Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification.

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or H2A.Z.1 with impaired acetylation (acetyl-defective) by replacing the same lysines with alanine (KA). Expressing the H2A.Z.1 acetyl-mimic (H2A.Z.1KQ) improved memory under weak learning conditions, whereas expressing the acetyl-defective H2A.Z.1KA generally impaired memory, indicating that the effect of H2A.Z.1 on memory depends on its acetylation status. RNA sequencing showed that H2A.Z.1KQ and H2A.Z.1KA uniquely impact the expression of different classes of genes in both females and males. Specifically, H2A.Z.1KA preferentially impacts genes involved in synaptic function, suggesting that acetyl-defective H2A.Z.1 impairs memory by altering synaptic regulation. Finally, we describe, for the first time, that H2A.Z is also involved in alternative splicing of neuronal genes, whereby H2A.Z depletion, as well as expression of H2A.Z.1 lysine mutants influence transcription and splicing of different gene targets, suggesting that H2A.Z.1 can impact behavior through effects on both splicing and gene expression. This is the first study to demonstrate that direct manipulation of H2A.Z post-translational modifications regulates memory, whereby acetylation adds another regulatory layer by which histone variants can fine tune higher brain functions through effects on gene expression and splicing.

The Effects of Cervical Orthoses on Head and Intervertebral Range of Motion.

STUDY DESIGN: Prospective Cohort. OBJECTIVE: Quantify and compare the effectiveness of cervical orthoses in restricting intervertebral kinematics during multiplanar motions. SUMMARY OF BACKGROUND DATA: Previous studies evaluating the efficacy of cervical orthoses measured global head motion and did not evaluate individual cervical motion segment mobility. Prior studies focused only on the flexion/extension motion. METHODS: Twenty adults without neck pain participated. Vertebral motion from the occiput through T1 was imaged using dynamic biplane radiography. Intervertebral motion was measured using an automated registration process with validated accuracy better than 1 degree. Participants performed independent trials of maximal flexion/extension, axial rotation, and lateral bending in a randomized order of unbraced, soft collar (foam), hard collar (Aspen), and cervical thoracic orthosis (CTO) (Aspen) conditions. Repeated-measures ANOVA was used to identify differences in the range of motion (ROM) among brace conditions for each motion. RESULTS: Compared with no collar, the soft collar reduced flexion/extension ROM from occiput/C1 through C4/C5, and reduced axial rotation ROM at C1/C2 and from C3/C4 through C5/C6. The soft collar did not reduce motion at any motion segment during lateral bending. Compared with the soft collar, the hard collar reduced intervertebral motion at every motion segment during all motions, except for occiput/C1 during axial rotation and C1/C2 during lateral bending. The CTO reduced motion compared with the hard collar only at C6/C7 during flexion/extension and lateral bending. CONCLUSIONS: The soft collar was ineffective as a restraint to intervertebral motion during lateral bending, but it did reduce intervertebral motion during flexion/extension and axial rotation. The hard collar reduced intervertebral motion compared with the soft collar across all motion directions. The CTO provided a minimal reduction in intervertebral motion compared with the hard collar. The utility in using a CTO rather than a hard collar is questionable, given the cost and little or no additional motion restriction.