scholarly journals Long-range interhemispheric projection neurons show biased response properties and fine-scale local subnetworks in mouse visual cortex

2019 ◽  
Author(s):  
Kenta M. Hagihara ◽  
Ayako W. Ishikawa ◽  
Yumiko Yoshimura ◽  
Yoshiaki Tagawa ◽  
Kenichi Ohki
Keyword(s):  
Long Range ◽  
Brain Regions ◽  
Projection Neurons ◽  
Fine Scale ◽  
Local Connectivity ◽  
Cortical Projection ◽  
Response Properties ◽  
Brain Functions ◽  
Mouse Visual Cortex

SummaryIntegration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral eye (with respect to their somata) preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons.

scholarly journals Long-Range Interhemispheric Projection Neurons Show Biased Response Properties and Fine-Scale Local Subnetworks in Mouse Visual Cortex

2020 ◽  
Author(s):  
Kenta M Hagihara ◽  
Ayako Wendy Ishikawa ◽  
Yumiko Yoshimura ◽  
Yoshiaki Tagawa ◽  
Kenichi Ohki
Keyword(s):  
Visual Cortex ◽  
Long Range ◽  
Projection Neurons ◽  
Fine Scale ◽  
Local Connectivity ◽  
Cortical Projection ◽  
Response Properties ◽  
Brain Functions ◽  
Mouse Visual Cortex

Abstract Integration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) in layer 2/3 of the mouse visual cortex as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral (to their somata) eye preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons.

scholarly journals An evolutionarily acquired microRNA shapes development of mammalian cortical projections

2020 ◽  
Author(s):  
Jessica L Diaz ◽  
Verl B Siththanandan ◽  
Victoria Lu ◽  
Nicole Gonzalez-Nava ◽  
Lincoln Pasquina ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Cognitive Skills ◽  
Corticospinal Tract ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Complex Motor ◽  
Callosal Projection ◽  
Cortical Projection Neuron

AbstractThe corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are co-expressed across multiple projection neuron subtypes. Here, we discover seventeen CSMN-enriched microRNAs (miRNAs), fifteen of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is the first demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians’ increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.Significance StatementThe mammalian central nervous system contains unique projections from the cerebral cortex thought to underpin complex motor and cognitive skills, including the corticospinal tract and corpus callosum. The neurons giving rise to these projections - corticospinal and callosal projection neurons - develop from the same progenitors, but acquire strikingly different fates. The broad evolutionary conservation of known genes controlling cortical projection neuron fates raises the question of how the more narrowly conserved corticospinal and callosal projections evolved. We identify a microRNA cluster selectively expressed by corticospinal projection neurons and exclusive to placental mammals. One of these microRNAs promotes corticospinal fate via regulation of the callosal gene LMO4, suggesting a mechanism whereby microRNA regulation during development promotes evolution of neuronal diversity.

scholarly journals A Modeling Study Suggesting a Possible Pharmacological Target to Mitigate the Effects of Ethanol on Reward-Related Dopaminergic Signaling

2008 ◽  
Vol 99 (5) ◽  
pp. 2703-2707 ◽  
Author(s):  
Michele Migliore ◽  
Claudio Cannia ◽  
Carmen C. Canavier
Keyword(s):  
Dopaminergic Neurons ◽  
Temporal Structure ◽  
Ionic Current ◽  
Brain Regions ◽  
Point Of View ◽  
Dopamine Level ◽  
Addictive Behaviors ◽  
Brain Functions

Midbrain dopaminergic neurons are involved in several critical brain functions controlling goal-directed behaviors, reinforcing/reward processes, and motivation. Their dysfunctions alter dopamine release and contribute to a vast range of neural disorders, from Parkinson's disease to schizophrenia and addictive behaviors. These neurons have thus been a natural target of pharmacological treatments trying to ameliorate the consequences of several neuropathologies. From this point of view, a clear experimental link has been recently established between the increase in the pacemaker frequency of dopaminergic neurons in vitro after acute ethanol application and a particular ionic current ( Ih). The functional consequences in vivo, however, are not clear and they are very difficult to explore experimentally. Here we use a realistic computational model of dopaminergic neurons in vivo to suggest that ethanol, through its effects on Ih, modifies the temporal structure of the spiking activity. The model predicts that the dopamine level may increase much more during bursting than during pacemaking activity, especially in those brain regions with a slow dopamine clearance rate. The results suggest that a selective pharmacological remedy could thus be devised against the rewarding effects of ethanol that are postulated to mediate alcohol abuse and addiction, targeting the specific HCN genes expressed in dopaminergic neurons.

scholarly journals Prefrontal somatostatin interneurons encode fear memory

2019 ◽  
Author(s):  
Kirstie A. Cummings ◽  
Roger L. Clem
Keyword(s):  
Specific Activity ◽  
Conditioned Fear ◽  
Gain Control ◽  
Brain Regions ◽  
Fear Learning ◽  
Causal Mechanism ◽  
Projection Neurons ◽  
Synaptic Organization ◽  
Cortical Projection ◽  
Output Neurons

AbstractTheories stipulate that memories are encoded within networks of cortical projection neurons (PNs). Conversely, GABAergic interneurons (INs) are thought to function primarily to inhibit PNs and thereby impose network gain control, an important but purely modulatory role. However, we found that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex (mPFC) somatostatin interneurons (SST-INs), and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST- and parvalbumin (PV)-INs provides a potential circuit basis for SST-IN-evoked disinhibition of mPFC output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that rather than constrain mnemonic processing, potentiation of SST-IN activity represents an important causal mechanism for conditioned fear.

scholarly journals Developmental stage-specific patterned activity contributes to callosal axon projections

2021 ◽  
Author(s):  
Yuta Tezuka ◽  
Kenta M Hagihara ◽  
Kenichi Ohki ◽  
Tomoo Hirano ◽  
Yoshiaki Tagawa
Keyword(s):  
Developmental Stage ◽  
Long Range ◽  
Distinct Pattern ◽  
Network Activity ◽  
Genetic Method ◽  
Axonal Projections ◽  
Developing Neocortex ◽  
Mouse Visual Cortex ◽  
Activity Dependent

The developing neocortex exhibits patterned spontaneous network activity with various synchrony levels. However, the role of such activity in the formation of cortical circuits remains unclear. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that spontaneous cortical network activity contributes to the region- and lamina-specific projections of callosal axons in the mouse visual cortex and that this process has a critical period: restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo imaging revealed that less correlated network activity was critical. Together, our findings suggest that a distinct pattern of spontaneous network activity in a specific developmental stage underlies the formation of long-range axonal projections in the developing neocortex.

scholarly journals Angle-Tuned Coils: Enabling Building Blocks for High Performance and Multisite TMS Systems

2021 ◽  
Author(s):  
Hedyeh Bagherzadeh ◽  
QINGLEI MENG ◽  
Zhi-De Deng ◽  
Hanbing Lu ◽  
Elliott Hong ◽  
...  
Keyword(s):  
Electric Field ◽  
Composite Structures ◽  
High Performance ◽  
Near Field ◽  
Building Blocks ◽  
Brain Regions ◽  
Brain Functions ◽  
Surface Areas ◽  
Head Surface

Objective: A novel angle-tuned ring coil is proposed for improving the depth-spread performance of Transcranial Magnetic Stimulation (TMS) coils and serve as the building blocks for high-performance composite coils and multisite TMS systems. Approach: Improving depth-spread performance by reducing field divergence through creating a more elliptical emitted field distribution from the coil. To accomplish that, instead of enriching the Fourier components along the planarized (x-y) directions, which requires different arrays to occupy large brain surface areas, we worked along the radial (z) direction by using tilted coil angles and stacking coil numbers to reduce the divergence of the emitted near field without occupying large head surface areas. The emitted electric field distributions were theoretically simulated in spherical and real human head models to analyze the depth-spread performance of proposed coils and compare with existing figure-8 coils. The results were then experimentally validated with field probes and in-vivo animal tests. Main Results: The proposed "angle-tuning" concept improves the depth-spread performance of individual coils with a significantly smaller footprint than existing and proposed coils. For composite structures, using the proposed coils as basic building blocks simplifies the design and manufacturing process and helps accomplish a leading depth-spread performance. In addition, the footprint of the proposed system is intrinsically small, making them suitable for multisite stimulations of inter and intra-hemispheric brain regions with an improved spread and less electric field divergence. Significance: Few brain functions are operated by isolated single brain regions but rather by coordinated networks involving multiple brain regions. Simultaneous or sequential multisite stimulations may provide tools for mechanistic studies of brain functions and the treatment of neuropsychiatric disorders. The proposed AT coil goes beyond the traditional depth-spread tradeoff rule of TMS coils, which provides the possibility of building new composite structures and new multisite TMS tools.

scholarly journals MicroRNA-dependent control of neuroplasticity in affective disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena Caria Martins ◽  
Gerhard Schratt
Keyword(s):  
Affective Disorders ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Functional Studies ◽  
Brain Functions ◽  
Small Regulatory Rnas ◽  
Therapeutic Tools ◽  
Mood And Cognition

AbstractAffective disorders are a group of neuropsychiatric disorders characterized by severe mood dysregulations accompanied by sleep, eating, cognitive, and attention disturbances, as well as recurring thoughts of suicide. Clinical studies consistently show that affective disorders are associated with reduced size of brain regions critical for mood and cognition, neuronal atrophy, and synaptic loss in these regions. However, the molecular mechanisms that mediate these changes and thereby increase the susceptibility to develop affective disorders remain poorly understood. MicroRNAs (miRNAs or miRs) are small regulatory RNAs that repress gene expression by binding to the 3ʹUTR of mRNAs. They have the ability to bind to hundreds of target mRNAs and to regulate entire gene networks and cellular pathways implicated in brain function and plasticity, many of them conserved in humans and other animals. In rodents, miRNAs regulate synaptic plasticity by controlling the morphology of dendrites and spines and the expression of neurotransmitter receptors. Furthermore, dysregulated miRNA expression is frequently observed in patients suffering from affective disorders. Together, multiple lines of evidence suggest a link between miRNA dysfunction and affective disorder pathology, providing a rationale to consider miRNAs as therapeutic tools or molecular biomarkers. This review aims to highlight the most recent and functionally relevant studies that contributed to a better understanding of miRNA function in the development and pathogenesis of affective disorders. We focused on in vivo functional studies, which demonstrate that miRNAs control higher brain functions, including mood and cognition, in rodents, and that their dysregulation causes disease-related behaviors.

scholarly journals Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration

2018 ◽  
Vol 29 (5) ◽  
pp. 2148-2159 ◽  
Author(s):  
Anna Hoerder-Suabedissen ◽  
Kim V Korrell ◽  
Shuichi Hayashi ◽  
Alexander Jeans ◽  
Denise M O Ramirez ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Hippocampal Neurons ◽  
Vesicle Fusion ◽  
Conditional Knockout ◽  
Snare Complex ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Markers Of Inflammation ◽  
Synaptic Vesicle Fusion

Abstract Synaptosomal associated protein 25 kDa (SNAP25) is an essential component of the SNARE complex regulating synaptic vesicle fusion. SNAP25 deficiency has been implicated in a variety of cognitive disorders. We ablated SNAP25 from selected neuronal populations by generating a transgenic mouse (B6-Snap25tm3mcw (Snap25-flox)) with LoxP sites flanking exon5a/5b. In the presence of Cre-recombinase, Snap25-flox is recombined to a truncated transcript. Evoked synaptic vesicle release is severely reduced in Snap25 conditional knockout (cKO) neurons as shown by live cell imaging of synaptic vesicle fusion and whole cell patch clamp recordings in cultured hippocampal neurons. We studied Snap25 cKO in subsets of cortical projection neurons in vivo (L5—Rbp4-Cre; L6—Ntsr1-Cre; L6b—Drd1a-Cre). cKO neurons develop normal axonal projections, but axons are not maintained appropriately, showing signs of swelling, fragmentation and eventually complete absence. Onset and progression of degeneration are dependent on the neuron type, with L5 cells showing the earliest and most severe axonal loss. Ultrastructural examination revealed that cKO neurites contain autophagosome/lysosome-like structures. Markers of inflammation such as Iba1 and lipofuscin are increased only in adult cKO cortex. Snap25 cKO can provide a model to study genetic interactions with environmental influences in several disorders.

scholarly journals A High-Resolution In Vivo Atlas of the Human Brain’s Benzodiazepine Binding Site of GABAA Receptors

2020 ◽  
Author(s):  
Martin Nørgaard ◽  
Vincent Beliveau ◽  
Melanie Ganz ◽  
Claus Svarer ◽  
Lars H Pinborg ◽  
...  
Keyword(s):  
High Resolution ◽  
Human Brain ◽  
Mrna Expression ◽  
Brain Regions ◽  
Mrna Levels ◽  
Gamma Aminobutyric Acid ◽  
Healthy Human ◽  
Brain Functions ◽  
The Brain

ABSTRACTGamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. The binding of benzodiazepines to the benzodiazepine receptor sites (BZR) located on GABAA receptors (GABAARs) potentiates the inhibitory effect of GABA leading to the anxiolytic, anticonvulsant and sedative effects used for treatment of those disorders. However, the function of GABAARs and the expression of BZR protein is determined by the GABAAR subunit stoichiometry (19 genes coding for individual subunits), and it remains to be established how the pentamer composition varies between brain regions and individuals.Here, we present a quantitative high-resolution in vivo atlas of the human brain BZRs, generated on the basis of [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association with mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein.This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain.

scholarly journals Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Georgia Panagiotakos ◽  
Christos Haveles ◽  
Arpana Arjun ◽  
Ralitsa Petrova ◽  
Anshul Rana ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Autism Spectrum ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Timothy Syndrome ◽  
Cortical Projection ◽  
Embryonic Mouse ◽  
Syndromic Asd

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

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