Rectified activity-dependent population plasticity implicates cortical adaptation for memory and cognitive functions.

Cortical network undergoes rewiring everyday due to learning and memory events. To investigate the trends of population adaptation in neocortex overtime, we record cellular activity of large-scale cortical populations in response to neutral environments and conditioned contexts and identify a general intrinsic cortical adaptation mechanism, naming rectified activity-dependent population plasticity (RAPP). Comparing each adjacent day, the previously activated neurons reduce activity, but remain with residual potentiation, and increase population variability in proportion to their activity during previous recall trials.

Kdm4a is an activity downregulated barrier to generate engrams for memory separation.

Memory engrams are a subset of learning activated neurons critical for memory recall, consolidation, extinction and separation. While the transcriptional profile of engrams after learning suggests profound neural changes underlying plasticity and memory formation, little is known about how memory engrams are selected and allocated. As epigenetic factors suppress memory formation, we developed a CRISPR screening in the hippocampus to search for factors controlling engram formation.

State-dependent memory retrieval: insights from neural dynamics and behavioral perspectives.

Memory retrieval is strikingly susceptible to external states (environment) and internal states (mood states and alcohol), yet we know little about the underlying mechanisms. We examined how internally generated states influence successful memory retrieval using the functional magnetic resonance imaging (fMRI) of laboratory mice during memory retrieval. Mice exhibited a strong tendency to perform memory retrieval correctly only in the reinstated mammillary body-inhibited state, in which mice were trained to discriminate auditory stimuli in go/no-go tasks.

Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b.

Background And Purpose: Psoriasis is a common autoimmune skin disease that significantly diminishes patients' quality of life. Interactions between primary afferents of the somatosensory system and the cutaneous immune system mediate the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanisms of how primary sensory neurons regulate psoriasis formation.

Acquiring new memories in neocortex of hippocampal-lesioned mice.

The hippocampus interacts with the neocortical network for memory retrieval and consolidation. Here, we found the lateral entorhinal cortex (LEC) modulates learning-induced cortical long-range gamma synchrony (20-40 Hz) in a hippocampal-dependent manner. The long-range gamma synchrony, which was coupled to the theta (7-10 Hz) rhythm and enhanced upon learning and recall, was mediated by inter-cortical projections from layer 5 neurons of the LEC to layer 2 neurons of the sensory and association cortices.

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons.

Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re-recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks.

ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder.

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior.

Single Image-Based Vignetting Correction for Improving the Consistency of Neural Activity Analysis in 2-Photon Functional Microscopy.

High-resolution functional 2-photon microscopy of neural activity is a cornerstone technique in current neuroscience, enabling, for instance, the image-based analysis of relations of the organization of local neuron populations and their temporal neural activity patterns. Interpreting local image intensity as a direct quantitative measure of neural activity presumes, however, a consistent within- and across-image relationship between the image intensity and neural activity, which may be subject to interference by illumination artifacts. In particular, the so-called vignetting artifact-the decrease of image intensity toward the edges of an image-is, at the moment, widely neglected in the context of functional microscopy analyses of neural activity, but potentially introduces a substantial center-periphery bias of derived functional measures.

Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models.

Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disability in young females. RTT is mainly caused by mutations found in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Despite extensive studies, the molecular mechanism underlying RTT pathogenesis is still poorly understood.

Egr1-EGFP transgenic mouse allows in vivo recording of Egr1 expression and neural activity.

Background: Immediate-early genes (IEGs) have been serving as markers of active neurons for their rapid responses to stimulation. With the development of IEG-EGFP reporters by the GENSAT project, application of the IEGs have been greatly expanded. However, detailed validations for these systems are still lacking, causing trouble in the interpretation of the fluorescence signals.

Detecting Abnormal Neuronal Activity in a Chronic Migraine Model by Egr1-EGFP Transgenic Mice.

Chronic migraine (CM) is a highly disabling neurological disorder characterized by recurrent headache accompanied by a variety of sensory and/or emotional symptoms. However, the mechanisms of migraine onset and its chronicity have not been elucidated. The present study was designed to search for brain regions and neurons that were abnormally activated by CM and might be related to its pathogenesis and different concomitant symptoms.

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown.

Multimodal Memory Components and Their Long-Term Dynamics Identified in Cortical Layers II/III but Not Layer V.

Activity patterns of cerebral cortical regions represent the current environment in which animals receive multi-modal inputs. These patterns are also shaped by the history of activity that reflects learned information on past multimodal exposures. We studied the long-term dynamics of cortical activity patterns during the formation of multimodal memories by analyzing high-resolution 2-photon mouse brain imaging data of Immediate Early Gene (IEG) expression, resolved by cortical layers.

Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning.

The laminar organization of the cerebral cortex is a fundamental characteristic of the brain, with essential implications for cortical function. Due to the rapidly growing amount of high-resolution brain imaging data, a great demand arises for automated and flexible methods for discriminating the laminar texture of the cortex. Here, we propose a combined approach of unsupervised and supervised machine learning to discriminate the hierarchical cortical laminar organization in high-resolution 2-photon microscopic neural image data of mouse brain without observer bias, that is, without the prerequisite of manually labeled training data.

Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex.

Fear extinction is generally considered a form of new learning that inhibits previously acquired fear memories. Here, by tracking immediate early gene expression in vivo, we found that contextual fear extinction training evoked distinct neural ensembles in mouse retrosplenial cortex (RSC). The optogenetic reactivation of these extinction-activated neurons in the RSC was sufficient to suppress a fear response, while the reactivation of conditioning-activated neurons in the same area promoted a fear response.

Mammillary body regulates state-dependent fear by alternating cortical oscillations.

State-dependent memory describes a phenomenon that memory will be efficiently retrieved only when the brain state during retrieval matches the state during encoding. While a variety of psychoactive drugs, such as ethanol, cocaine, morphine and NMDA receptor antagonists, are able to induce state-dependent memory, the biological hallmark of brain state and neural mechanism of its regulation are still unknown. In this study, we found that MK-801 enhanced delta oscillations in awake mice, representing a drug-induced brain state, in which fear memory could only be successfully retrieved when the same drug condition was presented.

How Does the Sparse Memory "Engram" Neurons Encode the Memory of a Spatial-Temporal Event?

Episodic memory in human brain is not a fixed 2-D picture but a highly dynamic movie serial, integrating information at both the temporal and the spatial domains. Recent studies in neuroscience reveal that memory storage and recall are closely related to the activities in discrete memory engram (trace) neurons within the dentate gyrus region of hippocampus and the layer 2/3 of neocortex. More strikingly, optogenetic reactivation of those memory trace neurons is able to trigger the recall of naturally encoded memory.

Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α.

Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism.

The role of epigenetic regulation in learning and memory.

The formation of long-term memory involves a series of molecular and cellular changes, including gene transcription, protein synthesis and synaptic plasticity dynamics. Some of these changes arise during learning and are subsequently retained throughout life. 'Epigenetic' regulation, which involves DNA methylation and histone modifications, plays a critical role in retaining long-term changes in post-mitotic cells.

Activity-dependent p25 generation regulates synaptic plasticity and Aβ-induced cognitive impairment.

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner.

In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain.

The dynamic processes of formatting long-term memory traces in the cortex are poorly understood. The investigation of these processes requires measurements of task-evoked neuronal activities from large numbers of neurons over many days. Here, we present a two-photon imaging-based system to track event-related neuronal activity in thousands of neurons through the quantitative measurement of EGFP proteins expressed under the control of the EGR1 gene promoter.

3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism.

Alzheimer's disease (AD) is induced by many reasons, including decreased cellular utilization of glucose and brain cell mitochondrial damages. Degradation product of microbially synthesized polyhydroxybutyrate (PHB), namely, 3-hydroxybutyrate (3HB), can be an alternative to glucose during sustained hypoglycemia. In this study, the derivative of 3HB, 3-hydroxybutyrate methyl ester (HBME), was used by cells as an alternative to glucose.

Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity.

Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity.

An epigenetic blockade of cognitive functions in the neurodegenerating brain.

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible.