Stimulating an Entorhinal Cortex Circuit is Antidepressive

What's the science?

Major depressive disorder can lead to many structural and functional changes in  the hippocampus, including slowed neurogenesis (new neuron formation). Stimulation of the entorhinal cortex (which sends information to the hippocampus) can improve learning and memory. It is possible that entorhinal cortex stimulation could also relieve depression. Current depression therapies, including transcranial magnetic stimulation and electroconvulsive therapy, often have side effects, so more treatment options are needed. This week in Nature Medicine, Yun and colleagues test whether stimulating an entorhinal circuit is antidepressive in mice and uncover the mechanisms involved.  

How did they do it?

They knocked down a protein subunit (TRIP8b) of a protein channel (hyperpolarization channel) using a viral-mediated approach which reduces the number and sensitivity of these protein channels found on neurons. This increases the excitability of neurons in the entorhinal cortex. The hypothesis was that increased excitation in the entorhinal cortex would increase neurogenesis in the hippocampus, and in turn reduce depressive behavior in mice. They performed several experiments: They tested whether psychosocial stress (a model of depression) increases TRIP8b levels in neurons. Using viral-mediated TRIP8b knockdown, they confirmed the increased excitability of entorhinal cortex neurons that project to the hippocampus (dentate gyrus). They measured neurogenesis in the hippocampus (dentate gyrus) in TRIP8b knockdown and controls. They then tested whether antidepressive behavior and memory were changed in knockdown vs. controls and whether this was dependent on neurogenesis. Lastly, they used gene transfer and transgenic mice combined with chemogenetics to activate glutamatergic neurons (i.e. excitatory neurons) in the entorhinal cortex, in order to observe the effects on antidepressive behavior.

What did they find?

They found that psychosocial stress in mice resulted in increased levels of TRIB8b in entorhinal neurons that project to the dentate gyrus. After knockdown of TRIP8b, they found increased excitability of entorhinal cells and increased neurogenesis in the connected hippocampus (in the dentate gyrus), confirming the hypothesis that increased activity in the entorhinal cortex results in neurogenesis in the hippocampus. TRIP8b knockdown in the entorhinal cortex also resulted in antidepressive-like behavior and improved memory in mice. To test whether this was dependent on neurogenesis in the hippocampus, they used X-ray irradiation to ablate new neurons and found that antidepressive behavior was dependent on hippocampal neurogenesis. Using chemogenetics to chronically stimulate glutamatergic neurons in the entorhinal cortex, they found that glutamatergic neurons drove neurogenesis in the hippocampus and were responsible for antidepressive behavior.

What's the impact?

This is the first study to show that activity in the entorhinal-hippocampal circuit results in both the formation of new neurons in the hippocampus and antidepressive behaviors in mice. Altering activity in this entorhinal cortex circuit - previously appreciated only as a memory circuit - by stimulating it could be a new way to reduce symptoms of depression in humans.

S. Yun et al., Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive. Nature Medicine (2018). Access the original scientific publication here.

Brain Beta-Amyloid Levels Increase after Sleep Deprivation

What's the science?

Beta-amyloid is a protein that accumulates in the brain in Alzheimer’s disease and with aging. Sleep is thought to be important for clearance of beta-amyloid as a “waste product” and a lack of sleep over time has been associated with higher beta-amyloid in the brain. There is evidence that beta-amyloid is elevated in brain fluid in mice after acute sleep deprivation, however, it is not clear how acute sleep deprivation affects beta-amyloid levels in the human brain. This week in PNAS, Shokri-Kojori and colleagues use Positron Emission Tomography (PET) to assess whether beta-amyloid is elevated after short-term sleep deprivation in humans.

How did they do it?

PET imaging with a radiotracer called 18F-florbetaben which binds to beta-amyloid in the living human brain, was used to measure beta-amyloid levels in 20 healthy participants. Participants were scanned once after a healthy night of sleep and once after a night of sleep deprivation (no sleep) to compare beta-amyloid levels with and without proper sleep. Participants were given questionnaires related to their mood. Data about sleep history and quality were also collected. The authors hypothesized that beta-amyloid levels would be higher in the hippocampus (one of the first brain regions affected by Alzheimer’s disease) after one night of sleep deprivation and that a poor sleep history would be associated with higher beta-amyloid in brain regions known to be affected by Alzheimer’s disease: the medial prefrontal cortex, the hippocampus and the precuneus.

What did they find?

Beta-amyloid accumulation (measured with 18F-florbetaben) was higher in the right hippocampus after one night of sleep deprivation compared to after a good night’s sleep. The extent to which beta-amyloid increased varied between individuals. Mood was found to be worse after sleep deprivation, and this was correlated with the level of beta-amyloid in the regions showing elevated beta-amyloid such as the hippocampus. Reported hours of sleep per night was negatively correlated with beta-amyloid accumulation (i.e. higher sleep, lower beta-amyloid) in the right hippocampus and thalamus where acute sleep deprivation effects were seen. In a separate whole-brain regression analysis, hours of sleep was also negatively correlated with beta-amyloid levels in the putamen, parahippocampal gyrus and right precuneus (brain regions affected by beta-amyloid in Alzheimer’s disease) confirming that these are key regions affected by hours of sleep.

Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to show that one night of sleep deprivation is associated with higher beta-amyloid in the human brain. This study also highlights the relationship between hours of sleep (self-reported sleep history) and beta-amyloid accumulation. This study emphasizes that sleep is important for regulating beta-amyloid levels and that sleep deprivation could be one risk factor for brain protein accumulation in Alzheimer’s disease and aging.

E. Shokri-Kojori et al., β-Amyloid accumulation in the human brain after one night of sleep deprivation. PNAS (2018).  Access the original scientific publication here.

Antiepileptic Drugs Induce Mislocalization of Neurons in the Hippocampus

What's the science?

Valproic acid is an anti-epileptic drug prescribed to some pregnant women who have epilepsy. Use of the drug during pregnancy is associated with autism and Attention Deficit Hyperactivity Disorder in offspring, and these disorders are associated with a higher risk for seizures. High seizure risk has also been linked to mislocalized neural stem cells/progenitor cells in the hippocampus (which will become neurons in the hippocampus; a brain region involved in learning and memory). This week in PNAS, Sakai and colleagues explored whether exposure to valproic acid increased seizure susceptibility through hippocampal mechanisms in mice.

How did they do it?

To test whether exposure to valproic acid could cause seizures, they gave kainic acid (activates glutamate receptors and can promote seizure activity) to mice (at 12 weeks old) who had or had not been previously exposed to valproic acid prenatally. They used immunohistochemistry to locate progenitor cells in these mice. Next they used RNA-sequencing of neural stem cells/progenitor cells in the hippocampus at embryonic day 15, postnatal day 5, and 12 weeks old to identify differentially expressed genes whose expression levels varied due to prenatal valproic acid exposure at embryonic day 12, 13, and 14 (3 times). They then matched abnormal gene expression to known gene function (Gene Ontology analysis). Finally, they examined whether exercise (voluntary running) might mitigate the effects of valproic acid on seizure activity, due to its known role in neurogenesis (production of new neurons).

What did they find?

Mice exposed to valproic acid experienced increased susceptibility to seizures at 12 weeks of age, and increased mislocalization of newly generated neurons from stem cells/progenitor cells within the dentate gyrus (decreased in the granule cell layer, increased at the hilus). Several differentially expressed genes were present at different developmental stages in mice exposed to valproic acid, indicating that valproic acid affects gene expression in stem cells/progenitor cells the hippocampus. Using Gene Ontology, they identified several genes involved in cell and neuronal migration, including Cxcr4. When mice exposed to valproic acid voluntarily exercised (ran) for eight weeks, their susceptibility to seizures decreased and their Cxcr4 expression normalized, indicating that exercise may mitigate the effects of valproic acid on the hippocampus through Cxcr4.

What's the impact?

This is the first study to link valproic acid with mislocalization of hippocampal neurons and seizure susceptibility in the offspring of pregnant mice. We now have a better understanding of the mechanisms underlying the harmful effects of valproic acid. Exercise may be a particular avenue for focus, as it may mitigate the effects of improper hippocampal neuron placement on susceptibility to seizures.

A. Sakai et al., Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice. PNAS (2018). Access the original scientific publication here.