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Recent analyses have found waves of neural activity traveling across entire visual cortical areas in awake animals. These traveling waves modulate the excitability of local networks and perceptual sensitivity. The general computational role of these spatiotemporal patterns in the visual system, however, remains unclear. Here, we hypothesize that traveling waves endow the visual system with the capacity to predict complex and naturalistic inputs. We present a network model whose connections can be rapidly and efficiently trained to predict individual natural movies. After training, a few input frames from a movie trigger complex wave patterns that drive accurate predictions many frames into the future solely from the network’s connections. When the recurrent connections that drive waves are randomly shuffled, both traveling waves and the ability to predict are eliminated. These results suggest traveling waves may play an essential computational role in the visual system by embedding continuous spatiotemporal structures over spatial maps. Waves of neural activity travel across single regions in the visual cortex, but their computational role is unclear. Here, the authors present a neural network model demonstrating that waves traveling over retinotopic maps can enable short-term predictions of future inputs.

Studies of sensory-evoked neuronal responses often focus on mean spike rates, with fluctuations treated as internally-generated noise. However, fluctuations of spontaneous activity, often organized as traveling waves, shape stimulus-evoked responses and perceptual sensitivity. The mechanisms underlying these waves are unknown. Further, it is unclear whether waves are consistent with the low rate and weakly correlated “asynchronous-irregular” dynamics observed in cortical recordings. Here, we describe a large-scale computational model with topographically-organized connectivity and conduction delays relevant to biological scales. We find that spontaneous traveling waves are a general property of these networks. The traveling waves that occur in the model are sparse, with only a small fraction of neurons participating in any individual wave. Consequently, they do not induce measurable spike correlations and remain consistent with locally asynchronous irregular states. Further, by modulating local network state, they can shape responses to incoming inputs as observed in vivo. Spontaneous traveling cortical waves shape neural responses. Using a large-scale computational model, the authors show that transmission delays shape locally asynchronous spiking dynamics into traveling waves without inducing correlations and boost responses to external input, as observed in vivo.

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in less well-studied cortical regions. Further, the analysis can be susceptible to noise on individual channels resulting in errors in assigning laminar boundaries. Here, we have analyzed linear array recordings in multiple cortical areas in both the common marmoset and the rhesus macaque. We describe a pattern of laminar spike–field phase relationships that reliably identifies the transition between input and deep layers in cortical recordings from multiple cortical areas in two different non-human primate species. This measure corresponds well to estimates of the location of the input layer using CSDs, but does not require averaging or specific evoked activity. Laminar identity can be estimated rapidly with as little as a minute of ongoing data and is invariant to many experimental parameters. This method may serve to validate CSD measurements that might otherwise be unreliable or to estimate laminar boundaries when other methods are not practical.

INTRODUCTION Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21‐activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo. METHODS Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS‐PAK1‐1, a selective PAK1 inhibitor. NVS‐PAK1‐1 was orally administered to 5xFAD mice. The effects of NVS‐PAK1‐1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho‐PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses. RESULTS NVS‐PAK1‐1 prevented oAβ and oTau–induced spine loss in vitro. In 5xFAD mice, NVS‐PAK1‐1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ. DISCUSSION PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential. Highlights p21‐activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau–induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS‐PAK1‐1, a selective PAK1 inhibitor, protects against oAβ‐induced spine loss in a dose‐dependent manner (EC50 = 2 nM). Oral administration of NVS‐PAK1‐1 achieves brain penetration and bioavailability in normal CD‐1 mice, and target engagement in 5xFAD mice. Chronic NVS‐PAK1‐1 treatment mitigates spine loss in the somatosensory cortex of 6‐month‐old 5xFAD female mice. Chronic treatment with NVS‐PAK1‐1 restores proteomic abundance of actin cytoskeleton and dendritic spine‐associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.

Perceptual sensitivity varies from moment to moment. One potential source of this variability is spontaneous fluctuations in cortical activity that can travel as waves 1 . Spontaneous travelling waves have been reported during anaesthesia 2 – 7 , but it is not known whether they have a role during waking perception. Here, using newly developed analytic techniques to characterize the moment-to-moment dynamics of noisy multielectrode data, we identify spontaneous waves of activity in the extrastriate visual cortex of awake, behaving marmosets ( Callithrix jacchus ). In monkeys trained to detect faint visual targets, the timing and position of spontaneous travelling waves before target onset predicted the magnitude of target-evoked activity and the likelihood of target detection. By contrast, spatially disorganized fluctuations of neural activity were much less predictive. These results reveal an important role for spontaneous travelling waves in sensory processing through the modulation of neural and perceptual sensitivity. Timing and position of spontaneously arising waves of activity in the visual cortex predict the sensitivity of visual perception in awake, behaving marmosets ( Callithrix jacchus ).

Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches. This study describes structures of the transcription factor brachyury revealing the mechanism of DNA recognition. They identify fragments using X-ray fragment screening and optimize these into potent ligands with potential as cancer therapeutics.

The segregation and maintenance of eye-specific inputs in the dorsal lateral geniculate nucleus (dLGN) during early postnatal development requires the patterned spontaneous activity of retinal waves. In contrast to the development of the mouse, ferret eye-specific segregation is not complete at the start of stage III glutamatergic retinal waves, and the remaining overlap is limited to the C/C1 lamina of the dLGN. To investigate the role of patterned spontaneous activity in this late segregation, we disrupted retinal waves pharmacologically for 5 day windows from postnatal day (P) 10 to P25. Multi-electrode array recordings of the retina in vitro reveal that the cholinergic agonist epibatidine disrupts correlated retinal activity during stage III waves. Epibatidine also prevents the segregation of eye-specific inputs in vivo during that period. Our results reveal a novel role for cholinergic influence on stage III retinal waves as an instructive signal for the continued segregation of eye-specific inputs in the ferret dLGN.

High-density linear probes, like Neuropixels, provide an unprecedented opportunity to understand how neural populations within specific laminar compartments contribute to behavior. Marmoset monkeys, unlike macaque monkeys, have a lissencephalic (smooth) cortex that enables recording perpendicular to the cortical surface, thus making them an ideal animal model for studying laminar computations. Here we present a method for acute Neuropixels recordings in the common marmoset ( ). The approach replaces the native dura with an artificial silicon-based dura that grants visual access to the cortical surface, which is helpful in avoiding blood vessels, ensures perpendicular penetrations, and could be used in conjunction with optical imaging or optogenetic techniques. The chamber housing the artificial dura is simple to maintain with minimal risk of infection and could be combined with semi-chronic microdrives and wireless recording hardware. This technique enables repeated acute penetrations over a period of several months. With occasional removal of tissue growth on the pial surface, recordings can be performed for a year or more. The approach is fully compatible with Neuropixels probes, enabling the recording of hundreds of single neurons distributed throughout the cortical column.

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in less well studied cortical regions. Further the analysis can be susceptible to noise on individual channels resulting in errors in assigning laminar boundaries. Here, we have analyzed linear array recordings in multiple cortical areas in both the common marmoset and the rhesus macaque. We describe a pattern of laminar spike-field phase relationships that reliably identifies the transition between input and deep layers in cortical recordings from multiple cortical areas in two different non-human primate species. This measure corresponds well to estimates of the location of the input layer using CSDs, but does not require averaging or specific evoked activity. Laminar identity can be estimated rapidly with as little as a minute of ongoing data and is invariant to many experimental parameters. This method may serve to validate CSD measurements that might otherwise be unreliable or to estimate laminar boundaries when other methods are not practical. Competing Interest Statement The authors have declared no competing interest. Footnotes * http://github.com/zwdsalk/LaminarPhaseCoupling

Perceptual sensitivity varies from moment to moment. One potential source of variability is spontaneous fluctuations in cortical activity that can travel as a wave. Spontaneous traveling waves have been reported during anesthesia, but questioned as to whether they are relevant to waking cortical function. Using newly developed analytic techniques, we find spontaneous waves of activity in extrastriate visual cortex of awake marmosets (Callithrix jacchus). In monkeys trained to detect faint visual targets, the timing and position of spontaneous traveling waves, prior to target onset, predict the magnitude of evoked activity and the likelihood of detection. In contrast, spatially disorganized fluctuations of neural activity are much less predictive. These results reveal an important role for spontaneous traveling waves in sensory processing through modulating neural and perceptual sensitivity.