Search bioRxiv⌕ Search

Biology subjects

Beggs, J.

Publications and source records attributed to Beggs, J..

8 recordsLinked to original sources

Living Neurosheets: Engineering readily deployable neural architectures

Inspired by the ability of brain structures to support cognitive processing, the need for reliable queryable neural models, and emerging biohybrid applications, we present Living Neurosheets: practical, malleable, modular, and scalable systems for realizing living neural architectures, bio-inspired or beyond evolutionary precedent. By innervating porous sheets, paper-like substrates are endowed with neural function while retaining exceptional versatility. Pre-programmed porosity anchors deposited neurons for reliable spatial control. Cutting, folding, and stacking allow intuitive design, modular composition, and batch fabrication (by the hundreds) of complex neural motifs that preserve geometry and function for months. Reversible integration with tissue-matched optoelectronics enables both sample reuse across hardware and hardware multiplexing across samples, for high-throughput, multimodal investigations. We illustrate these aspects across tissue topologies, gyri-inspired manifolds, and laminar cortical mimics, attaining control over entrainment, synchronization, propagation, suppression, and augmentation dynamics--key features of in vivo neural activity. Finally, via cross-instrument portability, we fuse spatial transcriptomics and electrophysiology, linking gene programs to emergent dynamics.

neuroscience↗

Self-organization of in vitro neuronal assemblies drives to complex network topology

Activity-dependent self-organization plays an important role in the formation of specific and stereotyped connectivity patterns in neural circuits. By combining neuronal cultures, tools with approaches from network neuroscience and information theory, we can study how complex network topology emerges from local neuronal interactions. We constructed effective connectivity networks using a transfer entropy analysis of electrophysiological signals recorded from rat embryo dissociated hippocampal neuron cultures between 6 and 35 days in vitro to investigate how the neuronal network topology evolves during maturation. The methodology for constructing the networks considered the synapse delay and addressed the influence of firing rate and population bursts as well as spurious effects on the inference of connections. We found that the number of links in the networks grew over the course of development, shifting from a segregated to a more integrated architecture. As part of this progression, three significant aspects of complex network topology emerged. In agreement with previous in silico and in vitro studies, a small-world architecture was detected, largely due to strong clustering among neurons. Additionally, the networks developed in a modular community topology, with most modules comprising nearby neurons. Finally, highly active neurons acquired topological characteristics that made them important nodes to the network and integrators of communities. These findings leverage new insights into how neuronal effective network topology relates to neuronal assembly self-organization mechanisms.

neuroscience↗

Inhibition-Dominated Rich-Club Shapes Dynamics in Cortical Microcircuits of Awake Behaving Mice

Functional networks of cortical neurons contain highly interconnected hubs, forming a rich-club structure. However, the cell type composition within this distinct subnetwork and how it influences large-scale network dynamics is unclear. Using spontaneous activity recorded from hundreds of cortical neurons in orbitofrontal cortex of awake behaving mice and from organotypic cultures, we show that the rich-club is disproportionately composed of inhibitory neurons, and that inhibitory neurons within the rich-club are significantly more synchronous than other neurons. At the population level, neurons in the rich-club exert higher than expected Granger causal influence on overall population activity at a broad range of frequencies compared to other neurons. Finally, neuronal avalanche duration is significantly correlated with the fraction of rich neurons that participate in the avalanche. Together, these results suggest an unexpected role of a highly connected, inhibition-rich subnetwork in driving and sustaining activity in local cortical networks. SIGNIFICANCE STATEMENTIt is widely believed that the relative abundance of excitatory and inhibitory neurons in cortical circuits is roughly 4:1. This relative abundance has been widely used to construct numerous cortical network models. Here we show that contrary to this notion, a sub-network of highly connected hub neurons (rich-club) consists of a higher abundance of inhibitory neurons compared to that found in the entire network or the non-rich subnetwork. Inhibitory hub neurons contribute to higher synchrony within the rich club compared to the rest of the network. Strikingly, higher activation of the inhibition-dominated rich club strongly correlates with longer avalanches in cortical circuits. Our findings reveal how network topology combined with cell-type specificity orchestrates population wide activity in cortical microcircuits.

neuroscience↗

A computational examination of the two-streams hypothesis: which pathway needs a longer memory?

The two visual streams hypothesis is a robust example of neural functional specialization that has inspired countless studies over the past four decades. According to one prominent version of the theory, the fundamental goal of the dorsal visual pathway is the transformation of retinal information for visually-guided motor behavior. To that end, the dorsal stream processes input using absolute (or veridical) metrics only when the movement is initiated, necessitating very little, or no, memory. Conversely, because the ventral visual pathway does not involve motor behavior (its output does not influence the real world), the ventral stream processes input using relative (or illusory) metrics and can accumulate or integrate sensory evidence over long time constants, which provides a substantial capacity for memory. In this study, we tested these relations between functional specialization, processing metrics, and memory by training identical recurrent neural networks to perform either a viewpoint-invariant object classification task or an orientation/size determination task. The former task relies on relative metrics, benefits from accumulating sensory evidence, and is usually attributed to the ventral stream. The latter task relies on absolute metrics, can be computed accurately in the moment, and is usually attributed to the dorsal stream. To quantify the amount of memory required for each task, we chose two types of neural network models. Using a long-short-term memory (LSTM) recurrent network, we found that viewpoint-invariant object categorization (object task) required a longer memory than orientation/size determination (orientation task). Additionally, to dissect this memory effect, we considered factors that contributed to longer memory in object tasks. First, we used two different sets of objects, one with self-occlusion of features and one without. Second, we defined object classes either strictly by visual feature similarity or (more liberally) by semantic label. The models required greater memory when features were self-occluded and when object classes were defined by visual feature similarity, showing that self-occlusion and visual similarity among object task samples are contributing to having a long memory. The same set of tasks modeled using modified leaky-integrator echo state recurrent networks (LiESN), however, did not replicate the results, except under some conditions. This may be because LiESNs cannot perform fine-grained memory adjustments due to their network-wide memory coefficient and fixed recurrent weights. In sum, the LSTM simulations suggest that longer memory is advantageous for performing viewpoint-invariant object classification (a putative ventral stream function) because it allows for interpolation of features across viewpoints. The results further suggest that orientation/size determination (a putative dorsal stream function) does not benefit from longer memory. These findings are consistent with the two visual streams theory of functional specialization.

neuroscience↗

Differential Effects of Propofol and Ketamine on Critical Brain Dynamics

Whether the brain operates at a critical tipping" point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as dissociative anaesthesia"). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness. Author summaryHere we explore how different anaesthetic drugs change the nature of brain dynamics, using neural activity recorded from sub-dural electrophysiological arrays implanted in a macaque brain. Previous research has suggested that loss of consciousness under anaesthesia is associated with a movement away from critical brain dynamics, towards a less flexible regime. When comparing ketamine and propofol, two anaesthetics with largely different effects on consciousness, we find that propofol, but not ketamine, produces a dramatic reduction in the complexity of brain activity and restricts the range of scales where critical dynamics are plausible. These results suggest that maintenance of critical dynamics may be important for regulation and control of conscious awareness.

neuroscience↗

One-stop Microfluidic Assembly of Human Brain Organoids to Model Prenatal Cannabis Exposure

Prenatal cannabis exposure (PCE) influences human brain development, but it is challenging to model PCE using animals and current cell culture techniques. Here, we developed a one-stop microfluidic platform to assemble and culture human cerebral organoids from human embryonic stem cells (hESC) to investigate the effect of PCE on early human brain development. By incorporating perfusable culture chambers, air-liquid interface, and one-stop protocol, this microfluidic platform can simplify the fabrication procedure, and produce a large number of organoids (169 organoids per 3.5 cm x 3.5 cm device area) without fusion, as compared with conventional fabrication methods. These one-stop microfluidic assembled cerebral organoids not only recapitulate early human brain structure, biology, and electrophysiology but also have minimal size variation and hypoxia. Under on-chip exposure to the psychoactive cannabinoid, delta-9-tetrahydrocannabinol (THC), cerebral organoids exhibited reduced neuronal maturation, downregulation of cannabinoid receptor type 1 (CB1) receptors, and impaired neurite outgrowth. Moreover, transient on-chip THC treatment also decreased spontaneous firing in microfluidic assembled brain organoids. This one-stop microfluidic technique enables a simple, scalable, and repeatable organoid culture method that can be used not only for human brain organoids, but also for many other human organoids including liver, kidney, retina, and tumor organoids. This technology could be widely used in modeling brain and other organ development, developmental disorders, developmental pharmacology and toxicology, and drug screening.

bioengineering↗

Revisiting the window of opportunity for co-transcriptional splicing efficiency and fidelity

Recently, we reported that changes in transcription elongation rate affect the efficiency and fidelity of precursor mRNA (pre-mRNA) splicing, especially of ribosomal protein (RP) transcripts. Here, we analyse these results in more detail, finding that the majority of RP transcripts with non-consensus 5 splice sites have reduced splicing efficiency with faster transcription elongation, and improved efficiency with slower elongation, as might be predicted by the \"window of opportunity\" model for co-transcriptional splicing. In contrast, both faster and slower elongation reduce splicing fidelity, often for the same splicing events, and both faster and slower transcription increase fidelity with a different set of splicing events. We propose that certain non-consensus 5 splice sites in ribosomal protein transcripts confer a stronger effect of transcription elongation rate on splicing efficiency, possibly by causing a rate-limiting step that delays activation of spliceosomes. The effects of different rates of transcription elongation on splicing fidelity are more difficult to explain by a simple window of opportunity model. We discuss these new findings in the context of current models of co-transcriptional splicing and splicing fidelity.

molecular biology↗

Extremely fast and incredibly close: co-transcriptional splicing in budding yeast

RNA splicing, an essential part of eukaryotic pre-messenger RNA processing, can be simultaneous with transcription by RNA polymerase II. Here, we compare and review independent next-generation sequencing methods that quantify co-transcriptional splicing in budding yeast. Splicing in yeast is fast, taking place within seconds of intron transcription, while polymerase is within a few dozens of nucleotides of the 3 splice site. Ribosomal protein mRNAs are spliced particularly fast and co-transcriptionally. Intron-mediated regulation of some genes is also likely to be co-transcriptional. We suggest that intermediates of the splicing reaction, missing from current datasets, may hold key information about splicing kinetics.\n\nTrendsO_LIIndependent next-generation sequencing methods quantify co-transcriptional splicing in budding yeast\nC_LIO_LIRibosomal protein mRNAs are spliced particularly fast and co-transcriptionally\nC_LIO_LIIntron-mediated regulation of DBP2 and RPS9A is likely co-transcriptional\nC_LIO_LISplicing intermediates, missing from current datasets, may hold key information\nC_LI

biochemistry↗