Tumor-Infiltrating Nerves Functionally Alter Brain Circuits and Modulate Behavior in a Male Mouse Model of Head-and-Neck Cancer

Core Concepts

Tumor-infiltrating nerves connect to distinct brain regions via the trigeminal ganglion, leading to heightened neuronal activity in these brain areas and associated behavioral alterations in tumor-bearing mice.

Abstract

The content describes how nerves infiltrating head and neck squamous cell carcinoma (HNSCC) tumors in male mice connect to specific brain regions, including the spinal nucleus of the trigeminal, parabrachial nucleus, and central amygdala, via the ipsilateral trigeminal ganglion. This tumor-brain circuit exhibits functional alterations, with increased neuronal activity in the connected brain regions, as evidenced by elevated cFos and ΔFosB expression.
The activation of this neuronal circuitry leads to behavioral changes in tumor-bearing mice, such as decreased nest-building, increased latency to eat a cookie, and reduced voluntary wheel running. Genetic ablation of the TRPV1-expressing nociceptor neurons that infiltrate the tumor mitigates these behavioral alterations, suggesting that the tumor-brain communication mediated by these neurons contributes to the observed behavioral changes.
While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running, indicating that pain is not the exclusive driver of these behavioral shifts. The findings highlight the complex interplay between the tumor, infiltrating nerves, and the brain, which is crucial for understanding and developing targeted interventions to alleviate the mental health burdens associated with cancer.

Stats

Tumor-infiltrating nerves express increased levels of neuronal signaling/receptor genes (Gabrg1, Gabra4, Grin2c, Grm3) and synaptic transmission genes (Gria2) compared to control trigeminal ganglia neurons.
Tumor-infiltrating trigeminal neurons exhibit heightened calcium responses to capsaicin stimulation compared to control neurons.
Tumor-bearing mice show increased cFos and ΔFosB expression in the spinal nucleus of the trigeminal, parabrachial nucleus, and central amygdala compared to control mice.
Tumor-bearing mice with genetic ablation of TRPV1-expressing nociceptor neurons show decreased cFos and ΔFosB expression in the parabrachial nucleus and spinal nucleus of the trigeminal compared to tumor-bearing mice with intact nociceptor neurons.

Quotes

"Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer."
"While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running, indicating that pain is not the exclusive driver of these behavioral shifts."

Key Insights Distilled From

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer

by Barr,J., Wal... at www.biorxiv.org 10-20-2023

https://www.biorxiv.org/content/10.1101/2023.10.18.562990v2

Deeper Inquiries

How do the transcriptional and functional changes in tumor-infiltrating nerves influence the long-term mental health outcomes of cancer survivors, even after successful treatment and tumor removal?

The transcriptional and functional changes in tumor-infiltrating nerves can have long-lasting effects on the mental health outcomes of cancer survivors, even after successful treatment and tumor removal. These changes can lead to alterations in brain circuits and neuronal activity, impacting behavior and emotional well-being. For example, the heightened sensitivity of tumor-infiltrating neurons to noxious stimuli, as indicated by increased TRPV1 expression and phosphorylation, can contribute to chronic pain and discomfort even after the tumor is removed. This persistent pain can lead to depressive symptoms, anxiety, and reduced quality of life in cancer survivors.
Furthermore, the altered neuronal connections between the tumor and the brain can result in changes in brain regions associated with mood regulation and emotional processing. These changes may predispose cancer survivors to long-term mental health issues, such as depression and anxiety, even after successful treatment. The disruption of the tumor-brain circuit, as seen in the study with the genetic elimination of nociceptor neurons, can attenuate these behavioral alterations and improve mental health outcomes in cancer survivors.

What other factors, beyond pain, might contribute to the cancer-associated behavioral changes observed in the voluntary wheel running behavior of tumor-bearing mice?

In addition to pain, several other factors may contribute to the cancer-associated behavioral changes observed in the voluntary wheel running behavior of tumor-bearing mice. These factors include:

Fatigue: Cancer-related fatigue is a common symptom experienced by cancer patients, which can lead to reduced physical activity and exercise tolerance. The energy demands of the tumor and the host's skeletal muscles may compete, resulting in decreased voluntary wheel running behavior in tumor-bearing mice.

Depression: Cancer patients often experience depressive symptoms, which can manifest as reduced motivation, interest in activities, and overall lethargy. Depressive-like behaviors, such as decreased voluntary wheel running, may be a result of the psychological impact of cancer on the brain and behavior.

Treatment side effects: The side effects of cancer treatments, such as chemotherapy and radiation therapy, can cause fatigue, muscle weakness, and decreased physical activity. These treatment-related factors can contribute to the behavioral changes observed in tumor-bearing mice, including reduced voluntary wheel running.

Neurological changes: The altered neuronal connections between the tumor and the brain, as demonstrated in the study, can influence brain regions involved in motor control and movement. These neurological changes may impact voluntary wheel running behavior in tumor-bearing mice, independent of pain.

Could the insights gained from this study on the tumor-brain circuit be leveraged to develop novel therapeutic approaches for improving mental health in cancer patients, beyond just managing pain?

The insights gained from this study on the tumor-brain circuit offer promising opportunities for developing novel therapeutic approaches to improve mental health in cancer patients, beyond just managing pain. Some potential strategies include:

Targeted neuronal interventions: By targeting specific neuronal circuits involved in the tumor-brain communication, novel therapies could be developed to modulate brain activity and behavior in cancer patients. This targeted approach could help alleviate depressive symptoms, anxiety, and other mental health issues associated with cancer.

Neurotransmitter modulation: Understanding the neurotransmitter systems involved in the tumor-brain circuit could lead to the development of pharmacological interventions that target these pathways. By modulating neurotransmitter activity, such as serotonin or dopamine, novel therapies could be designed to improve mood and emotional well-being in cancer patients.

Behavioral interventions: Utilizing the knowledge of how tumor-infiltrating nerves influence behavior, behavioral interventions could be tailored to address specific mental health challenges faced by cancer patients. These interventions could include cognitive-behavioral therapy, mindfulness-based practices, and physical exercise programs to improve mental health outcomes.

Personalized medicine: Leveraging the insights from the tumor-brain circuit, personalized medicine approaches could be developed to target individual differences in neuronal responses and behavioral outcomes. By tailoring treatments to the specific needs of each patient, more effective and targeted interventions could be implemented to improve mental health in cancer patients.