bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, December 31st, 2023
| Time |
Event |
| 12:47a |
Protosequences in human cortical organoids model intrinsic states in the developing cortex
Neuronal firing sequences are thought to be the basic building blocks of neural coding and information broadcasting within the brain. However, when sequences emerge during neurodevelopment remains unknown. We demonstrate that structured firing sequences are present in spontaneous activity of human brain organoids and ex vivo neonatal brain slices from the murine somatosensory cortex. We observed a balance between temporally rigid and flexible firing patterns that are emergent phenomena in human brain organoids and early postnatal murine somatosensory cortex, but not in primary dissociated cortical cultures. Our findings suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by an innate preconfigured architecture established during neurogenesis. These findings highlight the potential for brain organoids to further explore how exogenous inputs can be used to refine neuronal circuits and enable new studies into the genetic mechanisms that govern assembly of functional circuitry during early human brain development. | | 12:47a |
Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation.
Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions. | | 12:47a |
Hexafluoro slows retinal degeneration and improves visual function in zebrafish models of Usher syndrome 1F
Usher syndrome is the leading genetic cause of deafblindness, affecting hundreds of thousands of people worldwide. The deafness can be addressed with hearing aids or cochlear implants, but there is currently no treatment for the vision loss, which is due to progressive degeneration of retinal photoreceptors. Studies in animal models of Usher syndrome have shown that photoreceptor degeneration is exacerbated by exposure to bright light, and other studies have shown that light-induced photostress reduces mitochondrial function. We previously synthesized hexafluoro and showed that it is a potent Sirt3 activator that promotes mitochondrial respiration. Here we examined the efficacy of hexafluoro as a potential therapeutic for treatment of vison loss in a zebrafish model of Usher syndrome type 1F, which exhibits early and severe vision defects along with vestibular dysfunction as seen in Usher type 1 pathology. We find that hexafluoro improves visual function, reduces photoreceptor degeneration, and protects the retina against exposure to bright light in this USH1F model. | | 1:15a |
Auditory training alters the cortical representation of both learned and task irrelevant sound features
Auditory learning is supported by long-term changes in the neural processing of sound. We mapped neural sensitivity to timbre, pitch and location in animals trained to discriminate the identity of artificial vowels based on their spectral timbre in a two-alternative forced choice (T2AFC, n=3, female ferrets) or to detect changes in fundamental frequency or timbre of repeating artificial vowels in a go/no-go task (n=2 female ferrets). Neural responses were recorded under anaesthesia in two primary cortical fields and two tonotopically organised non-primary fields. Responses were compared these data to that of naive control animals. We observed that in both groups of trained animals the overall sensitivity to sound timbre was reduced across three cortical fields but enhanced in non-primary field PSF. Neural responses in trained animals were able to discriminate vowels that differed in either their first or second formant frequency unlike control animals whose sensitivity was mostly driven by changes in the second formant. Neural responses in the T2AFC animals, who were required to generalise across pitch when discriminating timbre, became less modulated by fundamental frequency, while those in the go/no-go animals were unchanged relative to controls. Finally, both trained groups showed increased spatial sensitivity and altered tuning. Trained animals showed an enhanced representation of the midline, where the speaker was located in the experimental chamber. Overall, these results demonstrate training elicited widespread changes in the way in which auditory cortical neurons represent complex sounds with changes in how both task relevant and task-irrelevant features were represented. | | 1:46a |
The Primary Function of MTL is Memory, not Navigation: Grid Cells are Non-spatial (what) and Place Cells are Memories (what and where) that Cause Grid Fields through Retrieval
A theory and neurocomputational model are presented that explain grid cell responses as the byproduct of equally dissimilar hippocampal memories. On this account, place and grid cells are not best understood as providing a navigational system. Instead, place cells represent memories that are conjunctions of both spatial and non-spatial attributes, and grid cells primarily represent the non-spatial attributes (e.g., odors, surface texture, etc.) found throughout the two-dimensional recording enclosure. Place cells support memories of the locations where non- spatial attributes can be found (e.g., positions with a particular odor), which are arranged in a hexagonal lattice owing to memory encoding and consolidation processes (pattern separation) as applied to situations in which the non-spatial attributes are found at all locations of a two-dimensional surface. Grid cells exhibit their spatial firing pattern owing to feedback from hippocampal place cells (i.e., a hexagonal pattern of remembered locations for the non-spatial attribute represented by a grid cell). The model explains: 1) grid fields that appear to be centered outside the box; 2) the toroidal nature of grid field representations; 3) grid field alignment with the enclosure borders; 4) modules in which grid cells have the same orientation and spacing but different phases; 5) head direction conjunctive grid cells that become simple head direction cells in the absence of hippocampal feedback; 6) the instant existence of grid fields in a novel environment; 7) the slower learning of place cells; 8) the manner in which head direction sensitivity of place cells changes near borders and in narrow passages; 9) the kinds of changes that underlie remapping of place cells; and 10) grid-like responses for two-dimensional coordinate systems other than navigation. | | 4:37a |
Gliogenesis from the subventricular zone modulates the extracellular matrix at the glial scar after brain ischemia
Activation of the subventricular zone (SVZ) after cerebral ischemia is one of the early responses in the brain to counteract the loss of neurons and reduce tissue damage. Impaired brain regions communicate with the SVZ through many chemotactic messages that result in neural stem cells (NSC) migration and differentiation. However, the activation of gliogenesis and the role of newborn astrocytes in the post-ischemic scenario is still under debate. We have previously shown that adenosine release after brain ischemia prompts the SVZ to generate new astrocytes. Here, we use transient brain ischemia in mice to define the cellular origin of these astrocytes in the SVZ neurogenic niche and investigate their role in the pathological process. By combining immunofluorescence, BrdU-tracing and genetic cellular labelling, we tracked the migration of newborn astrocytes, positive for the proteoglycan marker Thbs4, from the dorsal and medial SVZ to the glial scar surrounding the ischemic core. We found that these Thbs4-positive astrocytes modulate the dense extracellular matrix at the scar by synthesis but also degradation of hyaluronan. We also show that while the accumulation of this polymer at the scar is sufficient to recruit newborn astrocytes, its degradation at the SVZ correlates with gliogenesis. These results point to newborn astrocytes as a plausible pharmacological target to modulate the glial scar after brain ischemia and facilitate tissue regeneration. |
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