Does the Gut-Brain Axis Play a Role In the Emergence of Psychiatric Disorders?

Post by Lani Cupo

The takeaway

The gut-brain axis undergoes many changes in adolescence, and these can, in turn, impact the nervous system. It is possible that environmental changes impacting the gut may influence the emergence of psychiatric disorders during adolescence, but more research is required on the topic.

What's the science?

Over the past two decades, the gut-brain axis has increasingly been investigated as important to mental, psychiatric, and neurological health. Most research, however, has focused on the first years of life or old age, with few studies investigating the period of adolescence where both the gut microbiome and brain undergo many changes and psychiatric disorders commonly emerge. This week in Biological Psychiatry, McVey and colleagues sought to synthesize the current knowledge base around the impact of the environment on the gut-brain axis and its role in the emergence of psychiatric disorders during adolescence.

What did they review?

The authors performed a review of the literature on adolescent development and plasticity — or changeability — of the gut microbiome and the brain in adolescence in both human and nonhuman animal studies. The gut-brain axis comprises several component parts investigated in this review. The gut microbiome includes the microorganisms that live in the intestines. The enteric nervous system (ENS) comprises neural and glial cells that directly control the digestive tract (from the esophagus to the anus). While it operates largely independently of the central nervous system, the vagal nerves carry signals to and from the brain to the ENS. Finally, the review examined brain development during adolescence in the context of psychiatric development and atypicality.

What did they find?

First, examining the gut microbiome during adolescence, the authors found that the diversity and stability of microorganisms in the gut were altered, with important sex differences. Specifically, they found that during puberty male gut microbiomes became less diverse, whereas female microbiomes remained stable. There was evidence of bidirectional influence of gut microbiome and sex hormones, meaning the microbiome influences sex hormones and sex hormones influence the microbiome. An altered diet during adolescence is known to impact the gut microbiome as well, drawing attention to the impact of the adolescent environment.

While the authors found there was a lack of studies examining the ENS during adolescence, there was some evidence pointing to changes to the neurons and glia of the ENS during adolescence. For example, in the duodenum, the ratio of neurons to glia was reduced, but in the colon, it was increased. Regarding the vagal nerve, there is some association between changes in vagal tone, measured via heart-rate variability (changes in the interval between heartbeats), and poorer psychological and physical outcomes. Specifically low (worse) vagal tone in adolescence has been associated with later life cardiovascular disease risk, adolescent asthma, emotional dysregulation in adolescents with autism spectrum disorders, and clinical depression.

Adolescence is a period defined by many brain changes, including in the frontal lobes, which continue to develop well after puberty. Two major areas of brain development include synaptic density (synapses are pruned through childhood and adolescence) and myelination (which increases during early life and adolescence). Both of these processes result in greater efficiency of brain networks from childhood to early adolescence. The authors draw attention to the psychiatric disorders that emerge in adolescence, including major depressive disorder, anxiety disorders, eating disorders, and alcohol use disorders, for all of which there is evidence pointing to the association of alterations in the gut microbiome.

The authors also summarize evidence from nonhuman animal studies linking alterations in communication between the microbiome, gut, and brain and clinical dysfunction. The work they highlight indicates the role of the gut microbiome in modulating the HPA axis activity in response to acute stress, as well as the possibility of moderating the gut microbiome, gene expression in the brain, and behaviors with diet.

What's the impact?

The results of this review first draw attention to the potential role the gut microbiome may play in moderating the emergence of psychiatric disorders in adolescence. Importantly, however, this review identifies a lack of studies that comprehensively investigate this topic, and therefore more research is needed to understand how the gut microbiome influences the development of psychiatric disorders.

Access the original scientific publication here

Glioma Tumors Hijack Healthy Mechanisms of Neuroplasticity in Order to Grow

Post by Trisha Vaidyanathan 

The takeaway

Healthy neurons can form synapses with glioma tumor cells. These neuron-to-glioma synapses undergo a form of synaptic plasticity similar to healthy neurons, that is dependent on the release of brain-derived neurotrophic factor (BDNF), allowing tumor cells to proliferate and tumors to grow. 

What's the science?

Gliomas are the most common form of brain cancer in children and adults and glioma tumor progression is highly regulated by the activity of surrounding neurons. However, it is not known precisely how neuronal activity regulates tumor progression. Neurons and glioma cells can interact through the secretion of signals and through direct neuron-to-glioma synapses. One hypothesis is that neuron-to-glioma synapses are strengthened through a form of neuroplasticity in which glioma cells increase their sensitivity to the excitatory neurotransmitter glutamate by recruiting more AMPA glutamate receptors to the membrane. This form of neuroplasticity can occur between two healthy neurons via the signaling molecule BDNF and the BDNF receptor, TrkB. This week in Nature, Taylor and colleagues used patient-derived glioma cells and mouse models to demonstrate that gliomas recruit BDNF signaling to strengthen the neuron-glioma connection and drive tumor proliferation and progression.

How did they do it?

First, the authors transplanted patient-derived glioma cells into mice, a process called xenografting. This allowed the authors to manipulate each component of the BDNF signaling pathway and assess the effect on tumor proliferation and animal survival. In a series of experiments, the authors (1) removed neuronal release of BDNF with a mutant mouse model, (2) used CRISPR to remove the BDNF receptor, TrkB, from the glioma cells, (3) administered a potential therapeutic drug (entrectinib) that blocks the family of Trk BDNF receptors, and (4) used pharmacology to block AMPA receptors.

Second, the authors directly tested whether BDNF drives plasticity in glioma cells by using patch-clamp electrophysiology to measure the glioma cell response to glutamate with or without BDNF and with or without the BDNF receptor.

Third, to assess whether glioma cell plasticity led to increased AMPA receptor signaling, the authors created cultures of the glioma cells and used a sophisticated method called cell-surface biotinylation to quantity the amount of AMPA receptor protein on the glioma membrane with and without BDNF exposure. Additionally, the authors used the pH-sensitive sensor, pHluorin, to visualize AMPA receptors moving to the membrane in real time after BDNF exposure.

Fourth, the authors assessed how well the glioma cells with or without the BDNF receptor were able to associate with the surrounding neuronal network by quantifying the number of neuron-to-glioma synapses with immuno-electron microscopy.

Lastly, the authors sought to validate their hypothesis that increased synapse strength led to higher tumor growth by stimulating glioma cells to varying degrees with optogenetics and measuring the resulting tumor growth.  

What did they find?

First, the authors found that disrupting any part of the BDNF neuroplasticity pathway – either removing neuronal release of BDNF, removing or blocking the BDNF receptor in glioma cells, or blocking AMPA receptors – increased the survival of the xenografted mice and reduced tumor proliferation. This demonstrated that BDNF signaling is a critical component of how neuronal activity promotes tumor growth.

Second, the authors demonstrated that BDNF was sufficient to increase the glioma cell response to a puff of glutamate. Further, BDNF could not elicit this response if the glioma cell lacked the BDNF receptor TrkB confirming the importance of the BDNF-TrkB signaling pathway for glioma plasticity.

Third, the authors found increased AMPA receptor protein at the membrane of glioma cell cultures that were exposed to BDNF. They also were able to visualize AMPA receptors moving to the membrane after BDNF exposure in real-time with their pH-sensitive sensor. This confirmed that BDNF signaling in glioma cells drives neuroplasticity by increasing the number of AMPA receptors at the membrane, the same mechanism used by healthy neurons.

Fourth, immuno-electron microscopy revealed that glioma xenografts that lacked the BDNF receptor TrkB had fewer neuron-to-glioma synapses than xenografts that had TrkB expression. These data revealed that BDNF-TrkB not only strengthens the synapse but also promotes the formation of synapses.

Lastly, the authors clearly demonstrated the importance of neuron-to-glioma synapse plasticity for tumor growth by showing that robust optogenetic stimulation to depolarize glioma cells resulted in more tumor proliferation than mild optogenetic depolarization.

What's the impact?

The finding that glioma tumor cells hijack a well-established method of neuroplasticity to strengthen their integration into neuronal networks and proliferate is critical to our understanding of how brain cancer both influences and is influenced by, the surrounding healthy tissue. This work will provide several novel targets that could result in effective treatment for brain cancer, some of which the authors have already started to explore in this paper. 

Access the original scientific publication here

The Role of Frontal Theta-Band Activity in Regulating Risk-Taking Behavior

Post by Kulpreet Cheema

The takeaway

Previous research suggests that frontal cortex theta-band activity - a rhythm of neural activity between 4-8 Hz - plays a significant role in modulating decision-making involving risk. Theta-band activity in the left dorsolateral prefrontal cortex (DLPFC) specifically, is associated with increased risk-taking behavior. 

What's the science?

We face risky choices constantly in everyday life, from small decisions like whether to take an umbrella out with us based on the weather forecast, to larger decisions like deciding how to invest our money in the stock market. Electroencephalography (EEG) studies have shown that frontal theta-band activity is associated with cognitive control, response inhibition, reward anticipation, and conflict detection processes that are essential in risk-taking behavior. The dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (MPFC) are two crucial frontal brain regions involved in decision-making, particularly in a risky context. This week in NeuroImage, Dantas and colleagues aimed to understand the role of frontal cortex theta-band activity in regulating risk-taking behavior. 

How did they do it?

Thirty-nine participants performed the Maastricht Gambling Task (MGT) while their right or left DLPFC were stimulated with transcranial alternating current stimulation (tACS). tACS is a unique form of brain stimulation used to modulate brain activity and in some cases induce neural plasticity. The MGT was carefully selected to assess risk-taking behavior, controlling for the effects of other variables like loss aversion and memory and learning effects. In each trial, participants had to guess the color of a box hiding a token, with varying probabilities of success and corresponding payoffs. Two tACS stimulation intensities (1.5 mA and 3 mA) were applied to assess the impact of intensity on risk-taking. The researchers analyzed behavioral data, including risk, value, and response time, as well as EEG data, to understand how brain stimulation affected risk-taking behavior. 

What did they find?

The results showed that stimulating the left DLPFC with theta-band tACS led to increased risk-taking behavior. However, when the right DLPFC was stimulated, no significant changes in risk-taking were observed. Participants' ‘value’, which reflects their attraction to larger payoffs or rewards in a given trial of the gambling task, increased significantly during left DLPFC stimulation, especially with higher intensity. In contrast, right DLPFC stimulation, particularly at higher intensity, led to a significant reduction in value. EEG data revealed increased theta power after sham stimulation and an overall increase in frontal theta power after left DLPFC tACS. However, no significant EEG aftereffects were observed following right DLPFC tACS. 

What's the impact?

This study sheds light on the differential role of right and left frontal theta-band activity in risk-taking behavior. Researchers found that stimulating specific brain regions can influence decision-making under risk, with left DLPFC stimulation increasing risk-taking, and right DLPFC stimulation reducing it, particularly at higher intensities. Understanding these relationships has potential applications in clinical settings, as these findings could inform intervention in cases involving abnormal risk-taking behavior. The research also highlights the importance of tACS stimulation intensity, indicating that higher intensities may be necessary to induce consistent behavioral responses. 

Access the original scientific publication here.