Helen Anscomb

TNF-α and its receptors modulate complex behaviours and neurotrophins in transgenic mice.

UNLABELLED Tumour necrosis factor-α (TNF-α) plays an important role not only in immunity but also in the normal functioning of the central nervous system (CNS). At physiological levels, studies have shown TNF-α is essential to maintain synaptic scaling and thus influence learning and memory formation while also playing a role in modulating pathological states of anxiety and depression. TNF-α signals mainly through its two receptors, TNF-R1 and TNF-R2, however the exact role that these receptors play in TNF-α mediated behavioural phenotypes is yet to be determined. METHODS We have assessed TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice against C57BL/6 wild-type (WT) mice from 12 weeks of age in order to evaluate measures of spatial memory and learning in the Barnes maze (BM) and Y-maze, as well as other behaviours such as exploration, social interaction, anxiety and depression-like behaviour in a battery of tests. We have also measured hippocampal and prefrontal cortex levels of the neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) as well as used immunohistochemical analyses to measure number of proliferating cells (Ki67) and immature neurons (DCX) within the dentate gyrus. RESULTS We have shown that young adult TNF(-/-) and TNF-R1(-/-) mice displayed impairments in learning and memory in the BM and Y-maze, while TNF-R2(-/-) mice showed good memory but slow learning in these tests. TNF(-/-)and TNF-R2(-/-) mice also demonstrated a decrease in anxiety like behaviour compared to WT mice. ELISA analyses showed TNF(-/-) and TNF-R2(-/-) mice had lower levels of NGF compared to WT mice. CONCLUSION These results indicate that while lack of TNF-α can decrease anxiety-like behaviour in mice, certain basal levels of TNF-α are required for the development of normal cognition. Furthermore our results suggest that both TNF-R1 and TNF-R2 signalling play a role in normal CNS function, with knockout of either receptor impairing cognition on the Barnes maze.

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

BackgroundTumour necrosis factor - alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS).AimThe aim of this review is to critically analyse neurobiological, immunological and molecular mechanisms through which TNF-α influences the development of cognitive dysfunction.Principal findings/resultsThe review presents several lines of original research showing that the immunological properties of TNF-α exacerbate inflammatory responses in the central nervous system such as microglial and endothelial activation, lymphocytic and monocytic infiltration and the expression of downstream pro-inflammatory cytokines and apoptotic factors. Depression, schizophrenia, and MS all manifest symptoms of activated immune response along with cognitive dysfunction, with TNF-α overexpression as a central clinical feature common to these disorders. Furthermore, TNF-α acts negatively on neuroplasticity and the molecular mechanisms of memory and learning (i.e., long-term potentiation and long-term depression). TNF-α also exerts influence over the production of neurotrophins (i.e., nerve growth factor and brain-derived neurotrophic factor), neurogenesis, and dendritic branching.Conclusions/significanceThis review outlines that TNF-α and its receptors have a substantial yet underappreciated influence on the development and progression of neuropsychiatric symptoms across several disease entities. An improved understanding of these underlying mechanisms may help develop novel therapeutic targets in the form of drugs specifically targeting downstream products of TNF-α activation within the central nervous system.

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF)-α has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated the effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviors and microglia and astrocyte numbers. Twelve-week-old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 h before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioral analyses for locomotion, memory, and anxiety-like behavior 24 h post-etanercept/aCSF treatment, and tissue was collected to estimate the numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behavior, which was significantly improved following treatment with etanercept (two-way ANOVA: Interaction: F(1,30)=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023). For cognition, a significant interaction effect found by two-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared with Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (two-way ANOVA: Interaction: F(1,15)=11.41, P=0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08). Centrally administered etanercept improved anxiety-like behavior but not spatial memory under a peripheral immune challenge and was associated with a decrease in the hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behavior possibly mediated by a reduction of TNF-α-related central inflammation.

Tumor necrosis factor alpha and its receptors in behaviour and neurobiology of adult mice, in the absence of an immune challenge.

Tumor necrosis factor alpha (TNF-α) is a vital component of the immune system and CNS. We previously showed that 3-month-old TNF-α and TNF-α receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-α effects in the brain, we investigated the behaviour of 6-month-old TNF-α knockout mice and their neurobiological correlates. 6-month-old TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippocampal levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1β were measured. TNF-R1(-/-) and TNF(-/-) mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1(-/-) mice displayed better memory than WT and TNF-R2(-/-) mice. Both TNF(-/-) and TNF-R2(-/-) mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF(-/-) mice expressed significantly lower levels of BDNF than WT mice in the hippocampus while TNF-R1(-/-) mice displayed significantly lower BDNF levels compared to both WT and TNF-R2(-/-) mice. TNF-R2(-/-) mice also displayed significantly higher levels of NGF compared to TNF-R1(-/-) mice. These results illustrate that TNF-α and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-α and its receptors even under immunologically unchallenged conditions.

Can teaching delivery mode lead to ongoing changes in student performance within human anatomy

In a 6-year MBBS course, students can undertake optional “selective” study in human anatomy during year 3. This subject is an advanced regional and applied study of human anatomy taught through cadaveric dissection. Recently, the offering of this subject has changed from a traditional semester offering (internal study, 13 weeks, 5 h per week) to an intensive “block mode” offering, where students engage in ∼60 h of dissection over 2 weeks, outside of semester. No change in student assessment has occurred, only the timeframe of teaching and assessment activities. The block mode study option for this subject has led to a significant increase in student performance within the subject (38% attained HD grade), whilst no significant change in student demographics has been identified (i.e., student GPA, prior study). Preliminary investigations (n 5 27) into the change in student performance has demonstrated continued improved performance(using anatomy assessment tasks aligned to the dissection subject) 6 months after finishing study, when compared to a control group (n 5 25). Students were also surveyed to determine their reflections and perceptions of the subject. Students reported that the combination of mode of delivery and teaching method allowed a deeper study of the subject and greater achievement.

Approaches to improve student academic success in a mixed year 1 anatomy and physiology subject

In a 6-year MBBS course, students can undertake optional “selective” study in human anatomy during year 3. This subject is an advanced regional and applied study of human anatomy taught through cadaveric dissection. Recently, the offering of this subject has changed from a traditional semester offering (internal study, 13 weeks, 5 h per week) to an intensive “block mode” offering, where students engage in ∼60 h of dissection over 2 weeks, outside of semester. No change in student assessment has occurred, only the timeframe of teaching and assessment activities. The block mode study option for this subject has led to a significant increase in student performance within the subject (38% attained HD grade), whilst no significant change in student demographics has been identified (i.e., student GPA, prior study). Preliminary investigations (n 5 27) into the change in student performance has demonstrated continued improved performance(using anatomy assessment tasks aligned to the dissection subject) 6 months after finishing study, when compared to a control group (n 5 25). Students were also surveyed to determine their reflections and perceptions of the subject. Students reported that the combination of mode of delivery and teaching method allowed a deeper study of the subject and greater achievement.

Designing a clinical anatomy and pathology curriculum for 'transition' into clinical training, through the application of First Year Curriculum (FYC) principles

Background: Social media (SoMe) are increasingly becoming fundamental components of networking and dissemination at academic conferences, for which Twitter can be a valuable tool [1,2]. We sought to investigate the role, usage and contributions of Twitter at Anatomical Society (AS) conferences in order to identify the value of this approach to delegates, members and the Society. The increased availability and utility of SoMe analytics have allowed detailed investigations of SoMe activity to be performed.

Authentic and career-relevant teaching and assessment approaches in medical human anatomy

Good teaching practice aims to create a constructivist environment for learning where the student is centrally placed, actively engaged, and deep learning is promoted. This can be achieved through an integrated curriculum where the boundaries imposed by traditional discipline areas are transcended and a career-relevant context for the assimilation of content, skills, and processes is achieved. However, current integrated curriculum designs appear better to align some disciplines than others. Human anatomy is an important preclinical discipline that links directly to clinical skills and to postgraduate surgical specializations. Yet through some teaching approaches, preclinical human anatomy can fail to focus on the skills, strategies, values, and principles that link to clinical practice in a meaningful framework. This article describes the design and development of a preclinical human anatomy module within an integrated medical curriculum. The module design not only complements the current integrated curriculum, it does so in a way that fully engages and motivates students and develops a preclinical–clinical learning continuum. This is achieved through the use of authentic assessment tasks and by repositioning assessment within the module to align meaningfully with the ultimate career relevant goals and needs of the student. Student satisfaction, experience, and competencies in anatomy were then assessed. Human anatomy is a discipline area potentially widely underserved by current integrated curricular design and assessment practices. The teaching and learning strategies applied here have lead to demonstrated improvement in the understanding and clinical application of anatomy and an enhanced student learning experience.