Visual recognition memory: a view from V1

Although work in primates on higher-order visual areas has revealed how the individual and concerted activity of neurons correlates with behavioral reports of object recognition, very little is known about the underlying mechanisms for visual recognition memory. Low-level vision, even as early as primary visual cortex (V1) and even in subjects as unsophisticated as rodents, promises to fill this void. Although this latter approach sacrifices interrogation of many of the most astounding features of visual recognition, it does provide experimental constraint, proximity to sensory input, and a wide range of interventional approaches. The tractability of rodent visual cortex promises to reveal the molecular mechanisms and circuits that are essential for a fundamental form of memory.National Eye Institute (Grant RO1EY023037

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Visual experience induces long-term potentiation in the primary visual

Stimulus-specific response potentiation (SRP) is a robust form of experience-dependent plasticity that occurs in primary visual cortex. In awake mice, visual evoked potentials (VEPs) recorded in layer 4 of binocular visual cortex undergo increases in amplitude with repeated presentation of a sinusoidal grating stimulus over days. This effect is highly specific to the experienced stimulus. Here, we test whether the mechanisms of thalamocortical long-term potentiation (LTP), induced with a theta burst electrical stimulation (TBS) of the dorsal lateral geniculate nucleus, are sufficient to account for SRP. First, we demonstrate that LTP similarly enhances the amplitude of VEPs, but in a way that generalizes across multiple stimuli, spatial frequencies, and contrasts. Second, we show that LTP occludes the subsequent expression of SRP. Third, we reveal that previous SRP occludes TBS-induced LTP of the VEP evoked by the experienced stimulus, but not by unfamiliar stimuli. Finally, we show that SRP is rapidly and selectively reversed by local cortical infusion of a peptide that inhibits PKMζ, a constitutively active kinase known to maintain NMDA receptor-dependent LTP and memory. Thus, SRP is expressed by the same core mechanisms as LTP. SRP therefore provides a simple assay to assess the integrity of LTP in the intact nervous system. Moreover, the results suggest that LTP of visual cortex, like SRP, can potentially be exploited to improve vision.National Eye Institute (Grant R01 EY018323-01

Experience-Dependent Equilibration of AMPAR-Mediated Synaptic Transmission during the Critical Period

Experience-dependent synapse refinement is essential for functional optimization of neural circuits. However, how sensory experience sculpts excitatory synaptic transmission is poorly understood. Here, we show that despite substantial remodeling of synaptic connectivity, AMPAR-mediated synaptic transmission remains at equilibrium during the critical period in the mouse primary visual cortex. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity. With normal visual experience, loss of Ng decreased AMPAR-positive synapse numbers, prevented AMPAR-silent synapse maturation, and increased spine elimination. Importantly, visual deprivation halted synapse loss caused by loss of Ng, revealing that Ng coordinates experience-dependent AMPAR-silent synapse conversion to AMPAR-active synapses and synapse elimination. Loss of Ng also led to sensitized long-term synaptic depression (LTD) and impaired visually guided behavior. Our synaptic interrogation reveals that experience-dependent coordination of AMPAR-silent synapse conversion and synapse elimination hinges upon Ng-dependent mechanisms for constructive synaptic refinement during the critical period.JPB FoundationWhitehall FoundationStanley Center for Psychiatric Research at Broad Institut

Visual recognition memory, manifested as long-term habituation, requires synaptic plasticity in V1

Familiarity with stimuli that bring neither reward nor punishment, manifested through behavioral habituation, enables organisms to detect novelty and devote cognition to important elements of the environment. Here we describe in mice a form of long-term behavioral habituation to visual grating stimuli that is selective for stimulus orientation. Orientation-selective habituation (OSH) can be observed both in exploratory behavior in an open arena and in a stereotyped motor response to visual stimuli in head-restrained mice. We found that the latter behavioral response, termed a 'vidget', requires V1. Parallel electrophysiological recordings in V1 revealed that plasticity, in the form of stimulus-selective response potentiation (SRP), occurred in layer 4 of V1 as OSH developed. Local manipulations of V1 that prevented and reversed electrophysiological modifications likewise prevented and reversed memory demonstrated behaviorally. These findings suggest that a form of long-term visual recognition memory is stored via synaptic plasticity in primary sensory cortex.Howard Hughes Medical InstituteNational Eye Institute (Grant RO1EY023037)Picower Institute for Learning and Memory (Innovation Fund)Picower Institute for Learning and Memory (Neurological Disorder Research Fund)JPB Foundation (Fellowship)National Institute of Mental Health (U.S.) (Training Grant 5T32MH074249)National Institute of Mental Health (U.S.) (Grant K99MH099654

Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3β is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3β phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3β. The LTP deficits can be attenuated/rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3β in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.Supported by the Wellcome Trust and an Alzheimer's Research Trust Fellowship for F.P.Peer reviewe