Sensory environments are commonly characterized by specific physical features, which sensory systems might exploit using dedicated processing mechanisms. In the tactile sense, one such characteristic feature is frictional movement, which gives rise to short-lasting (<10ms), information-carrying integument vibrations. Rather than generic integrative encoding (i.e. averaging or spectral analysis capturing the ‘intensity’ and ‘best frequency’), the tactile system might benefit from, what we call a ‘temporally local’ coding scheme that instantaneously detects and analyzes shapes of these short-lasting features. Here, by employing analytic psychophysical measurements, we tested whether the prerequisite of temporally local coding exists in the human tactile system. We employed pulsatile skin indentations at the fingertip that allowed us to trade manipulation of local pulse shape against changes in global intensity and frequency, achieved by adding pulses of the same shape. We found that manipulation of local pul...

The ability to learn dexterous motor skills is a fundamental aspect of human behavior. However, the underlying neural circuit mechanisms for dexterous skill learning are unclear. Advancing our understanding of motor skill learning requires the integration of modern neuroscientific techniques with a rigorously characterized dexterous task. The development of automated rodent skilled reaching with paw tracking allows detailed analysis of how reach-to-grasp kinematics evolve during learning. We assessed how both ‘gross’ forelimb and ‘fine’ digit kinematics changed as rats learned skilled reaching. Rats whose success rates increased (learners) consistently reduced the variability in their reach trajectories. Refinement of fine digit control generally continued after consistency in gross hand transport to the pellet plateaued. Interestingly, most rats whose success rates did not increase (non-learners) also converged on consistent reach kinematics. Some non-learners, however, maintained substantial variability ...

Neuromodulation via the intracellular second messenger, cyclic adenosine monophosphate (cAMP), is ubiquitous at presynaptic nerve terminals. This modulation of synaptic transmission allows exocytosis to adapt to stimulus levels and reliably encode information. The AII amacrine cell (AII-AC) is a central hub for signal processing in the mammalian retina. The main apical dendrite of the AII-AC is connected to several lobular appendages that release glycine onto OFF cone bipolar cells (OFF-CBCs) and ganglion cells. However, the influence of cAMP on glycine release is not well understood. Using membrane capacitance (Cm) measurements from mouse AII-ACs to directly measure exocytosis, we observe that intracellular dialysis of 1 mM cAMP enhances exocytosis without affecting the L-type Ca2+ current. Responses to depolarizing pulses of various durations show that the size of the readily releasable pool (RRP) of vesicles nearly doubles with cAMP, while paired-pulse depression experiments suggest that release probabi...

KCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. Here, we show that Kv7 channel activity is up-regulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons from rats of both sex, thus resulting in a synergistic long-term depression of intrinsic neuronal excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for their induction. However, while LTD is dependent on CB1 receptors LTD-IE is not. Molecular modeling shows strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons. SIGNIFICANCE STATEMENT In...

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation and cognition in the same mice advance our understanding of epi...

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...

When encoding new episodic memories, visual and semantic processing is proposed to make distinct contributions to accurate memory and memory distortions. Here, we used fMRI and preregistered representational similarity analysis to uncover the representations that predict true and false recognition of unfamiliar objects. Two semantic models captured coarse-grained taxonomic categories and specific object features, respectively, while two perceptual models embodied low-level visual properties. Twenty-eight female and male participants encoded images of objects during fMRI scanning, and later had to discriminate studied objects from similar lures and novel objects in a recognition memory test. Both perceptual and semantic models predicted true memory. When studied objects were later identified correctly, neural patterns corresponded to low-level visual representations of these object images in the early visual cortex, lingual, and fusiform gyri. In a similar fashion, alignment of neural patterns with fine-gra...

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 ...

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...

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...