How should we be using exercise as a tool to protect our brains?

It is well-accepted that physical exercise is beneficial for your health, but researchers are still investigating how exactly these benefits translate in the brain.  Many studies have shown that aerobic exercise increases neurogenesis and improves cognitive performance, but the exact mechanism connecting these two observations is still unclear. Two recent publications have reported interesting results describing how exercise type, genetic variance, and external stress affect the brain. The experiments are both done in rodents, so take the results with a grain of salt.

What the best type of exercise I can do for my brain?

While most clinicians are likely to encourage any physical activity, Nokia et al investigated the effects of three different types of exercise on neurogenesis in the hippocampus, the region of the brain critical for memory, learning, and stress response. Rodent exercise research generally employs a running wheel to simulate aerobic exercise, but here the authors compared three different exercise regimens: 1) sustained aerobic endurance exercise (ie. Voluntary running wheel or motorized treadmill), 2) high-intensity interval training (speed intervals on treadmill) and, 3) anaerobic resistance training (ie. weighted climbing). Interestingly, the authors found markers of cell proliferation, maturation, and survival- all indicative of neurogenesis- were only significant in rats that had completed the endurance training, which included voluntary running on a running wheel 3 times per week for 6 weeks. Moreover, they found the effects were most significant in rats genetically predisposed to respond to physical exercise (ie. maximal running distance increased following 8 weeks of treadmill training as opposed to no change). Take home: Sustained aerobic exercise is the most effective training paradigm to promote hippocampal neurogenesis, especially if you are running voluntarily and genetically predisposed to show gains in aerobic fitness with training.

Can exercise protect my brain?

Stress is known to negatively impact mood and impair memory, while simultaneously eliminating dendritic spines in the brain. Because exercise is known to improve memory function, Chen et al investigated whether exercise could rescue the negative effects of stress on behavior and spine stability. This study was carried out in mice who expressed fluorescent protein in their cortical neurons enabling in vivo transcranial monitoring of dendritic spine dynamics before and after exercise/stress intervention. Mice were physically stressed for 14days with or without one hour of continuous treadmill exercise, followed by behavioral testing, imaging, and brain protein/transcript quantification. The results showed that exercise not only prevented stress-induced anxiety and working memory loss, but also physically prevented spine elimination and enhancing survival of newly formed spines. The authors confirmed that the observed neuroprotective effects of exercise were conferred through the BDNF/TrkB pathway. Take home: Regular sustained aerobic activity can prevent the deleterious effects of stress on your brain.

Better get moving!


Chen et al. Treadmill exercise suppressed stress0induced dendritic spine elimination in mouse barrel cortex and improved working memory via BDNF/TrkB pathway. Transl Psychiatry (2017) 7, e1069.

Nokia et al. Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained. J. Physiol 594. (2016) pp 1855-1873.


Schizophrenia and amyotrophic lateral sclerosis have more in common than we thought!

On the surface schizophrenia (SCZ) and amyotrophic lateral sclerosis (ALS) are quite different! SCZ is a chronic psychotic disorder that presents as a myriad of symptoms such as hallucinations and cognitive deficits, while ALS is a progressive neurodegenerative disorder that destroys motor neurons and downstream muscle movement. However, unexpected epidemiology links have emerged; higher than predicted rates of SCZ were discovered in relatives of ALS patients1 and polygenetic risk factors were identified in both patient populations2,3. Recently, McLaughlin et al. conducted a genome wide association study (GWAS) to compare polygenic risk factors between SCZ and ALS patients4. Association mapping of over 100,000 individuals identified a positive genetic correlation of 14%4. Interestingly, this correlation was specific to SCZ and was not found when comparing ALS to bipolar disorder, major depressive disorder, autism spectrum disorder, or Alzheimer’s disease. Supporting these results, authors found that SCZ polygenetic risk factors were significantly higher among ALS patients compared to healthy controls. Through this work novel ALS-associated genes were discovered, including genes with roles in axon connectivity and autoimmunity. The authors speculated that shared genetic risk factors between SCZ and ALS may converge on neural network dysregulation. The authors further suggested that therapeutic strategies beneficial for ALS may be beneficial for SCZ and vice versa.  

Given the shared genetic background and pathophysiological differences between SCZ and ALS, it is tempting to envision a role for epigenetic mechanisms in disease divergence. Moving forward it would be interesting to profile the occupancy of epigenetic enzymes on shared risk factor genes. It would also be interesting to compare in vivo epigenetic enzyme expression (for example with neuroepigenetic PET imaging!) in SCZ and ALS populations.



1) Byrne, S. et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case–control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann. Neurol. 74, 699–708 (2013).

2) Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

3) van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043–1048 (2016).

4) McLaughlin, R. et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat. Communications 8:14774 (2017).


Everybody Makes Mistakes

Just when you thought you could beat cancer by staying healthy and maybe taking a wheatgrass shot here and there, science comes and tells you you’re wrong. A new study at Johns Hopkins found that DNA copying errors might cause some cases of cancer. These cancers occur more often than others and usually are prevalent most among patients that are relatively healthy. This study took a mathematical approach to how likely a cancer is to occur based on environmental factors, genes, or DNA replication errors. Cancer types that are most likely due to replication errors are colon, brain, bone, and pancreatic cancers. The more our cells divide, the greater the chance that errors will occur. This is problematic for a society that has an increasing lifespan. While this study does not say environmental factors are not detrimental, it does mean that many cancers are unavoidable if a healthy cell decides to be lazy during the replication process. Moral of the story: stop pretending like you enjoy wheatgrass shots and live a little. 





65 is the new 77, in some; TMEM106B gene variants accelerate normal brain aging

Understanding factors linked to normal development and aging of the brain is an essential step in defining molecular features of brain disease. Age-related research is challenging – vast differences are apparent on an individual level with respect to chronological age and cognition (to take only a single example!). Even in the aging people I know (sorry, parents, it’s true!) it’s obvious that even in good health, age impacts each brain differently.  

 A new report from Columbia University Medical Center in the journal Cell Systems has used gene expression and genome-wide association (GWAS) methods to refine genetic details of normal age-associated phenotypes via ‘differential aging’. Using postmortem samples from cerebral cortex, authors Rhinn and Abeliovich first investigated the transcriptome profiles from nearly 2000 individuals. They used these data to identify an age-dependent set of genes and then based on the correlation of gene expression with known age, estimated the aging rate of each individual sample. Amazingly, in samples from individuals >65 years old, the aging rate in the cerebral cortex was found to be accelerated by as many as 12 years.

 Some samples suggested that aging was progressing faster than in others. To further understand this, the authors then used GWAS analysis to investigate the relationship of genetic polymorphisms (like typographical errors in the sequences of genes) throughout the genome to rate of aging.  Two surprising results came back:

In a Manhattan plot, the tallest ‘skyscrapers’ evident in plots of the GWAS data suggested that a highly significant impact on ageing rate was linked to polymorphisms in the gene TMEM106B and, to a lesser extent, GRN (the gene encoding the granulin protein). 

 TMEM106B encodes the transmembrane protein 106B, involved in the maintenance of dendrites – essential branch-like projections from neural cells that enable communication between cells in the brain.  Work in the last 5-10 years has already implicated TMEM106B and GRN in age-related neurodegenerative diseases including Frontotemporal dementia and Alzheimer’s disease (see further reading). However, the new results from Rhinn and Abeliovich demonstrate that genetic issues with TMEM106B and GRN contribute to age-related decline in cognition, elevated neuroinflammation and neuronal loss, even in the absence of known brain disease.

 Our lab’s ongoing work is actively visualizing new targets that may be related to brain aging. Overlaying information about TMEM106B and GRN polymorphisms could enrich our understanding about comprehensive factors that influence the way the healthy brain ages – and better map the molecular profiles of unhealthy brain aging via brain disease.


 Article: Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes. Rinn H & Abeliovich A. Cell Systems, Online March 16, 2017,



Further Reading:

1. What we know about TMEM106B in Neurodegeneration. Nicholson AM & Rademakers R. Acta Neuropathol. 2016 Nov; 132(5):639-651. 

2. Reassessment of Risk Genotypes (GRN, TMEM106B, and ABCC9 Variants) Associated with Hippocampal Sclerosis of Aging Pathology. Nelson PT, et al. J.Neuropathol.Exp.Neurol. 2015 Jan;74(1):75-84.

3. TMEM106B, the Risk Gene for Frontotemporal Dementia, is Regulated by the microRNA-132/212 Cluster and Affects Progranulin Pathways. Chen-Plotkin AS, et al. J.Neurosci. 2012 Aug 15; 32(33):11213-27.

4. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Finch N, et al. Neurology. 2011 Feb 1; 76(5):467-74. 


Big, Bigger, Giant (Viruses)

When researchers in 1992 took a closer look at Legionellosis, they came across big lumps visible in light microscopy inside amoeba, which they thought were gram positive bacteria.[1] When they found out however, that those gram positive lumps were actually viruses, they earned themselves the name Mimivirus, as they were MImicking MIcrobes quite well.[2] Since the initial realization that viruses can be just as big as some bacteria, even bigger strains have been discovered: Megavirus chilensis was the virus with the biggest capsid known until in 2013 pandoraviruses appeared on the virological landscape. Their capsids reach up to a micrometer in size and their genome is about 2.5 MB long! While that is the biggest viral genome known today, pithoviruses have the biggest capsids with around 1.5 micrometers.[3] 

Those newly discovered giant viruses are genomically diverse. A large part of their genetic information remains to be better understood, but some findings so far are already changing the way we look at the origins of cellular organisms. Mimiviruses encode proteins that resemble aminoacyl-tRNA-synthetases[4] and a rudimentary immune system against virophages.[5] Because they’re viruses however, they need a host to reproduce. The confusion starts when considering that those giant viruses might be older than cellular organisms. Hypotheses about Mimivirus’ crucial role in the development of life on earth,[6] or about viral origins of the three domains of life.[7] Others suggest that giant viruses represent remains of entire other “domains”.[8]


[1] Richard Birtles; TJ

 Rowbotham; C Storey; TJ Marrie; Didier Raoult (29 Mar 1997). "Chlamydia-like obligate parasite of free-living amoebae". The Lancet. 349: 925–926

[2] Bernard La Scola; Stéphane Audic; Catherine Robert; Liang Jungang; Xavier de Lamballerie; Michel Drancourt; Richard Birtles; Jean-Michel Claverie; Didier Raoult. (2003). "A giant virus in amoebae". Science. 299 (5615): 2033

[3] Yong, Ed (3 March 2014). "Giant virus resurrected from 30,000-year-old ice : Nature News & Comment". Nature

[4] Suzan-Monti M., La Scola B., Raoult D. (2006). "Genomic and evolutionary aspects of Mimivirus". Virus Research. 117 (1): 145–155.

[5] Levasseur A., Bekliz M., Chabriere E., Pontarotti P., La Scola B., Raoult D. MIMIVIRE is a defence system in mimivirus that confers resistance to virophage Nature 531, 249–252

[6] Siebert, Charles (2006-03-15). "Unintelligent Design". Discover Magazine

[7] Forterre, Patrick (2006). "Three RNA cells for ribosomal lineages and three DNA viruses to replicate their genomes: A hypothesis for the origin of cellular domain". PNAS. 103 (10): 3669–3674

[8] Garry Hamilton (Jan 23, 2016). "How giant viruses could rewrite the story of life on Earth". New Scientist.