Check out some of the papers that were recently published by DMCBH members:

Haakon Nygaard, Brian MacVicar, Stephanie Willerth: hiPSC-derived GRN-deficient astrocytes delay spiking activity of developing neurons

Journal: Neurobiology of Disease

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders that are characterized by pathology predominantly localized to the frontal and temporal lobes. Approximately 40% of FTD cases are familial, and up to 20% of these are caused by heterozygous loss of function mutations in the gene encoding for progranulin (PGRN), GRN. While astrocytes and microglia have long been linked to the neuropathology of FTD due to mutations in GRN (FTD-GRN), a primary mechanistic role of these supporting cells have not been thoroughly addressed.

Here, the researchers utilized human induced pluripotent stem cell (hiPSC)-derived neural tissue carrying a homozygous GRN knock-in mutation to investigate GRN mutant astrocytes effect on neurons. This work represents one of the first studies investigating astrocyte-induced neuronal pathology in GRN mutant hiPSCs, and supports the hypothesis of astrocyte involvement in the early pathophysiology of FTD.


Cheryl Wellington, Peter Cripton and David Vocadlo: Altered Tau Kinase Activity in rTg4510 Mice after a Single Interfaced CHIMERA Traumatic Brain Injury

Journal: International Journal of Molecular Sciences

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative diseases. In this study,  the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) was used to investigate the effects of a single high-energy TBI in rTg4510 mice, a mouse model of tauopathy.

Immediately after injury, the TBI mice showed significant mortality and a prolonged duration of loss of the righting reflex. At 2 month post-injury, surviving mice displayed significant microgliosis and axonal injury. Western blotting indicated a reduced p-GSK-3β (S9):GSK-3β ratio in TBI mice, suggesting chronic activation of tau kinase. There were no significant differences in brain total or p-tau levels. In summary, this study shows that a single high-energy head impact induces chronic white matter injury and altered GSK-3β activity without an apparent change in post-injury tauopathy in rTg4510 mice.

 

Sarah Kraeutner: What we imagine learning from watching others: how motor imagery modulates competency perceptions resulting from the repeated observation of a juggling action

Journal: Psychological Research

Although motor learning can occur from observing others perform a motor skill (action observation; AO), observers’ confidence in their own ability to perform the skill can be falsely increased compared to their actual ability. Unlike AO, motor imagery (MI; the mental rehearsal of a motor skill) is thought to be linked to an understanding of movement consequences and kinaesthetic information. MI may thus provide the learner with movement-related diagnostic information, leading to greater accuracy in assessing ability.

The present study was designed to evaluate the effects of MI when paired with AO in assessments of one’s own motor capabilities in an online observation task. The addition of MI appeared to reduce confidence that resulted from repeated AO alone. Data supports the hypothesis that AO and MI are separable and that MI allows better access to sensory information than AO.

 

Kamyar Keramatian, Trisha Chakrabarty and Lakshmi Yatham: New Pharmacologic Approaches to the Treatment of Bipolar Depression

Journal: Drugs

Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression. Here, the researchers reviewed treatments for BD depression which are emergent or on the horizon.

Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics have demonstrated efficacy in randomized controlled trials (RCT). Non-racemic amisulpride showed potential therapeutic benefit in one RCT. Three small RCTs examined the efficacy of ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation.

 

Silke Appel-Cresswell: The Pain in Dystonia Scale (PIDS)—Development and Validation in Cervical Dystonia

Journal: Movement Disorders

A better understanding of pain in adult-onset idiopathic dystonia (AOID) is needed to implement effective therapeutic strategies. The objective of this study was to develop a new rating instrument for pain in AOID and validate it in cervical dystonia (CD). Development and validation of the Pain in Dystonia Scale (PIDS) comprised three phases. In phase 1, the preliminary items were generated and evaluated for content validity. In phase 2, the PIDS was drafted and revised, followed by cognitive interviews to ensure self-administration suitability. In phase 3, the PIDS psychometric properties were assessed in 85 participants with CD and retested in 40 participants.

The final version of PIDS evaluates pain severity, functional impact, and external modulating factors. Test–retest reliability showed a high-correlation coefficient for the total. The overall PIDS severity score showed high internal consistency. Convergent validity analysis revealed a strong correlation between the PIDS severity score and three other pain scales.

 

Shernaz Bamji: Activity-dependent post-translational regulation of palmitoylating and depalmitoylating enzymes in the hippocampus

Journal: Journal of Cell Science

Activity-induced changes in protein palmitoylation can regulate the plasticity of synaptic connections, critically impacting learning and memory. Palmitoylation is a reversible post-translational modification regulated by palmitoyl-acyl transferases and palmitoyl thioesterases. However, it is not clear how fluctuations in synaptic activity can mediate the palmitoylation of neuronal proteins.

Using primary hippocampal cultures, the researchers demonstrated that synaptic activity does not impact the transcription of palmitoylating and depalmitoylating enzymes, changes in thioesterase activity, or post-translational modification of the depalmitoylating enzymes of the ABHD17 family. In contrast, synaptic activity does mediate post-translational modification of the palmitoylating enzymes of the ZDHHC family. The findings demonstrate that signaling events activated by synaptic activity largely impact activity of the ZDHHC family of palmitoyl-acyl transferases with less influence on the activity of palmitoyl thioesterases.

 

Stephanie Willerth and Haakon Nygaard: Recent advances in personalized 3D bioprinted tissue models

Journal: MRS Bulletin

Three-dimensional (3D) bioprinting uses the defined layer-by-layer deposition of living cells incorporated into biocompatible materials that can be used to create 3D models of human tissues. Functional 3D in vitro models can better mimic the complex architecture of human tissues in vivo providing more accurate cell-to-cell and cell-to-matrix interactions, and a better supply of nutrients, oxygen, and drugs to cells than standard two-dimensional cultures.

This article examines recent advances and employments of these personalized models in cardiac, cancer, skin, and neuronal tissue applications based on the use of 3D printing and patient-derived cells, including induced pluripotent stem cells. These models can be used to generate patient-specific organ prototypes, drug screening platforms in preclinical studies, and engraftable tissues suitable for clinical practice proving themselves as promising new avenues for disease modeling, drug discovery, and regenerative medicine.

 

Liisa Galea: Are we moving the dial? Canadian health research funding trends for women’s health, 2S/LGBTQ + health, sex, or gender considerations

Journal: Biology of Sex Differences

The health of women and members of the Two-Spirit, Lesbian, Gay, Bisexual, Transgender, Queer or Questioning (2S/LGBTQ +) community is often compromised as they experience delays in diagnosis. Distinct knowledge gaps in the health of these populations have prompted funding agencies to mandate incorporation of sex and gender into research. The Canadian Institutes of Health Research (CIHR) implemented a sex and gender-based analysis (SGBA) framework.

To examine whether this mandate resulted in increased mention of sex or gender in funded research abstracts, the researchers searched the publicly available database of grant abstracts funded by CIHR. Overall, under 3% of grant abstracts explicitly mentioned sex and/or gender. Although there was an increased number of grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. These findings suggest more work needs to be done to ensure the public can evaluate what populations will be examined with respect to sex and gender to advance awareness and health equity in research.