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 MedicineYun 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.

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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.

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

Functional Connections in the Brain are Stronger in Females Resilient to Depression

What's the science?

One third of females will be diagnosed with depression (major depressive disorder) during their adolescence. Resilience refers to the ability to adapt well in response to stress and bounce back from challenging life experiences. Currently, we don’t know the brain mechanisms that underlie resilience in adolescents who are at risk for depression. This week in JAMA Psychiatry, Fischer and colleagues test whether brain functional connectivity can be a biomarker for resilience in adolescent females at risk for depression (i.e. depression runs in their family).

How did they do it?

65 adolescent females were recruited: 25 low risk control participants who did not develop depression (control), 20 whose parents had a history of depression and developed depression themselves (i.e. converted) and 20 whose parents had a history of major depressive disorder but did not develop depression (i.e. resilient). The brains of all participants were scanned several times using  resting-state fMRI (which measures brain function at rest) over several years. They compared functional connectivity (synchronous brain activity) between resilient and converted females and between resilient and control females. They assessed the functional connectivity profiles of three brain regions known to be involved in depression: the amygdala (emotion), the anterior insula (attention/cognition) and the dorsolateral prefrontal cortex (planning). They measured the relationship between functional brain connections and life events.

What did they find?

Females who were resilient to depression showed stronger functional connections in the brain between the amygdala (involved in fear and emotion) and the orbitofrontal cortex (involved in impulse control and modulating emotions). A stronger connection between these regions was associated with more positive life events. Resilient individuals also showed stronger connections between the dorsolateral prefrontal cortex (involved in planning and executive function) and the frontotemporal cortex (involved in cognitive control). Both resilient and converted groups had stronger functional connectivity within the salience network (a network of regions involved in attention and cognition) compared to the control group

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What's the impact?

This is the first study to show that functional connections in the brain can be markers for resilience to depression in adolescent females at high risk for depression. Stronger functional connections could represent adaptation in the brain in response to positive life experience. It is crucial to understand how adolescents can develop resilience to depression in order to better prevent and treat depression.

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A. Fischer et al., Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder. JAMA Psychiatry (2018). Access the original scientific publication here.