Rigorous anterograde trans-monosynaptic tracing of genetic defined neurons with retargeted HSV1 H129

AbstractNeuroanatomical tracing technology is fundamental for unraveling the complex network of brain connectome. Tracing tools that could spread between neurons are urgently needed, especially the rigorous trans-monosynaptic anterograde tracer is still lacking. HSV1 strain H129 was proved to be an anterograde tracer and has been used to trace neuronal networks in several reports. However, H129 has a serious defect that it was demonstrated to infect neurons via axon terminals. Thus, when using H129 to dissect output neural circuit, its terminal take up capacity should be carefully considered. Here, we report a recombinant H129 that carrying the anti-Her2 scFv in glycoprotein D to target genetically defined neurons. With the usage of helper virus complementarily expressing Her2 and gD, we can realize the elucidation of direct projection regions of either a given brain nucleus or a specific neuron type. The retargeted H129 system complements the current neural circuit tracer arsenal, which provides a rigorous and practical anterograde trans-monosynaptic tool.

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Ramsey’s Theory Meets The Human Brain Connectome

10.20944/preprints202109.0412.v1 ◽

2021 ◽

Author(s):

Arturo Tozzi

Keyword(s):

Neural Networks ◽

Human Brain ◽

Network Theory ◽

Neuronal Networks ◽

Top Down ◽

Bottom Up ◽

Functional Interactions ◽

Brain Connectome

Ramsey’s theory (RAM) from combinatorics and network theory goes looking for regularities and repeated patterns inside structures equipped with nodes and edges. RAM represents the outcome of a dual methodological commitment: by one side a top-down approach evaluates the possible arrangement of specific subgraphs when the number of graph’s vertices is already known, by another side a bottom-up approach calculates the possible number of graph’s vertices when the arrangement of specific subgraphs is already known. Since natural neural networks are often represented in terms of graphs, we suggest to utilize RAM for the analytical and computational assessment of a peculiar structure supplied with neuronal vertices and axonal edges, i.e., the human brain connectome. We discuss how a RAM approach in neuroscientific issues might be able to locate and trace unexplored motifs shared between different cortical and subcortical subareas. Furthermore, we will describe how notable RAM outcomes, such as the Ramsey’s theorem and the Ramsey’s number, could contribute to uncover still unknown anatomical connexions endowed in neuronal networks and unexpected functional interactions among grey zones of the human brain.

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Resting-state connectivity predicts patient-specific effects of deep brain stimulation for Parkinson’s disease

10.1101/203406 ◽

2017 ◽

Author(s):

Xiaoyu Chen ◽

Chencheng Zhang ◽

Yuxin Li ◽

Pei Huang ◽

Qian Lv ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Brain Stimulation ◽

Neural Circuit ◽

Patient Specific ◽

Neural Network Modeling ◽

Brain Connectome ◽

Diffusion Dynamics ◽

Deep Brain

AbstractNeural circuit-based guidance for optimizing patient screening, target selection and parameter tuning for deep brain stimulation (DBS) remains limited. To this end, we propose a functional brain connectome-based modeling approach that simulates network-spreading effects of stimulating different brain regions and quantifies rectification of abnormal network topology in silico. We validate these analyses by predicting nuclei in basal-ganglia circuits as top-ranked targets for 43 local patients with Parkinson’s disease and 90 patients from public database. However, individual connectome-based predictions demonstrate that globus pallidus and subthalamic nucleus (STN) constituted as the best choice for 21.1% and 19.5% of patients, respectively. Notably, the priority rank of STN significantly correlated with motor symptom severity in the local cohort. By introducing whole-brain network diffusion dynamics, these findings unfold a new dimension of brain connectomics and underscore the importance of neural network modeling for personalized DBS therapy, which warrants experimental investigation to validate its clinical utility.

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GABAA presynaptic inhibition regulates the gain and kinetics of retinal output neurons

eLife ◽

10.7554/elife.60994 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jenna Nagy ◽

Briana Ebbinghaus ◽

Mrinalini Hoon ◽

Raunak Sinha

Keyword(s):

Presynaptic Inhibition ◽

Neural Circuits ◽

Neural Circuit ◽

Ganglion Cells ◽

Gain Control ◽

Light Response ◽

Mouse Retina ◽

Axon Terminals ◽

Kinetics Of

Output signals of neural circuits, including the retina, are shaped by a combination of excitatory and inhibitory signals. Inhibitory signals can act presynaptically on axon terminals to control neurotransmitter release and regulate circuit function. However, it has been difficult to study the role of presynaptic inhibition in most neural circuits due to lack of cell-type specific and receptor-type specific perturbations. In this study, we used a transgenic approach to selectively eliminate GABAA inhibitory receptors from select types of second order neurons - bipolar cells - in mouse retina and examined how this affects the light response properties of the well-characterized ON alpha ganglion cell retinal circuit. Selective loss of GABAA receptor-mediated presynaptic inhibition causes an enhanced sensitivity and slower kinetics of light-evoked responses from ON alpha ganglion cells thus highlighting the role of presynaptic inhibition in gain control and temporal filtering of sensory signals in a key neural circuit in the mammalian retina.

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Pax3 induces neural circuit repair through a developmental program of directed axon outgrowth

10.1101/2021.02.25.432898 ◽

2021 ◽

Author(s):

JS Jara ◽

HX Avci ◽

I Kouremenou ◽

M Doulazmi ◽

J Bakouche ◽

...

Keyword(s):

Neural Circuit ◽

Polysialic Acid ◽

Treatment Strategies ◽

Axon Outgrowth ◽

Bdnf Expression ◽

Axon Terminals ◽

Developmental Program ◽

Neural Cell Adhesion ◽

Neuronal Connections ◽

Underlying Mechanisms

ABSTRACTAlthough neurotrophins can reorganise surviving neuronal connections after a lesion, clinical improvement is minimal and underlying mechanisms ill-defined, which impedes the development of effective treatment strategies. Here we show that the neurotrophin brain derived neurotrophic factor (BDNF) upregulates the transcription factor Pax3, which in turn induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on Pax3 increasing polysialic acid-neural cell adhesion molecule (PSA-NCAM), which is both essential for, and mediates the amount of, reinnervation. Pax3 acts pre-synaptically: its expression in reinnervating neurons induces significant axonal growth, and Pax3 knockdown abolishes reinnervation induced by BDNF, either endogenous BDNF expression during spontaneous developmental repair, or exogenous BDNF treatment in the mature nervous system. This is a novel role for Pax3. We propose that neuronal Pax3 induces PSA-NCAM expression on axon terminals to increase their motility and outgrowth, thereby promoting neural circuit reorganisation and repair.

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Cat's medullary reticulospinal and subnucleus reticularis dorsalis noxious neurons form a coupled neural circuit through collaterals of descending axons

Journal of Neurophysiology ◽

10.1152/jn.00603.2015 ◽

2016 ◽

Vol 115 (1) ◽

pp. 324-344 ◽

Cited By ~ 2

Author(s):

Roberto Leiras ◽

Francisco Martín-Cora ◽

Patricia Velo ◽

Tania Liste ◽

Antonio Canedo

Keyword(s):

Spatial Organization ◽

Neural Circuit ◽

Afferent Input ◽

Cervical Cord ◽

Noxious Stimulation ◽

Human Beings ◽

Network Function ◽

Descending Fibers ◽

Anterograde Tracer ◽

Phaseolus Vulgaris Leucoagglutinin

Animals and human beings sense and react to real/potential dangerous stimuli. However, the supraspinal mechanisms relating noxious sensing and nocifensive behavior are mostly unknown. The collateralization and spatial organization of interrelated neurons are important determinants of coordinated network function. Here we electrophysiologically studied medial medullary reticulospinal neurons (mMRF-RSNs) antidromically identified from the cervical cord of anesthetized cats and found that 1) more than 40% (79/183) of the sampled mMRF-RSNs emitted bifurcating axons running within the dorsolateral (DLF) and ventromedial (VMF) ipsilateral fascicles; 2) more than 50% (78/151) of the tested mMRF-RSNs with axons running in the VMF collateralized to the subnucleus reticularis dorsalis (SRD) that also sent ipsilateral descending fibers bifurcating within the DLF and the VMF. This percentage of mMRF collateralization to the SRD increased to more than 81% (53/65) when considering the subpopulation of mMRF-RSNs responsive to noxiously heating the skin; 3) reciprocal monosynaptic excitatory relationships were electrophysiologically demonstrated between noxious sensitive mMRF-RSNs and SRD cells; and 4) injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin evidenced mMRF to SRD and SRD to mMRF projections contacting the soma and proximal dendrites. The data demonstrated a SRD-mMRF network interconnected mainly through collaterals of descending axons running within the VMF, with the subset of noxious sensitive cells forming a reverberating circuit probably amplifying mutual outputs simultaneously regulating motor activity and spinal noxious afferent input. The results provide evidence that noxious stimulation positively engages a reticular SRD-mMRF-SRD network involved in pain-sensory-to-motor transformation and modulation.

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Acetylated α-tubulin residue K394 regulates microtubule stability to shape the growth of axon terminals

10.1101/2021.04.01.438108 ◽

2021 ◽

Author(s):

Harriet A. J. Saunders ◽

Dena M. Johnson-Schlitz ◽

Brian V. Jenkins ◽

Peter J. Volkert ◽

Sihui Z. Yang ◽

...

Keyword(s):

Nervous System ◽

Neuron Type ◽

Dimer Interface ◽

Tubulin Dimer ◽

Over Expression ◽

Axon Terminals ◽

Microtubule Stability ◽

The Stability ◽

And Function ◽

Conserved Residue

Microtubules are essential to neuron shape and function. Therefore, the stability of the microtubule cytoskeleton must be carefully regulated. Acetylation of tubulin has the potential to directly tune microtubule stability, and proteomic studies have identified several acetylation sites in α-tubulin. This includes the highly conserved residue lysine 394 (K394), which is located at the αβ-tubulin dimer interface. Using a fly model, we show that α-tubulin K394 is acetylated in the nervous system and is an essential residue. We found that an acetylation-blocking mutation in endogenous α-tubulin, K394R, perturbs the synaptic morphogenesis of motoneurons by reducing microtubule stability. Intriguingly, the K394R mutation has opposite effects on the growth of two functionally and morphologically distinct motoneurons, revealing neuron-type-specific responses when microtubule stability is altered. Eliminating the deacetylase HDAC6 increases K394 acetylation, and the over-expression of HDAC6 reduces microtubule stability similar to the K394 mutant. Thus, our findings implicate α-tubulin K394 and its acetylation in the regulation of microtubule stability and suggest that HDAC6 regulates K394 acetylation during synaptic morphogenesis.

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A Connectome-Based, Corticothalamic Model of State- and Stimulation-Dependent Modulation of Rhythmic Neural Activity and Connectivity

Frontiers in Computational Neuroscience ◽

10.3389/fncom.2020.575143 ◽

2020 ◽

Vol 14 ◽

Author(s):

John D. Griffiths ◽

Anthony Randal McIntosh ◽

Jeremie Lefebvre

Keyword(s):

Functional Connectivity ◽

Brain Stimulation ◽

Neural Circuit ◽

Spatial Scales ◽

Oscillatory Activity ◽

Neural Mass Model ◽

Cognitive State ◽

Mass Model ◽

Brain Connectome ◽

The Impact

Rhythmic activity in the brain fluctuates with behaviour and cognitive state, through a combination of coexisting and interacting frequencies. At large spatial scales such as those studied in human M/EEG, measured oscillatory dynamics are believed to arise primarily from a combination of cortical (intracolumnar) and corticothalamic rhythmogenic mechanisms. Whilst considerable progress has been made in characterizing these two types of neural circuit separately, relatively little work has been done that attempts to unify them into a single consistent picture. This is the aim of the present paper. We present and examine a whole-brain, connectome-based neural mass model with detailed long-range cortico-cortical connectivity and strong, recurrent corticothalamic circuitry. This system reproduces a variety of known features of human M/EEG recordings, including spectral peaks at canonical frequencies, and functional connectivity structure that is shaped by the underlying anatomical connectivity. Importantly, our model is able to capture state- (e.g., idling/active) dependent fluctuations in oscillatory activity and the coexistence of multiple oscillatory phenomena, as well as frequency-specific modulation of functional connectivity. We find that increasing the level of sensory drive to the thalamus triggers a suppression of the dominant low frequency rhythms generated by corticothalamic loops, and subsequent disinhibition of higher frequency endogenous rhythmic behaviour of intracolumnar microcircuits. These combine to yield simultaneous decreases in lower frequency and increases in higher frequency components of the M/EEG power spectrum during states of high sensory or cognitive drive. Building on this, we also explored the effect of pulsatile brain stimulation on ongoing oscillatory activity, and evaluated the impact of coexistent frequencies and state-dependent fluctuations on the response of cortical networks. Our results provide new insight into the role played by cortical and corticothalamic circuits in shaping intrinsic brain rhythms, and suggest new directions for brain stimulation therapies aimed at state-and frequency-specific control of oscillatory brain activity.

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Spatial reciprocity of connections between areas 17 and 18 in the cat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-188 ◽

1995 ◽

Vol 73 (9) ◽

pp. 1339-1347 ◽

Cited By ~ 15

Author(s):

P. A. Salin ◽

H. Kennedy ◽

J. Bullier

Keyword(s):

Area 17 ◽

Fluorescent Tracers ◽

Double Labeling ◽

Area 18 ◽

Axon Terminals ◽

Density Maps ◽

Anterograde Tracers ◽

Convergence And Divergence ◽

Areas 17 And 18 ◽

Anterograde Tracer

We examined whether the interconnections between areas 17 and 18 are spatially reciprocal, i.e., whether a column of cells in area 17 receives from the same region of area 18 as it sends projections to, and vice versa. We addressed this question by making side by side injections of retrograde fluorescent tracers in area 18, calculating the convergence and divergence of the connections from area 17 to 18. We compared these values with previously reported values of divergence and convergence of the projections from area 18 to area 17. The results demonstrate that there is a good match between the convergence and divergence of the area 17 to area 18 connection and, respectively, the divergence and convergence of the reverse connection. We confirmed directly the spatial reciprocity by injecting simultaneously in area 17 a retrograde and an anterograde tracer and by analyzing quantitatively the density of anterograde and retrograde labeling across the surface of area 18. There was an excellent match between the density maps of retrogradely labeled cells and anterogradely labeled axon terminals in area 18. Connections between areas 17 and 18 therefore exhibit large degrees of convergence and divergence and are spatially reciprocal. Thus, a given column of cells within one of these two areas is reciprocally interconnected with a large region of the opposite area. Such an organization may provide the basis for synchronization of firing of neurons across these two areas, as revealed by cross-correlation studies.Key words: double labeling, fluorescent tracers, retrograde and anterograde tracers, convergence and divergence.

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IDENTIFICATION OF A NOVEL BDNF-SPECIFIC CORTICOSTRIATAL CIRCUITRY

10.1101/2021.08.26.457842 ◽

2021 ◽

Author(s):

Yann Ehinger ◽

Drishti Soneja ◽

Khanhky Phamluong ◽

Dorit Ron

Keyword(s):

Motor Cortex ◽

Orbitofrontal Cortex ◽

Neural Circuit ◽

Dorsal Striatum ◽

Medial Part ◽

Striatal Neurons ◽

Bdnf Expression ◽

Axon Terminals ◽

Bdnf Signaling

BDNF is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF in the corticostriatal circuitry. First, we utilized Bdnf-Cre and Ribotag transgenic mouse lines to label BDNF-positive cells in the cortex, and detected BDNF expression in the motor cortex, medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Next, we used a retrograde viral tracing strategy, in combination with Bdnf-Cre knockin mice, to map the cortical outputs of BDNF neurons in the dorsal striatum. We found that the BDNF-positive prefrontal regions differentially project to the dorsal striatum. Specifically, BDNF-expressing neurons located in the mPFC project to both dorsolateral striatum (DLS) and dorsomedial striatum (DMS), and those located in the motor cortex project to the DLS. Surprisingly however, the BDNF-expressing OFC neurons differentially target the dorsal striatum depending on their mediolateral location. Specifically, the DMS is mainly innervated by the medial part of the OFC (mOFC) whereas, the DLS receives projections specifically from the ventrolateral region of the OFC (vlOFC). Next, using an anterograde viral tracing strategy, we confirmed the presence of a BDNF-specific vlOFC-DLS circuit. Finally, we show that overexpression of BDNF in the vlOFC activates TrkB signaling specifically in the DLS but not in the DMS demonstrating the functionality of this circuit. Our study uncovers a previously unknown neural circuit composed of BDNF-positive vlOFC neurons projecting to the DLS. These findings could have important implications for the role of BDNF signaling in the OFC as well as in other corticostriatal circuitries.

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Hypothalamic-extended amygdala circuit regulates temporal discounting

10.1101/577973 ◽

2019 ◽

Author(s):

Mark A. Rossi ◽

Haofang E. Li ◽

Glenn W. Watson ◽

H. Gregory Moore ◽

Min Tong Cai ◽

...

Keyword(s):

Choice Behavior ◽

Arcuate Nucleus ◽

Neural Circuit ◽

Temporal Discounting ◽

Neural Mechanisms ◽

Stria Terminalis ◽

Bed Nucleus ◽

Axon Terminals ◽

First Time ◽

Y Receptors

AbstractChoice behavior is characterized by temporal discounting, i.e., preference for immediate rewards over delayed rewards. Temporal discounting is often dysfunctional in psychiatric disorders, addiction, and eating disorders. However, the underlying neural mechanisms governing temporal discounting are still poorly understood. We found that food deprivation resulted in steep temporal discounting of food rewards, whereas satiation abolished discounting. In addition, optogenetic activation of AgRP-expressing neurons in the arcuate nucleus or their axon terminals in the posterior bed nucleus of stria terminalis (BNST) restored temporal discounting in sated mice. Activation of postsynaptic neuropeptide Y receptors (Y1Rs) within the BNST, which is influenced by neuropeptide released by AgRP neurons, was sufficient to restore temporal discounting. These results demonstrate for the first time a profound effect of motivational signals from hypothalamic feeding circuits on temporal discounting and reveal a novel neural circuit that regulates choice behavior.

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