Sunday, December 17th, 2023

Time	Event
12:30a	Imaging the voltage of neurons distributed across entire brains of larval zebrafish Neurons interact in networks distributed throughout the brain. Although much effort has focused on whole-brain calcium imaging, recent advances in genetically encoded voltage indicators (GEVIs) raise the possibility of imaging voltage of neurons distributed across brains. To achieve this, a microscope must image at high volumetric rate and signal-to-noise ratio. We present a remote scanning light-sheet microscope capable of imaging GEVI-expressing neurons distributed throughout entire brains of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage of ~1/3 of the neurons of the brain, distributed throughout. We observed that neurons firing at different times during a sequence were located at different brain locations, for sequences elicited by a visual stimulus, which mapped onto locations throughout the optic tectum, as well as during stimulus-independent bursts, which mapped onto locations in the cerebellum and medulla. Whole-brain voltage imaging may open up frontiers in the fundamental operation of neural systems. (Comment on this)
12:30a	Modulation of motion signals across the visual cortical hierarchy during bistable perception Top-down influences play a critical role in perception. In vision, an ideal paradigm for studying these influences exploits ambiguous sensory experience where perceptual interpretation fluctuates spontaneously over time. This allows addressing how the neural mechanisms of bottom-up and top-down signals interact during the construction of an internal representation of the outside world. An ambiguous visual experience reflects internally-driven representations varying over time and their resolution engages perceptual decision-making. With functional imaging, we investigated in human subjects how ambiguous perceptual states are represented within early visual areas using a bistable moving plaid that is alternatively perceived as two superimposed grating components sliding over each other obliquely or as a single rightward moving pattern. We show that direction-specific voxels encoding the current perceptual state are found across the entire cortical visual hierarchy, but unexpectedly that pattern selectivity is particularly strong in area V1. While oblique-tuned V1 voxels preferentially respond during the component percept, rightward-tuned voxels were selectively activated during the pattern perceptual state. Consideration of the intrinsic connectivity of area V1 suggests that complex pattern-selective activity at the lowest hierarchical level of visual cortex reflects feedback signals from higher-level areas. These findings address functional cortical hierarchy and the role of feedback signals on cortical processing underlying perception. (Comment on this)
1:49a	A cognitive map for value-guided choice in ventromedial prefrontal cortex The prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency -- occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples -- a key neural signature of planning and flexible behaviour -- in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex. (Comment on this)
3:45a	Developmentally unique cerebellar processing prioritizes self- over other-generated movements To compute internal models of movement, the cerebellum must distinguish sensory input arising from self- and other-generated movements (reafference and exafference, respectively). This distinction is enabled by copies of motor commands (i.e., corollary discharges) that are sent to the cerebellum. The capacity to compute internal models emerges gradually through a process that is not yet understood. Previously, we demonstrated in 8-day-old (P8) rats that precerebellar nuclei (including the inferior olive and lateral reticular nucleus) convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce self-generated limb twitches. By P20, the cerebellum is able to compute an internal model and convey it to motor thalamus via the interpositus nucleus (IP). Here, recording from IP in P12 rats, we compare reafferent and exafferent responses to twitches and limb stimulations, respectively. As expected, most IP units show robust and reliable responses to twitches. However, in contrast with other sensory structures throughout the brain, exafferent responses in IP are neither robust nor reliable. Upon finding that exafferent responses occur in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimics the effects of urethane on exafference. Finally, twitch-related corollary discharge and reafference are conveyed to IP and cerebellar cortex in parallel. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized input, thereby enabling the development of closed-loop circuits and, subsequently, internal models. (Comment on this)
3:45a	Rescue of Impaired Blood-Brain Barrier in Tuberous Sclerosis Complex Patient Derived Neurovascular Unit Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene. Dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). We generated disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. Using these microphysiological systems, we demonstrate that the BBB generated from TSC2 heterozygous mutant cells shows increased permeability which can be rescued by wild type astrocytes and with treatment with rapamycin, an mTOR kinase inhibitor. Our results further demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of the cell lineages contributing to TSC pathogenesis. (Comment on this)
4:38a	Parallel Peptide Actions Underlie Recruitment and Coordination of a Dual-Network Neuron Oscillatory networks underlying rhythmic motor behaviors, and sensory and complex neural processing, are flexible, even in their neuronal composition. Neuromodulatory inputs elicit neuronal switching, whereby neurons switch participation between networks, or into multiple networks simultaneously. In most examples of neuronal switching, recruitment and coordination occur via the same mechanism, neuromodulation of internetwork synapses. However, separate mechanisms could enable additional flexibility. Here we explored whether modulation of synaptic properties occurs for a neuron recruited into dual-network activity via modulation of intrinsic properties. The isolated stomatogastric nervous system of the crab, Cancer borealis, contains two well-defined feeding-related networks (pyloric, food filtering, ~1 Hz; gastric mill, food chewing, ~0.1 Hz). The projection neuron MCN5 uses the neuropeptide Gly1-SIFamide to recruit the typically pyloric-only LPG neuron into dual pyloric plus gastric mill-timed bursting via modulation of LPG intrinsic properties. However, modulation of LPG intrinsic properties is insufficient for coordinating LPG with the gastric mill network, because synapses between LPG and gastric mill neurons are not effective under baseline conditions. Here, we show that LPG and gastric mill neurons IC, LG, and DG entrain each other during Gly1-SIFamide application, indicating bidirectional, functional connectivity. Further, in two-electrode voltage clamp recordings, Gly1-SIFamide enhanced bidirectional graded inhibitory synaptic currents between LPG and LG, IC, and DG. Thus, a neuropeptide that recruits a switching neuron into dual-frequency oscillations also modulates synapses that enable network coordination. These parallel modulatory actions provide the possibility of independent regulation of recruitment and coordination for neuronal switching. (Comment on this)
4:38a	Cardiac afferent signals can facilitate visual dominance in binocular rivalry Sensory signals from the body's visceral organs (e.g. the heart) can robustly influence the perception of exteroceptive sensations. This interoceptive-exteroceptive interaction has been argued to underlie self-awareness by situating one's perceptual awareness of exteroceptive stimuli in the context of one's internal state, but studies probing cardiac influences on visual awareness have yielded conflicting findings. In this study, we presented separate grating stimuli to each of subjects' eyes as in a classic binocular rivalry paradigm - measuring the duration for which each stimulus dominates in perception. However, we caused the gratings to "pulse" at specific times relative to subjects' real-time electrocardiogram, manipulating whether pulses occurred during cardiac systole, when baroreceptors signal to the brain that the heart has contracted, or in diastole when baroreceptors are silent. The influential "Baroreceptor Hypothesis" predicts the effect of baroreceptive input on visual perception should be uniformly suppressive. In contrast, we observed that dominance durations increased for systole-entrained stimuli, inconsistent with the Baroreceptor Hypothesis. Further, we show that this cardiac-dependent rivalry effect is preserved in subjects who are at-chance discriminating between systole-entrained and diastole-presented stimuli in a separate interoceptive awareness task, suggesting that our results are not dependent on conscious access to heartbeat sensations. (Comment on this)
8:35a	Discovery of Novel Small Molecule CB2 Agonist for the Treatment of Glioblastoma Tumors Malignant brain tumors cause over 15,000 deaths per year in the United States. Survival for over five years is only 36%. Nearly 49% of malignant brain tumors are glioblastomas (GBM), and 30% of them have the ability to diffuse and infiltrate. Treatment frequently includes surgery, radiotherapy and chemotherapy. In case of GBM patients, combining temozolomide (TMZ) chemotherapy with radiation improved survival over radiotherapy alone (survival by 2 years: 17% vs. 11%; 5 years: 10% vs. 2%). Most primary GBM tumors from pediatric and adult patients express high levels of cannabinoid type II (CB2) receptors, and that expression correlated with tumor grade. Cannabinoids like tetrahydrocannabinol (THC) were shown to suppress GBM tumor growth, trigger apoptosis in GBM stem cells, and slow down angiogenesis, thus cutting GBM cells off of blood supply. These data led to local administration of THC in clinical trials in patients with recurrent glioblastomas, although the well known psychotropic effects of THC and related compounds mediated via the CB1 receptors have raised some concerns among clinicians. Thus, the medicinal usage of cannabinoids has been limited. One leading strategy to avoid the side effects is administration of CB2 selective nonpsychotic drugs. To create an effective solution, we designed a preclinical study to develop a novel GBM therapy, using NeuroTherapias lead molecule, the CB2 agonist NTRX07. We have already demonstrated that NTRX07 ameliorates Amyloid beta; production and deposition in the hippocampus, and thus restored Long Term Potentiation: the cellular mechanism for learning and memory formation. Consequently, we showed that NTRX07 has a highly competitive target compound profile, and that is safe in murine models, dogs and humans. NTRX07 has entered clinical trials for the management of AD as the first orally available CB2 agonist designed to be centrally active. The phase I single ascending dose study in normal volunteers demonstrated targeted plasma levels of the drug after oral administration with no serious adverse events or clinically significant changes in safety examinations or laboratory tests. In this pilot mouse GBM survival study, we found breakthrough evidence that our compound can exert potent anti cancer activity and significantly extend the survival of GBM animals; even without previously exposing them to radiotherapy or TMZ. Eventually, our main goal is to bring NTRX07 into the clinic as a new therapeutic for patients with GBM. (Comment on this)

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