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

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.

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Epigenetic signaling in psychiatric disorders: stress and depression

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2014.16.3/rbagot ◽

2014 ◽

Vol 16 (3) ◽

pp. 281-295 ◽

Cited By ~ 32

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.

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

10.1101/2020.08.31.273466 ◽

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.

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Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

Current Developments in Nutrition ◽

10.1093/cdn/nzaa155 ◽

2020 ◽

Vol 4 (11) ◽

Author(s):

Katherine M Ranard ◽

Matthew J Kuchan ◽

John W Erdman

Keyword(s):

Animal Model ◽

Vitamin E ◽

Mouse Model ◽

Wild Type ◽

Future Studies ◽

Neurological Outcomes ◽

Transfer Protein ◽

And Function ◽

The Brain ◽

Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

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Neural circuit function redundancy in brain disorders

Current Opinion in Neurobiology ◽

10.1016/j.conb.2021.07.008 ◽

2021 ◽

Vol 70 ◽

pp. 74-80

Author(s):

Beatriz E.P. Mizusaki ◽

Cian O'Donnell

Keyword(s):

Neural Circuit ◽

Brain Disorders ◽

Circuit Function

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Aberrant information transfer interferes with functional axon regeneration

eLife ◽

10.7554/elife.38829 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

Chen Ding ◽

Marc Hammarlund

Keyword(s):

Information Transfer ◽

Synapse Formation ◽

Axon Regeneration ◽

Behavioral Recovery ◽

Axon Injury ◽

Functional Regeneration ◽

Key Variables ◽

And Function ◽

Circuit Function ◽

Molecular Components

Functional axon regeneration requires regenerating neurons to restore appropriate synaptic connectivity and circuit function. To model this process, we developed an assay in Caenorhabditis elegans that links axon and synapse regeneration of a single neuron to recovery of behavior. After axon injury and regeneration of the DA9 neuron, synapses reform at their pre-injury location. However, these regenerated synapses often lack key molecular components. Further, synaptic vesicles accumulate in the dendrite in response to axon injury. Dendritic vesicle release results in information misrouting that suppresses behavioral recovery. Dendritic synapse formation depends on dynein and jnk-1. But even when information transfer is corrected, axonal synapses fail to adequately transmit information. Our study reveals unexpected plasticity during functional regeneration. Regeneration of the axon is not sufficient for the reformation of correct neuronal circuits after injury. Rather, synapse reformation and function are also key variables, and manipulation of circuit reformation improves behavioral recovery.

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Neural contributors to trauma resilience: a review of longitudinal neuroimaging studies

Translational Psychiatry ◽

10.1038/s41398-021-01633-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alyssa R. Roeckner ◽

Katelyn I. Oliver ◽

Lauren A. M. Lebois ◽

Sanne J. H. van Rooij ◽

Jennifer S. Stevens

Keyword(s):

Individual Differences ◽

Neural Circuit ◽

Major Life ◽

Stress Resilience ◽

Control Networks ◽

The Face ◽

Sensory Cortices ◽

Life Stressor ◽

Threat Cues ◽

And Function

AbstractResilience in the face of major life stressors is changeable over time and with experience. Accordingly, differing sets of neurobiological factors may contribute to an adaptive stress response before, during, and after the stressor. Longitudinal studies are therefore particularly effective in answering questions about the determinants of resilience. Here we provide an overview of the rapidly-growing body of longitudinal neuroimaging research on stress resilience. Despite lingering gaps and limitations, these studies are beginning to reveal individual differences in neural circuit structure and function that appear protective against the emergence of future psychopathology following a major life stressor. Here we outline a neural circuit model of resilience to trauma. Specifically, pre-trauma biomarkers of resilience show that an ability to modulate activity within threat and salience networks predicts fewer stress-related symptoms. In contrast, early post-trauma biomarkers of subsequent resilience or recovery show a more complex pattern, spanning a number of major circuits including attention and cognitive control networks as well as primary sensory cortices. This novel synthesis suggests stress resilience may be scaffolded by stable individual differences in the processing of threat cues, and further buttressed by post-trauma adaptations to the stressor that encompass multiple mechanisms and circuits. More attention and resources supporting this work will inform the targets and timing of mechanistic resilience-boosting interventions.

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Quantitative synapse analysis for cell-type specific connectomics

10.1101/386912 ◽

2018 ◽

Author(s):

Dika A. Kuljis ◽

Khaled Zemoura ◽

Cheryl A. Telmer ◽

Jiseok Lee ◽

Eunsol Park ◽

...

Keyword(s):

Large Scale ◽

Neural Circuit ◽

Apical Dendrite ◽

Automated Detection ◽

Cell Type ◽

Disease States ◽

Specific Localization ◽

Cell Type Specific ◽

Dendritic Branches ◽

Circuit Function

AbstractAnatomical methods for determining cell-type specific connectivity are essential to inspire and constrain our understanding of neural circuit function. We developed new genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue, using a fluorogen-activating protein (FAP)-or YFP-coupled, postsynaptically-localized neuroligin-1 targeting sequence (FAP/YFPpost). Sparse viral expression of FAP/YFPpost with the cell-filling, red fluorophore dTomato (dTom) enabled high-throughput, compartment-specific localization of synapses across diverse neuron types in mouse somatosensory cortex. High-resolution confocal image stacks of virally-transduced neurons were used for 3D reconstructions of postsynaptic cells and automated detection of synaptic puncta. We took advantage of the bright, far-red emission of FAPpost puncta for multichannel fluorescence alignment of dendrites, synapses, and presynaptic neurites to assess subtype-specific inhibitory connectivity onto L2 neocortical pyramidal (Pyr) neurons. Quantitative and compartment-specific comparisons show that PV inputs are the dominant source of inhibition at both the soma and across all dendritic branches examined and were particularly concentrated at the primary apical dendrite, a previously unrecognized compartment of L2 Pyr neurons. Our fluorescence-based synapse labeling reagents will facilitate large-scale and cell-type specific quantitation of changes in synaptic connectivity across development, learning, and disease states.

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Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons

eLife ◽

10.7554/elife.22234 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 15

Author(s):

Catherine M Drerup ◽

Amy L Herbert ◽

Kelly R Monk ◽

Alex V Nechiporuk

Keyword(s):

Neural Circuit ◽

Genetic Interaction ◽

Retrograde Transport ◽

Genetic Screen ◽

Binding Domain ◽

Loss Of Function ◽

Mitochondrial Transport ◽

Interaction Studies ◽

Mitochondrial Motility ◽

And Function

Mitochondrial transport in axons is critical for neural circuit health and function. While several proteins have been found that modulate bidirectional mitochondrial motility, factors that regulate unidirectional mitochondrial transport have been harder to identify. In a genetic screen, we found a zebrafish strain in which mitochondria fail to attach to the dynein retrograde motor. This strain carries a loss-of-function mutation in actr10, a member of the dynein-associated complex dynactin. The abnormal axon morphology and mitochondrial retrograde transport defects observed in actr10 mutants are distinct from dynein and dynactin mutant axonal phenotypes. In addition, Actr10 lacking the dynactin binding domain maintains its ability to bind mitochondria, arguing for a role for Actr10 in dynactin-mitochondria interaction. Finally, genetic interaction studies implicated Drp1 as a partner in Actr10-dependent mitochondrial retrograde transport. Together, this work identifies Actr10 as a factor necessary for dynactin-mitochondria interaction, enhancing our understanding of how mitochondria properly localize in axons.

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