Spatial distribution pattern and correlation of dominant populations in the shrub layer of Fengshui forest in Leizhou Peninsula, China.

To elucidate the spatial patterns of understory species in fragmented forests adjacent to human settlements, we examined the spatial distribution and intraspecific correlations of three dominant species Mallotus philippensis, Dasymashalon trichophorum, and Psychotria rubra by employing point pattern analysis, which were the top three in terms of importance value in the shrub layer of Fengshui forest in Leizhou Peninsula, Guangdong. The results showed that all the three species were mainly aggregated at the scale of 0-25 m, especially for young trees. The degree of aggregation gradually diminished with increasing age class. The spatial distribution patterns of three species were predominantly influenced by habitat heterogeneity, negative density dependence, and dispersal limitation. They showed positive association among different age classes, especially between young trees and middle age trees and between young trees and adult trees. Therefore, in the ecological restoration process of Leizhou Peninsula, M. philippensis, D. trichophorum, and P. rubra should be planted in clusters at a small scale within the range of 0-25 m, with the degree of clusters depending on plant morphology. For larger scales, a dispersed cultivation approach was advocated.

Cell Type-Specific Whole-Genome Landscape of ΔFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure.

BACKGROUND: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated. METHODS: We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons-D1 or D2 medium spiny neurons-after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. RESULTS: The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. CONCLUSIONS: These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.

Chromatin-mediated alternative splicing regulates cocaine-reward behavior.

Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.

[Spatial Patterns and Spatial Autocorrelations of Wetland Changes in China During 2003-2013].

Wetlands play an important role in maintaining ecosystem functions. Wetlands in China have suffered intensive human disturbance, especially before 2000, resulting in great losses and degradation. Therefore, two national wetland resource surveys were carried out by the Chinese government during 1998-2003 and 2008-2013 to determine the status of wetlands, understand their dynamics, and provide substantial data that can aid scientific wetland conservation. Based on the survey data, the spatial pattern and spatial autocorrelation were explored using the standard deviation ellipse as well as global and local spatial autocorrelation statistics. GIS mapping was employed to display the results via the visualization of the spatial patterns and relationships. Results indicate that:① Changes in the wetlands of China are significant and exhibit obvious regional differences. The center of the ellipse of the total wetlands has moved to the west, and the degree of spatial differentiation between natural wetlands and artificial wetlands is increasing. There is no significant spatial autocorrelation for changes in artificial wetlands. ② The changes in natural wetlands are significantly spatially autocorrelated and clustered, which are identified by global Moran's I and local Moran's I. The hotspots of natural wetland change are concentrated primarily in Qinghai, Tibet, and Sichuan. The individual hotspot is in Inner Mongolia and the cold spot is in Henan. The difference in spatial autocorrelation between natural and artificial wetland changes indicates that natural wetland changes have shown spatial continuity, while artificial wetland changes have shown strong spatial randomness. ③ Some useful spatial associations are used to delineate wetland conservation effects. Then, three major or five minor effective protection management regions are identified. Wetland conservation efforts should be continuously strengthened and improved, especially in the middle-lower Yangtze River region of central China. The use of Moran statistics helps to reveal spatial autocorrelation and identify the conservation effects in wetland changes, which can provide a basis for decision-making in regional wetland conservation and management systems.

Stress Regulation of Sustained Attention and the Cholinergic Attention System.

BACKGROUND: Stress exacerbates symptoms of schizophrenia and attention-deficit/hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. We investigated whether a 6-day variable stressor altered sustained attention and the cholinergic attention system in male and female rats. METHODS: Sustained attention was tested with the sustained attention task. Successful performance on the sustained attention task relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether variable stress (VS) altered the morphology of these neurons with a novel approach using a Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNA sequencing to identify VS-induced transcriptional changes in the NBM. RESULTS: VS impaired attentional performance in the sustained attention task and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of male rats. Quantification of global transcriptional changes revealed that although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes. CONCLUSIONS: These studies suggest that VS impairs attention by inducing molecular and morphological changes in the NBM. Identifying mechanisms by which stress regulates attention may guide the development of novel treatments for psychiatric disorders with attention deficits.

Recent advances in neuroepigenetic editing.

A wealth of studies in the mammalian nervous system indicate the role of epigenetic gene regulation in both basic neurobiological function and disease. However, the relationship between epigenetic regulation and neuropathology is largely correlational due to the presence of mixed cell populations within brain regions and the genome-wide effects of classical approaches to manipulate the epigenome. Locus-specific epigenetic editing allows direct epigenetic regulation of specific genes to elucidate the direct causal relationship between epigenetic modifications and transcription. This review discusses some of the latest innovations in the efficacy and flexibility in this approach that hold promise for neurobiological application.

Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition.

Cognitive decline is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet the causes remain unclear. Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, we postulated that its misregulation contributes to cognitive impairment preceding AD pathology. Here, we show that disruption of Tip60 histone acetlytransferase (HAT)/histone deacetylase 2 (HDAC2) homeostasis occurs early in the brain of an AD-associated amyloid precursor protein (APP) Drosophila model and triggers epigenetic repression of neuroplasticity genes well before Aß plaques form in male and female larvae. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD-associated APP brain restores Tip60 HAT/HDAC2 balance by decreasing HDAC2 levels, reverses neuroepigenetic alterations to activate synaptic plasticity genes, and reinstates brain morphology and cognition. Such Drosophila neuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. We suggest that Tip60 HAT/HDAC2-mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain.SIGNIFICANCE STATEMENT Mild cognitive impairment is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet its causes remain unclear. Although recent findings support elevated histone deacetylase 2 (HDAC2) as a cause for epigenetic repression of synaptic genes that contribute to cognitive deficits, whether alterations in histone acetlytransferase (HAT) levels that counterbalance HDAC2 repressor action occur and the identity of these HATs remain unknown. We demonstrate that disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the AD Drosophila brain and triggers epigenetic repression of neuroplasticity genes before Aß plaques form. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Our data suggest that disruption of the Tip60 HAT/HDAC2 balance is a critical initial step in AD.

Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC-dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole-cell patch-clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA-mEPSCs and synaptic NMDA-eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1-silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP-quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper-repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on page 264.