◽  
Neural Circuit ◽  
Oculomotor System ◽  
Gaze Stabilization ◽  
Ocular Disorders ◽  
Motor Apraxia ◽  
Premotor Pathways ◽  
And Function ◽  
Circuit Function

AbstractDown Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the role of dscaml1 in the zebrafish oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Loss of zebrafish dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses showed that mutants have abnormal gaze stabilization, impaired fixation, disconjugation, and faster fatigue. Notably, the saccade and fatigue phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, for which no animal model exists. Two-photon calcium imaging showed that loss of dscaml1 leads to impairment in the saccadic premotor pathway but not the pretectum-vestibular premotor pathway, indicating a subcircuit requirement for dscaml1. Together, we show that dscaml1 has both broad and specific roles in oculomotor circuit function, providing a new animal model to investigate the development of premotor pathways and their associated human ocular disorders.

scholarly journals Cytosolic PSD-95 Interactor Alters Functional Organization of Neural Circuits and AMPA Receptor Signaling Independent of PSD-95 Binding

2020 ◽  
pp. 1-72
Author(s):  
Ana R. Rodriguez ◽  
Erin D. Anderson ◽  
Kate M. O’Neill ◽  
Przemyslaw P. McEwan ◽  
Nicholas F. Vigilante ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Microelectrode Array ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Functional Organization ◽  
Protein Localization ◽  
Postsynaptic Density ◽  
Brain Regions ◽  
Receptor Signaling ◽  
And Function

Cytosolic PSD-95 interactor (cypin) regulates many aspects of neuronal development and function, ranging from dendritogenesis to synaptic protein localization. While it is known that removal of postsynaptic density protein-95 (PSD-95) from the postsynaptic density decreases synaptic NMDA receptors and that cypin overexpression protects neurons from NMDA-induced toxicity, little is known about cypin’s role in AMPA receptor clustering and function. Experimental work shows that cypin overexpression decreases PSD-95 levels in synaptosomes and the PSD, decreases PSD-95 clusters/μm2, and increases mEPSC frequency. Analysis of microelectrode array (MEA) data demonstrates that cypin or cypinΔPDZ overexpression increases sensitivity to CNQX and AMPA receptor mediated decreases in spike waveform properties. Network-level analysis of MEA data reveals that cypinΔPDZ overexpression causes networks to be resilient to CNQX-induced changes in local efficiency. Incorporating these findings into a computational model of a neural circuit demonstrates a role for AMPA receptors in cypin-promoted changes to networks and shows that cypin increases firing rate while changing network functional organization, suggesting cypin overexpression facilitates information relay but modifies how information is encoded among brain regions. Our data show that cypin promotes changes to AMPA receptor signaling independent of PSD-95 binding, shaping neural circuits and output to regions beyond the hippocampus.

scholarly journals Cellular diversity in the Drosophila midbrain revealed by single-cell transcriptomics

2017 ◽  
Author(s):  
Vincent Croset ◽  
Christoph D Treiber ◽  
Scott Waddell
Keyword(s):  
Single Cell ◽  
Neural Circuit ◽  
Cell Types ◽  
Brain Regions ◽  
Neurotransmitter Receptor ◽  
Neural Processes ◽  
Subunit Expression ◽  
Circuit Function ◽  
Fast Acting ◽  
The Brain

AbstractTo understand the brain, molecular details need to be overlaid onto neural wiring diagrams so that synaptic mode, neuromodulation and critical signaling operations can be considered. Single-cell transcriptomics provide a unique opportunity to collect this information. Here we present an initial analysis of thousands of individual cells from Drosophila midbrain, that were acquired using Drop-Seq. A number of approaches permitted the assignment of transcriptional profiles to several major brain regions and cell-types. Expression of biosynthetic enzymes and reuptake mechanisms allows all the neurons to be typed according to the neurotransmitter or neuromodulator that they produce and presumably release. Some neuropeptides are preferentially co-expressed in neurons using a particular fast-acting transmitter, or monoamine. Neuromodulatory and neurotransmitter receptor subunit expression illustrates the potential of these molecules in generating complexity in neural circuit function. This cell atlas dataset provides an important resource to link molecular operations to brain regions and complex neural processes.

scholarly journals Cellular diversity in the Drosophila midbrain revealed by single-cell transcriptomics

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Vincent Croset ◽  
Christoph D Treiber ◽  
Scott Waddell
Keyword(s):  
Single Cell ◽  
Neural Circuit ◽  
Cell Types ◽  
Brain Regions ◽  
Neurotransmitter Receptor ◽  
Neural Processes ◽  
Subunit Expression ◽  
Circuit Function ◽  
Fast Acting ◽  
The Brain

To understand the brain, molecular details need to be overlaid onto neural wiring diagrams so that synaptic mode, neuromodulation and critical signaling operations can be considered. Single-cell transcriptomics provide a unique opportunity to collect this information. Here we present an initial analysis of thousands of individual cells from Drosophila midbrain, that were acquired using Drop-Seq. A number of approaches permitted the assignment of transcriptional profiles to several major brain regions and cell-types. Expression of biosynthetic enzymes and reuptake mechanisms allows all the neurons to be typed according to the neurotransmitter or neuromodulator that they produce and presumably release. Some neuropeptides are preferentially co-expressed in neurons using a particular fast-acting transmitter, or monoamine. Neuromodulatory and neurotransmitter receptor subunit expression illustrates the potential of these molecules in generating complexity in neural circuit function. This cell atlas dataset provides an important resource to link molecular operations to brain regions and complex neural processes.

scholarly journals Extreme stiffness of neuronal synapses and implications for synaptic adhesion and plasticity

2020 ◽  
Author(s):  
Ju Yang ◽  
Nicola Mandriota ◽  
Steven Glenn Harrellson ◽  
John Anthony Jones-Molina ◽  
Rafael Yuste ◽  
...  
Keyword(s):  
Structural Changes ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Critical Role ◽  
Theoretical Models ◽  
Cell Types ◽  
Long Term Potentiation ◽  
Biophysical Model ◽  
And Function ◽  
Circuit Function

AbstractSynapses play a critical role in neural circuits, and they are potential sites for learning and memory. Maintenance of synaptic adhesion is critical for neural circuit function, however, biophysical mechanisms that help maintain synaptic adhesion are not clear. Studies with various cell types demonstrated the important role of stiffness in cellular adhesions. Although synaptic stiffness could also play a role in synaptic adhesion, stiffnesses of synapses are difficult to characterize due to their small size and challenges in verifying synapse identity and function. To address these challenges, we have developed an experimental platform that combines atomic force microscopy, fluorescence microscopy, and transmission electron microscopy. Here, using this platform, we report that functional, mature, excitatory synapses had an average elastic modulus of approximately 200 kPa, two orders of magnitude larger than that of the brain tissue, suggesting stiffness might have a role in synapse function. Similar to various functional and anatomical features of neural circuits, synaptic stiffness had a lognormal-like distribution, hinting a possible regulation of stiffness by processes involved in neural circuit function. In further support of this possibility, we observed that synaptic stiffness was correlated with spine size, a quantity known to correlate with synaptic strength. Using established stages of the long-term potentiation timeline and theoretical models of adhesion cluster dynamics, we developed a biophysical model of the synapse that not only explains extreme stiffness of synapses, their statistical distribution, and correlation with spine size, but also offers an explanation to how early biomolecular and structural changes during functional potentiation could lead to strengthening of synaptic adhesion. According to this model, synaptic stiffness serves as an indispensable physical messenger, feeding information back to synaptic adhesion molecules to facilitate maintenance of synaptic adhesion.

scholarly journals The connectome predicts resting state functional connectivity across the Drosophila brain

2020 ◽  
Author(s):  
Maxwell H Turner ◽  
Kevin Mann ◽  
Thomas R. Clandinin
Keyword(s):  
Functional Connectivity ◽  
Large Scale ◽  
Neural Circuit ◽  
Brain Networks ◽  
Brain Regions ◽  
Central Complex ◽  
Resting State Functional Connectivity ◽  
Brain Structure And Function ◽  
And Function

Connectomic datasets have emerged as invaluable tools for understanding neural circuits in many systems. What constraints does the connectome place on information processing and routing in a large scale neural circuit? For mesoscale brain networks, the relationship between cell and synaptic level connectivity and brain function is not well understood. Here, we use data from the Drosophila connectome in conjunction with whole-brain in vivo imaging to relate structural and functional connectivity in the central brain. We find that functional connectivity is strongly associated with the strength of both direct and indirect anatomical pathways. We also show that some brain regions, including the mushroom body and central complex, show considerably higher functional connectivity to other brain regions than is predicted based on their direct anatomical connections. We find several key topological similarities between mesoscale brain networks in flies and mammals, revealing conserved principles relating brain structure and function.

In Vivo Circuit Analysis

2017 ◽  
Author(s):  
Ryan Bowman ◽  
Hannah Schwennesen ◽  
Kafui Dzirasa ◽  
Rainbo Hultman
Keyword(s):  
Side Effects ◽  
Animal Models ◽  
Psychiatric Disorders ◽  
Neural Circuit ◽  
Brain Regions ◽  
Therapeutic Strategies ◽  
Dynamic Activity ◽  
Wide Range

Breakthroughs in understanding neural circuit activity hold much promise for developing next generation therapeutics for psychiatric disorders. Determination of how dynamic activity is coordinated across brain regions to effect specific behavioral function (or dysfunction) enables the development of therapeutics with increased specificity and fewer side effects. This chapter discusses methodologies for measuring neural circuit activity in humans and in animal models, and describes a bidirectional research pipeline whereby studies in humans are followed by tightly controlled studies in animal models that can then be applied back to humans. Targeted neural circuit manipulations from these studies are already being applied to a wide range of therapeutic strategies.

scholarly journals Regulation of Central Nervous System Myelination in Higher Brain Functions

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Mara Nickel ◽  
Chen Gu
Keyword(s):  
Prefrontal Cortex ◽  
Neural Plasticity ◽  
Lipid Membranes ◽  
Neural Circuit ◽  
Brain Regions ◽  
Research Field ◽  
Brain Functions ◽  
Experimental Systems ◽  
And Function ◽  
Higher Brain Functions

The hippocampus and the prefrontal cortex are interconnected brain regions, playing central roles in higher brain functions, including learning and memory, planning complex cognitive behavior, and moderating social behavior. The axons in these regions continue to be myelinated into adulthood in humans, which coincides with maturation of personality and decision-making. Myelin consists of dense layers of lipid membranes wrapping around the axons to provide electrical insulation and trophic support and can profoundly affect neural circuit computation. Recent studies have revealed that long-lasting changes of myelination can be induced in these brain regions by experience, such as social isolation, stress, and alcohol abuse, as well as by neurological and psychiatric abnormalities. However, the mechanism and function of these changes remain poorly understood. Myelin regulation represents a new form of neural plasticity. Some progress has been made to provide new mechanistic insights into activity-independent and activity-dependent regulations of myelination in different experimental systems. More extensive investigations are needed in this important but underexplored research field, in order to shed light on how higher brain functions and myelination interplay in the hippocampus and prefrontal cortex.

scholarly journals Foraging with the frontal cortex: A cross-species evaluation of reward-guided behavior

2021 ◽  
Author(s):  
Peter H. Rudebeck ◽  
Alicia Izquierdo
Keyword(s):  
Animal Models ◽  
Frontal Cortex ◽  
Psychiatric Disorders ◽  
Similarities And Differences ◽  
And Function ◽  
Future Work ◽  
Intense Debate

AbstractEfficient foraging is essential to survival and depends on frontal cortex in mammals. Because of its role in psychiatric disorders, frontal cortex and its contributions to reward procurement have been studied extensively in both rodents and non-human primates. How frontal cortex of these animal models compares is a source of intense debate. Here we argue that translating findings from rodents to non-human primates requires an appreciation of both the niche in which each animal forages as well as the similarities in frontal cortex anatomy and function. Consequently, we highlight similarities and differences in behavior and anatomy, before focusing on points of convergence in how parts of frontal cortex contribute to distinct aspects of foraging in rats and macaques, more specifically. In doing so, our aim is to emphasize where translation of frontal cortex function between species is clearer, where there is divergence, and where future work should focus. We finish by highlighting aspects of foraging for which have received less attention but we believe are critical to uncovering how frontal cortex promotes survival in each species.

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