Hippocampus and prefrontal cortex (PFC) circuits are thought to play a prominent role in human episodic memory, but the precise nature, and electrophysiological basis, of directed information flow between these regions and their role in verbal memory formation has remained elusive. Here we investigate nonlinear causal interactions between hippocampus and lateral PFC using intracranial EEG recordings (26 participants, 16 females) during verbal memory encoding and recall tasks. Direction-specific information theoretic analysis revealed higher causal information flow from the hippocampus to PFC than in the reverse direction. Crucially, this pattern was observed during both memory encoding and recall, and the strength of causal interactions was significantly greater during memory task performance than resting baseline. Further analyses revealed frequency specificity of interactions with greater causal information flow from hippocampus to the PFC in the delta-theta frequency band (0.5-8 Hz); in contrast, PFC to...

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson's disease (PD) or multiple system atrophy (MSA) who have gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients with gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the ga...

High molecular weight hyaluronan (HMWH), a well-established treatment for osteoarthritis pain, is anti-hyperalgesic in preclinical models of inflammatory and neuropathic pain. HMWH-induced anti-hyperalgesia is mediated by its action at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, which can signal via phosphoinositide 3-kinase (PI3K), a large family of kinases involved in diverse cell functions. We demonstrate that intrathecal administration of an oligodeoxynucleotide (ODN) antisense to mRNA for PI3Kγ (a Class I PI3K isoform) expressed in dorsal root ganglia (DRGs), and intradermal administration of a PI3Kγ-selective inhibitor (AS605240), markedly attenuates HMWH-induced anti-prostaglandin E2 (PGE2) hyperalgesia, in male and female rats. Intradermal administration of inhibitors of mammalian target of rapamycin (mTOR; rapamycin) and protein kinase B (AKT; AKT Inhibitor IV), signaling molecules downstream of PI3Kγ, also attenuates HMWH-induced anti-hyperalgesia. In vitro patch-clamp ...

Binocular disparity provides critical information about three-dimensional (3D) structures to support perception and action. In the past decade significant progress has been made in uncovering human brain areas engaged in the processing of binocular disparity signals. Yet, the fine-scale brain processing underlying 3D perception remains unknown. Here, we use ultra-high-field (7T) functional imaging at submillimeter resolution to examine fine-scale BOLD fMRI signals involved in 3D perception. In particular, we sought to interrogate the local circuitry involved in disparity processing by sampling fMRI responses at different positions relative to the cortical surface (i.e., across cortical depths corresponding to layers). We tested for representations related to 3D perception by presenting participants (male and female, N = 8) with stimuli that enable stable stereoscopic perception [i.e., correlated random dot stereograms (RDS)] versus those that do not (i.e., anticorrelated RDS). Using multivoxel pattern anal...

The connectome of the brain has a great impact on the function of the brain as the structure of the connectome affects the speed and efficiency of information transfer. As a highly energy-consuming organ, an efficient network structure is essential. A previous study has shown consistent overall brain connectivity across a large variety of species. This connectivity conservation was explained by a balance between interhemispheric and intrahemispheric connections; that is, spices with highly connected hemispheres appear to have weaker interhemisphere connections. This study examines this connectivity trade-off in the human brain using diffusion-based tractography and network analysis in the Human Connectome Project (970 subjects, 527 female). We explore the biological origins of this phenomenon, heritability, and the effect on cognitive measures. The proportion of commissural fibers in the brain had a negative correlation to hemispheric efficiency, pointing to a trade-off between inner hemispheric and inter...

Naoki Hisamoto, Yoshiki Sakai, Kohei Ohta, Tatsuhiro Shimizu, Chun Li, et al. (see pages [8309–8320][1]) A major impediment to axon regeneration in the adult CNS is the loss of axons' intrinsic ability to grow. Deciphering the signaling cascades required for axon regeneration in the PNS and in

The postinjury regenerative capacity of neurons is known to be mediated by a complex interaction of intrinsic regenerative pathways and external cues. In Caenorhabditis elegans , the initiation of axon regeneration is regulated by the nonmuscle myosin light chain-4 (MLC-4) phosphorylation signaling pathway. In this study, we have identified svh-16 / cdk-14 , a mammalian CDK14 homolog, as a positive regulator of axon regeneration in motor neurons. We then isolated the CDK-14-binding protein MIG-5/Disheveled (Dsh) and found that EGL-20/Wnt and the MIG-1/Frizzled receptor (Fz) are required for efficient axon regeneration. Further, we demonstrate that CDK-14 activates EPHX-1, the C. elegans homolog of the mammalian ephexin Rho-type GTPase guanine nucleotide exchange factor (GEF), in a kinase-independent manner. EPHX-1 functions as a GEF for the CDC-42 GTPase, inhibiting myosin phosphatase, which maintains MLC-4 phosphorylation. These results suggest that CDK14 activates the RhoGEF–CDC42–MLC phosphorylation axi...

In demyelinating diseases, such as multiple sclerosis, primary loss of myelin and subsequent neuronal degeneration throughout the CNS impair patient functionality. While the importance of mechanistic target of rapamycin (mTOR) signaling during developmental myelination is known, no studies have yet directly examined the function of mTOR signaling specifically in the oligodendrocyte (OL) lineage during remyelination. Here, we conditionally deleted Mtor from adult oligodendrocyte precursor cells (OPCs) using Ng2-CreERT in male adult mice to test its function in new OLs responsible for remyelination. During early remyelination after cuprizone-induced demyelination, mice lacking mTOR in adult OPCs had unchanged OL numbers but thinner myelin. Myelin thickness recovered by late-stage repair, suggesting a delay in myelin production when Mtor is deleted from adult OPCs. Surprisingly, loss of mTOR in OPCs had no effect on efficiency of remyelination after lysophosphatidylcholine lesions in either the spinal cord or...

Rhythmic rest-activity cycles are controlled by an endogenous clock. In Drosophila , this clock resides in ∼150 neurons organized in clusters whose hierarchy changes in response to environmental conditions. The concerted activity of the circadian network is necessary for the adaptive responses to synchronizing environmental stimuli. Thus far, work was devoted to unravel the logic of the coordination of different clusters focusing on neurotransmitters and neuropeptides. We further explored communication in the adult male brain through ligands belonging to the bone morphogenetic protein (BMP) pathway. Herein we show that the lateral ventral neurons (LNvs) express the small morphogen decapentaplegic (DPP). DPP expression in the large LNvs triggered a period lengthening phenotype, the downregulation of which caused reduced rhythmicity and affected anticipation at dawn and dusk, underscoring DPP per se conveys time-of-day relevant information. Surprisingly, DPP expression in the large LNvs impaired circadian re...