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The promyelocytic leukemia (PML) protein is the main component of PML nuclear bodies, which have many functions in a wide range of cell types. Until recently, PML was not known to have a function in the nervous system or even be expressed in the brain. However, recent reports have changed that view. PML is found in neurons and functions in many aspects of the nervous system, including brain development, circadian rhythms, plasticity, and the response to proteins that cause neurodegenerative disorders. While the investigation of PML in the brain is still in its infancy, it promises to be a fascinating subject that will contribute to our understanding of the brain. Here we summarize what is known about PML expression and function in the brain and highlight both discrepancies in the field and areas that are particularly important to future research. more...

Although MDD is one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments (1). Epidemiological studies have [...], Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors. more...

The development of standardized mental preparation procedures specific to cross country running performance is delineated, including a preliminary assessment of the relative efficacy of these interventions in 6 Division I [...] more...

Mutations in the gene encoding TDP-43-the major protein component of neuronal aggregates characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusion bodies-have been linked to familial forms of both disorders. Aggregates of TDP-43 in cortical and spinal motorneurons in ALS, or in neurons of the frontal and temporal cortices in FTLD, are closely linked to neuron loss and atrophy in these areas. However, the mechanism by which TDP-43 mutations lead to neurodegeneration is unclear. To investigate the pathogenic role of TDP-43 mutations, we established a model of TDP-43 proteinopathies by expressing fluorescently tagged wild-type and mutant TDP-43 in primary rat cortical neurons. Expression of mutant TDP-43 was toxic to neurons, and mutant-specific toxicity was associated with increased cytoplasmic mislocalization of TDP-43. Inclusion bodies were not necessary for the toxicity and did not affect the risk of cell death. Cellular survival was unaffected by the total amount of exogenous TDP-43 in the nucleus, but the amount of cytoplasmic TDP-43 was a strong and independent predictor of neuronal death. These results suggest that mutant TDP-43 is mislocalized to the cytoplasm, where it exhibits a toxic gain-of-function and induces cell death. [ABSTRACT FROM AUTHOR] more...

In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis. [ABSTRACT FROM AUTHOR] more...

The pathophysiology of neurodevelopmental disorders involves vulnerable neural populations, including striatal circuitry, and convergent molecular nodes, including chromatin regulation and synapse function. Despite this, how epigenetic regulation regulates striatal development is understudied. Recurrent de novo mutations in Zswim6 are associated with intellectual disability and autism. We demonstrate that ZSWIM6 localizes to the nucleus where it associates with repressive chromatin regulators. Disruption of Zswim6 in ventral telencephalic progenitors leads to increased chromatin accessibility and transcriptional dysregulation. Ablating Zswim6 in either striatal direct or indirect pathway spiny projection neurons resulted in similar cell-autonomous changes in excitatory but not inhibitory synaptic transmission. Specifically, Zswim6 disruption altered the desensitization properties of AMPA receptors, leading to enhanced synaptic recruitment of SPNs, explaining SPN-subtype specific effects on activity and behavioral sub-structure. Last, adult deletion of Zswim6 identified a continuing role in the maintenance of mature striatal synapses. Together, we describe a mechanistic role for Zswim6 in the epigenetic control of striatal synaptic development. [ABSTRACT FROM AUTHOR] more...

A cell's ability to respond and adapt to environmental stimuli relies in part on transcriptional programs controlled by histone proteins. Histones affect transcription through numerous mechanisms including through replacement with variant forms that carry out specific functions. We recently identified the first widely expressed H2B histone variant, H2BE and found that it promotes transcription and is critical for neuronal function and long-term memory. However, how H2BE is regulated by extracellular stimuli and whether it controls activity-dependent transcription and cellular plasticity remain unknown. We used CUT&Tag and RNA-sequencing of primary neurons, single-nucleus sequencing of cortical tissue, and multielectrode array recordings to interrogate the expression of H2BE in response to stimuli and the role of H2BE in activity-dependent gene expression and plasticity. We find that unlike Further, we show that neurons lacking H2BE are unable to mount proper long-term activity-dependent transcriptional responses both in cultured neurons and in animal models. Lastly, we demonstrate that H2BE knockout neurons fail to undergo the electrophysiological changes associated with homeostatic plasticity in neurons after long-term stimulation. In summary, these data demonstrate that H2BE expression is inversely correlated to activity and necessary for long-term activity-dependent responses, revealing the first instance of a histone variant involved in the homeostatic plasticity response in neurons., Competing Interests: Declaration of Interests: The authors have no conflicts of interest. more...

Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure., Competing Interests: Declaration of Interests: The authors have no conflicts of interest. more...

The basolateral amygdala (BLA) is essential for assigning positive or negative valence to sensory stimuli. Noxious stimuli that cause pain are encoded by an ensemble of noci ceptive BLA projection neurons (BLA noci ensemble). However, the role of the BLA noci ensemble in mediating behavior changes and the molecular signatures and downstream targets distinguishing this ensemble remain poorly understood. Here, we show that the same BLA noci ensemble neurons are required for both acute and chronic neuropathic pain behavior. Using single nucleus RNA-sequencing, we characterized the effect of acute and chronic pain on the BLA and identified enrichment for genes with known functions in axonal and synaptic organization and pain perception. We thus examined the brain-wide targets of the BLA noci ensemble and uncovered a previously undescribed noci ceptive hotspot of the nucleus accumbens shell (NAcSh) that mirrors the stability and specificity of the BLA noci ensemble and is recruited in chronic pain. Notably, BLA noci ensemble axons transmit acute and neuropathic noci ceptive information to the NAcSh, highlighting this noci ceptive amygdala-striatal circuit as a unique pathway for affective-motivational responses across pain states., Competing Interests: B.C.R. receives research funding from Novo Nordisk and Boehringer Ingelheim that was not used in support of these studies. The other authors declare no competing interests. more...