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The coordination of neural activity across brain areas during a specific behavior is often interpreted as neural communication involved in controlling the behavior. However, whether information relevant to the behavior is actually transferred between areas is often untested. Here, we used information-theoretic tools to quantify how motor cortex and striatum encode and exchange behaviorally relevant information about specific reach-to-grasp movement features during skill learning in rats. We found a temporal shift in the encoding of behaviorally relevant information during skill learning, as well as a reversal in the primary direction of behaviorally relevant information flow, from cortex-to-striatum during naive movements to striatum-to-cortex during skilled movements. Standard analytical methods that quantify the evolution of overall neural activity during learning-such as changes in neural signal amplitude or the overall exchange of information between areas-failed to capture these behaviorally relevant information dynamics. Using these standard methods, we instead found a consistent coactivation of overall neural signals during movement production and a bidirectional increase in overall information propagation between areas during learning. Our results show that skill learning is achieved through a transformation in how behaviorally relevant information is routed across cortical and subcortical brain areas and that isolating the components of neural activity relevant to and informative about behavior is critical to uncover directional interactions within a coactive and coordinated network., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To determine what actions to perform in each context, animals must learn how to execute motor programs in response to sensory cues. In rodents, the interface between sensory processing and motor planning occurs in the secondary motor cortex (M2). Here, we investigate dynamics in vasointestinal peptide (VIP) and somatostatin (SST) interneurons in M2 during acquisition of a cue-based, reach-to-grasp (RTG) task in mice. We observe the emergence of preparatory activity consisting of sensory responses and ramping activation in a subset of VIP interneurons during motor learning. We show that preparatory and movement activities in VIP neurons exhibit compartmentalized dynamics, with principal component 1 (PC1) and PC2 reflecting primarily movement and preparatory activity, respectively. In contrast, we observe later and more synchronous activation of SST neurons during the movement epoch with learning. Our results reveal how VIP population dynamics might support sensorimotor learning and compartmentalization of sensory processing and movement execution., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer is a systemic disease that involves malignant cell-intrinsic and -extrinsic metabolic adaptations. Most studies have tended to focus on elucidating the metabolic vulnerabilities in the primary tumor microenvironment, leaving the metastatic microenvironment less explored. In this opinion article, we discuss the current understanding of the metabolic crosstalk between the cancer cells and the tumor microenvironment, both at local and systemic levels. We explore the possible influence of the primary tumor secretome to metabolically and epigenetically rewire the nonmalignant distant organs during prometastatic niche formation and successful metastatic colonization by the cancer cells. In an attempt to understand the process of prometastatic niche formation, we have speculated how cancer may hijack the inherent regenerative propensity of tissue parenchyma during metastatic colonization., Competing Interests: Declaration of interests A.C.K. has financial interests in Vescor Therapeutics and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, targeting alanine transporters, and the autophagic control of iron metabolism. A.C.K. is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals, OncoRev and has been a consultant for Deciphera and Abbvie. The other author declares no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers., Competing Interests: Declaration of interests S.K.B. is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Stroke is a leading cause of disability. While neurotechnology has shown promise for improving upper limb recovery after stroke, efficacy in clinical trials has been variable. Our central thesis is that to improve clinical translation, we need to develop a common neurophysiological framework for understanding how neurotechnology alters network activity. Our perspective discusses principles for how motor networks, both healthy and those recovering from stroke, subserve reach-to-grasp movements. We focus on neural processing at the resolution of single movements, the timescale at which neurotechnologies are applied, and discuss how this activity might drive long-term plasticity. We propose that future studies should focus on cross-area communication and bridging our understanding of timescales ranging from single trials within a session to across multiple sessions. We hope that this perspective establishes a combined path forward for preclinical and clinical research with the goal of more robust clinical translation of neurotechnology., Competing Interests: Declaration of interests K.G. was previously a consultant to Cala Health. K.G. holds a patent that was filed by the UC Regents (Patent no: US 11,147,971 for closed-loop brain stimulation in stroke). A second patent application on nerve stimulation for stroke is pending (K.G.). K.G. and P.K. have filed a provisional patent through the UC Regents on waveform optimization for electrical stimulation in stroke. D.J.L. has served as a consultant for Boehringer Ingelheim and Neurotrauma Sciences. The MGH Translational Research Center has clinical research support agreements with BrainQ, Constant Therapeutics, Constant Therapy, and Imago Rehab, for which D.J.L. provides consultative input., (Published by Elsevier Inc.)

Sleep is known to promote recovery after stroke. Yet it remains unclear how stroke affects neural processing during sleep. Using an experimental stroke model in rats along with electrophysiological monitoring of neural firing and sleep microarchitecture, here we show that sleep processing is altered by stroke. We find that the precise coupling of spindles to global slow oscillations (SOs), a phenomenon that is known to be important for memory consolidation, is disrupted by a pathological increase in "isolated" local delta waves. The transition from this pathological to a physiological state-with increased spindle coupling to SO-is associated with sustained performance gains during recovery. Interestingly, post-injury sleep could be pushed toward a physiological state via a pharmacological reduction of tonic γ-aminobutyric acid (GABA). Together, our results suggest that sleep processing after stroke is impaired due to an increase in delta waves and that its restoration can be important for recovery., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

The human hand is unique in the animal kingdom for unparalleled dexterity, ranging from complex prehension to fine finger individuation. How does the brain represent such a diverse repertoire of movements? We evaluated mesoscale neural dynamics across the human "grasp network," using electrocorticography and dimensionality reduction methods, for a repertoire of hand movements. Strikingly, we found that the grasp network represented both finger and grasping movements alike. Specifically, the manifold characterizing the multi-areal neural covariance structure was preserved during all movements across this distributed network. In contrast, latent neural dynamics within this manifold were surprisingly specific to movement type. Aligning latent activity to kinematics further uncovered distinct submanifolds despite similarities in synergistic coupling of joints between movements. We thus find that despite preserved neural covariance at the distributed network level, mesoscale dynamics are compartmentalized into movement-specific submanifolds; this mesoscale organization may allow flexible switching between a repertoire of hand movements., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Skilled movements rely on a coordinated cortical and subcortical network, but how this network supports motor recovery after stroke is unknown. Previous studies focused on the perilesional cortex (PLC), but precisely how connected subcortical areas reorganize and coordinate with PLC is unclear. The dorsolateral striatum (DLS) is of interest because it receives monosynaptic inputs from motor cortex and is important for learning and generation of fast reliable actions. Using a rat focal stroke model, we perform chronic electrophysiological recordings in motor PLC and DLS during long-term recovery of a dexterous skill. We find that recovery is associated with the simultaneous emergence of reliable movement-related single-trial ensemble spiking in both structures along with increased cross-area alignment of spiking. Our study highlights the importance of consistent neural activity patterns across brain structures during recovery and suggests that modulation of cross-area coordination can be a therapeutic target for enhancing motor function post-stroke., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Electrical stimulation is a promising tool for modulating brain networks. However, it is unclear how stimulation interacts with neural patterns underlying behavior. Specifically, how might external stimulation that is not sensitive to the state of ongoing neural dynamics reliably augment neural processing and improve function? Here, we tested how low-frequency epidural alternating current stimulation (ACS) in non-human primates recovering from stroke interacted with task-related activity in perilesional cortex and affected grasping. We found that ACS increased co-firing within task-related ensembles and improved dexterity. Using a neural network model, we found that simulated ACS drove ensemble co-firing and enhanced propagation of neural activity through parts of the network with impaired connectivity, suggesting a mechanism to link increased co-firing to enhanced dexterity. Together, our results demonstrate that ACS restores neural processing in impaired networks and improves dexterity following stroke. More broadly, these results demonstrate approaches to optimize stimulation to target neural dynamics., Competing Interests: Declaration of interests P.K. and K.G. have submitted a provisional patent application that includes the findings reported here., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sleep has been implicated in both memory consolidation and forgetting of experiences. However, it is unclear what governs the balance between consolidation and forgetting. Here, we tested how activity-dependent processing during sleep might differentially regulate these two processes. We specifically examined how neural reactivations during non-rapid eye movement (NREM) sleep were causally linked to consolidation versus weakening of the neural correlates of neuroprosthetic skill. Strikingly, we found that slow oscillations (SOs) and delta (δ) waves have dissociable and competing roles in consolidation versus forgetting. By modulating cortical spiking linked to SOs or δ waves using closed-loop optogenetic methods, we could, respectively, weaken or strengthen consolidation and thereby bidirectionally modulate sleep-dependent performance gains. We further found that changes in the temporal coupling of spindles to SOs relative to δ waves could account for such effects. Thus, our results indicate that neural activity driven by SOs and δ waves have competing roles in sleep-dependent memory consolidation., (Published by Elsevier Inc.)

Previous research has shown that mental rehearsal can improve performance. A new study by Vyas et al. (2018) reveals that direct modulation of neural dynamics using a brain-computer interface can also modify physical movements. The study further demonstrates that "mental practice" and physical movements share a common neural subspace., (Copyright © 2018. Published by Elsevier Inc.)

During motor learning, movements and underlying neural activity initially exhibit large trial-to-trial variability that decreases over learning. However, it is unclear how task-relevant neural populations coordinate to explore and consolidate activity patterns. Exploration and consolidation could happen for each neuron independently, across the population jointly, or both. We disambiguated among these possibilities by investigating how subjects learned de novo to control a brain-machine interface using neurons from motor cortex. We decomposed population activity into the sum of private and shared signals, which produce uncorrelated and correlated neural variance, respectively, and examined how these signals' evolution causally shapes behavior. We found that initially large trial-to-trial movement and private neural variability reduce over learning. Concomitantly, task-relevant shared variance increases, consolidating a manifold containing consistent neural trajectories that generate refined control. These results suggest that motor cortex acquires skillful control by leveraging both independent and coordinated variance to explore and consolidate neural patterns., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Much progress has been made in understanding how behavioral experience and neural activity can modify the structure and function of neural circuits during development and in the adult brain. Studies of physiological and molecular mechanisms underlying activity-dependent plasticity in animal models have suggested potential therapeutic approaches for a wide range of brain disorders in humans. Physiological and electrical stimulations as well as plasticity-modifying molecular agents may facilitate functional recovery by selectively enhancing existing neural circuits or promoting the formation of new functional circuits. Here, we review the advances in basic studies of neural plasticity mechanisms in developing and adult nervous systems and current clinical treatments that harness neural plasticity, and we offer perspectives on future development of plasticity-based therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Coincident pre- and postsynaptic activation is known to induce long-term modification of glutamatergic synapses. We report here that, in both hippocampal cultures and acute hippocampal slices, repetitive postsynaptic spiking within 20 ms before and after the activation of GABAergic synapses also led to a persistent change in synaptic strength. This synaptic modification required Ca2+ influx through postsynaptic L-type Ca2+ channels and was due to a local decrease in K+-Cl- cotransport activity, effectively reducing the strength of inhibition. Thus, GABAergic synapses can detect and be modified by coincident pre- and postsynaptic spiking, allowing the level of inhibition to be modulated in accordance to the temporal pattern of postsynaptic excitation.

GABA is the main inhibitory neurotransmitter in the adult brain. Early in development, however, GABAergic synaptic transmission is excitatory and can exert widespread trophic effects. During the postnatal period, GABAergic responses undergo a switch from being excitatory to inhibitory. Here, we show that the switch is delayed by chronic blockade of GABA(A) receptors, and accelerated by increased GABA(A) receptor activation. In contrast, blockade of glutamatergic transmission or action potentials has no effect. Furthermore, GABAergic activity modulated the mRNA levels of KCC2, a K(+)-Cl(-) cotransporter whose expression correlates with the switch. Finally, we report that GABA can alter the properties of depolarization-induced Ca(2+) influx. Thus, GABA acts as a self-limiting trophic factor during neural development.

The envelope gene of HTLV-III, the retrovirus directly linked to AIDS, encodes a protein of 856 amino acids. Our sequence analysis of the cloned HTLV-III (HXB-3) env gene and its comparison with other isolates reveal significant divergence, especially in the external portion of this protein. A large segment of the env gene (1800 bp) was inserted into the expression vector pEV-vrf3, and a corresponding 68 kd protein, which encompasses both the extracellular and the membrane-associated regions of the native protein, was produced in E. coli. Several smaller polypeptides, which appear to be internal initiation products, were also produced. All 50 AIDS patient sera obtained from different locations in the United States specifically recognized the bacterially synthesized envelope proteins, as judged by Western blots. This suggests that these proteins will be useful for the diagnosis of HTLV-III infection and possibly as a vaccine against AIDS.