Changes in Gut Microbiota Lead to Depressive Behavior Through the Vagus Nerve in Mice

Post by Megan McCullough

The takeaway

Chronic stress induces changes in the gut microbiome that leads to deficits in hippocampal neurogenesis (i.e. the growth of new neurons) and increases in depression-related behaviors. The vagus nerve plays a key role in mediating these gut associated effects on the brain.  

What's the science?

Beyond being a major risk factor for depression, chronic stress has been shown to disrupt the gut microbiome. Previous research has shown that an imbalance in the gut microbiome can affect hippocampal neurogenesis and induce behaviors associated with depression, although the exact mechanisms of this relationship are unclear. One proposed explanation for the relationship between the gut and the brain is the vagus nerve - known to facilitate bidirectional communication between the two. This week in Molecular Psychiatry, Siopi and colleagues examined the effects of gut microbiome changes on brain and behavior by transferring fecal microbiota from stressed mice into healthy mice and evaluating the effect on neurogenesis and neurotransmission. The authors then removed the vagus nerve in mice to study its impact on the relationship between gut microbiome and the brain.

How did they do it? 

First, the authors exposed a group of male mice to unpredictable mild stressors such as cage shaking and cage tilting over a period of 8 weeks. After this period, fecal samples were harvested from the group of stressed mice and transferred into the gut microbiomes of mice that did not undergo these stress procedures. The authors then verified that this inoculation of stress-triggered gut microbiota activated the vagus nerve by looking at neuronal activity in the region of the brain where the vagus nerve projects.

Next, the authors studied whether vagus nerve activation affected neuronal activity in the hippocampus. This brain region is pertinent to depression research because it is involved in memory, learning, and emotional processing, and is also a site for neurogenesis. To examine the effects of vagus nerve activation on hippocampal neurons, the authors measured the levels of c-Fos proteins, a protein expressed when neurons fire action potentials. The authors then examined the behavioral effects of receiving a stressed gut microbiome. Behavioral tests to measure depression related behaviors such as the sucrose preference and novelty suppressed feeding tests were administered on the mice.

Finally, the authors tested the hypothesis that the vagus nerve mediates the effects of a stressed gut on neurogenesis and depression-related behaviors. To assess this, a group of both control mice and mice with a stressed gut microbiome underwent a procedure damaging the vagus nerve. Neuronal activity and behavior were then measured in this group of mice and compared to the groups of mice that did not have the vagotomy.

What did they find?

The authors found that transferring the gut microbiota from stressed mice into healthy mice activated the vagus nerve; there were significant c-Fos immunoreactivity patterns sustained for up to at least 24 hours after the fecal transplant. This vagus nerve activation affected neuronal activity in the hippocampus; there were also increases of c-Fos immunoreactivity in the dentate gyrus of the mice.  Furthermore, the authors found a decrease in the expression of enzymes that synthesize serotonin and dopamine and decreases in the production of new neurons in the hippocampus. This suggests that changes in the gut microbiome due to stress have an impact on the neurogenesis and neuronal activity in the hippocampus. These changes in the brain translated to changes in behavior; mice with stressed gut bacteria displayed more depression-like behaviors than control mice.

When the authors studied a group of mice that underwent a vagotomy (damage to the vagal nerve), they found that these mice did not display the same depression-like behaviors nor have the same changes in brain chemistry as did mice with an intact vagus nerve. Damage to the vagus nerve was a protective factor against the neurological effects of changes in gut microbiota due to stress.

What's the impact?

This study is the first to investigate the role of the vagus nerve in mediating the effects of changes in gut microbiota due to chronic stress on neurogenesis and behaviors in adult mice. The authors found that chronic stress changes gut microbiota and activates the vagus nerve, leading to deficits in serotonin and dopamine neurotransmission that leads to decreases in neurogenesis and increases in depression related behaviors. These changes in the brain require an intact vagus nerve which illustrates the key role that the vagus nerve has in brain-gut communication. This research provides an opportunity for new therapies for treatment resistant depression. 

Access the original scientific publication here.

How Does Episodic-Like Memory Formation Develop?

Post by Baldomero B. Ramirez Cantu

The takeaway

The development of the hippocampus from birth involves multiple stages of functional maturation, which are responsible for increases in the precision of episodic and episodic-like memory as we age. Engram sparsity (i.e. how scattered or distributed it is across brain regions) and the maturation of a specific subset of inhibitory interneurons are key features of this development.

What's the science?

Episodic memory refers to an individual's personal recollection of experiences, events, and situations, which is not innate but rather developed through brain maturation. However, the specific neurobiological mechanisms underlying the transition from gist-like memories to more precise, detailed memories remain unclear. This week in Science, Ramsaran and colleagues provide insights into the underlying neurobiological basis of the development of episodic-like memory. 

How did they do it?

The authors used a variety of techniques in order to investigate the development of hippocampal engrams (i.e. physical memory traces in the brain) and episodic-like memory in mice. They primarily relied on behavioral assays of memory, optogenetic and chemogenetic manipulations, and immediate early gene expression markers. First, the authors trained mice in contextual fear conditioning tasks at different ages in order to test their ability to recall a particular context as a function of their age. They optogenetically silenced the activity of the CA1 region of the hippocampus while the mice performed this task in order to first check whether the task was hippocampus dependent in juvenile and adult mice.

Next, they manipulated CA1 activity by expressing either excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs) and observed the effect that these manipulations had on engram size and sparsity. The authors then tested the role of CA1 neurons in memory recall in mice aged 20, 24, and 60 days by expressing both excitatory and inhibitory opsins in the same subset of neurons. They expressed an inhibitory DREADD into parvalbumin expressing (PV) inhibitory interneurons to test the role of these neurons in engram density and sparsity. Furthermore, the authors perturbed the expression of perineuronal nets (PNNs) — crucial for the appropriate development and function of parvalbumin inhibitory interneurons — using a viral vector approach.

What did they find?

Inhibiting a subset of CA1 neurons with inhibitory DREADDs prior to memory acquisition decreased engram size and led juvenile mice to display adult-like memory precision. Conversely, activating these neurons with excitatory DREADDs increased engram size and caused adult mice to exhibit juvenile-like memory. Silencing of CA1 neurons using the bidirectional optogenetic strategy described above hindered fear recall in 24 and 60 day old mice, but not in 20 day old mice. This suggests that information is stored in a much broader subset of neurons in the 20 day old mice and therefore that the sparser the engram is, the more precise the memory is. Therefore inhibiting only a subset of these neurons is not sufficient to fully impair memory recall. Chemogenetic inhibition of PV neurons during learning caused the expression of juvenile-like memory allocation and imprecision. These findings support the hypothesis that immature PV neuron function may underlie juvenile-like memory phenotypes. Perturbing and destabilizing CA1 PNN resulted in imprecision of contextual memory, while accelerating the maturation of CA1 PNN led to adult-like engram formation and precise contextual memory acquisition.

What's the impact?

This study expands our understanding of how memory develops and is stored in the brain and can inform the development of strategies for enhancing memory function and treating memory-related disorders. In addition, this research provides important insights into the complex processes of neural development and maturation. 

Targeting the Gene that Produces Tau to Fight Alzheimer’s Disease

Post by Christopher Chen

The takeaway

MAPT is a gene in the body that codes for tau, one of the key pathological markers of Alzheimer’s disease (AD). By using a new therapeutic designed to disrupt MAPT, researchers found that treated patients saw more than a 50% reduction in tau levels.

What's the science?

Affecting over 50 million people worldwide, AD is a neurodegenerative disease resulting in severe cognitive decline and decreases in quality of life. A critical pathological marker in AD is tau, a protein in neurons that at certain levels will prevent a neuron’s ability to “talk” with other neurons, a process called neurotransmission. Animal models that express AD-like phenotypes show marked increases in tau accumulation as well as decreased overall brain function. Conversely, researchers have found that lowering tau production in animal models leads to enhancements in memory and overall brain functioning.

In humans, the gene MAPT codes for tau production. Thus, strategies aimed at reducing MAPT activity may lead to reductions in tau levels and improvement in symptoms of AD. Synthetic molecules called antisense-nucleotide oligonucleotides (ASO) can hijack a gene’s ability to make new proteins (like tau), thus making them good potential therapeutic agents to use in the fight against AD. In a recent article in Nature Medicine, researchers conducted a clinical trial where they injected patients with AD with an ASO called MAPTRx to see if doing so would lead to a reduction in tau levels. 

How did they do it?

The randomized, double-blind, placebo-controlled clinical trial was conducted over a 36-week period (13-week treatment period + 23-week post-treatment period) across multiple research centers and focused on 46 total patients (34 experimental, 12 placebo) with mild AD. In short, patients were given a spinal injection of either MAPTRx or placebo at fixed intervals throughout a 13-week period with tau levels in the cerebrospinal fluid (CSF) taken at specific timepoints during the 36-week period.  

One of the trial’s primary goals was the overall safety of MAPTRx so researchers employed a diverse set of techniques to measure physiological and cognitive health throughout the trial. Specifically, researchers recorded any adverse events patients experienced, gave neurological and physical exams, took bloodwork, and measured readouts from MRI and electrocardiograms (EEG).

There were also therapeutic goals that focused on how well patients metabolized the drug and whether it lowered overall tau levels. To understand MAPTRx’s pharmacokinetics (PK), or how the drug was metabolized in the body, researchers used a variety of specialized measurement techniques to quantify whether increasing dosages of MAPTRx resulted in higher baseline levels in the body. As for quantifying the amount of tau, researchers used similar measurement techniques to compare the concentration of tau in the CSF from experimental and control cohorts.  

What did they find?

Considering the trial was early phase, researchers were primarily focused on the safety of MAPTRx. First, injection of MAPTRx did not lead to any adverse events deemed severe or serious, with all symptoms being recorded as either mild (88%) or moderate (12%). The most common symptom was a post-lumbar puncture headache, which was a mild headache following the spinal injection. As for the drug’s metabolic profile, MAPTRx concentrations were found in dose-dependent concentrations, showing that the body did not eliminate it immediately and suggesting that the drug remains in the body long enough to exert its therapeutic effects.

In terms of lowering overall tau concentration, MAPTRx-treated patients expressed on average ~50% reduction in CSF tau concentration compared to controls. However, no significant therapeutic effects of these reductions were seen on cognitive assessments in post-treatment analysis. It should be noted that this study was not powered to show a cognitive benefit; such a trial would require larger numbers of participants. The authors are exploring this in a phase 2 trial that is ongoing. The value of the exploratory cognitive measures is in how they will inform future clinical trials more focused on the effects of MAPTRx on AD-related health outcomes.

What's the impact?

This clinical trial was the first of its kind using ASO-mediated treatment of AD. It showed that the drug was relatively well-tolerated in the body and that such treatment did not lead to any severe side effects in patients. Perhaps most significantly, it showed target engagement: treated patients saw on average a 50% reduction in tau levels in the body. While the drug’s overall ability to slow the cognitive decline associated with AD is still unclear, researchers acknowledged that more comprehensive trials are needed to determine the full therapeutic potential of MAPTRx.

Access the original scientific publication here.