Unveiling the Connection Between Testosterone and Anxiety

Anxiety disorders significantly impact daily lives. Patients suffering from anxiety sometimes show low testosterone in their blood and can benefit from testosterone treatment. Our recent article discovered the link between low testosterone, anxiety, and the role of TACR3.
Unveiling the Connection Between Testosterone and Anxiety

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Anxiety is a typical stress response, but it can become overwhelming for those grappling with anxiety disorders, significantly impacting their daily lives. Research indicates a close association between low testosterone levels and anxiety, even though the precise nature of this relationship remains somewhat enigmatic.  Clinical evidence hints at the potential of testosterone in alleviating anxiety and depression, particularly in males with low testosterone due to hypogonadism. However, this connection has lacked a comprehensive explanation until now. 

Our Scientific Journey:

We embarked on an intriguing scientific quest to decipher the intricate relationship between anxiety and testosterone—a question that has puzzled researchers for years.

How It All Started:

Our journey began with a captivating discovery: rats prone to anxiety exhibited lower levels of a specific receptor called Tachykinin receptor 3 (TACR3) in their ventral hippocampus. TACR3 is part of a group of receptors known as tachykinin receptors, and it responds to a substance called neurokinin B (NKB). This observation sparked our curiosity and set the stage for a deep exploration into the connections between TACR3 deficiency, sex hormones, anxiety, and synaptic plasticity.

Our Investigation:

We began by categorizing the rats based on their behavior in an elevated plus maze—a commonly used test to measure rodent anxiety levels. We then isolated the rats' hippocampi and used gene expression analysis to identify genes that behaved differently in rats with very low anxiety compared to those with severe anxiety. One gene that stood out was tacr3. Further research revealed that mutations in genes related to neurokinin B (TAC3) and its receptor (TACR3) lead to a condition known as non-syndromic normosmic congenital hypogonadotropic hypogonadism (CHH). CHH results in a lack of gonadal hormones, including lower testosterone levels. Notably, young men with low testosterone often experience depression and anxiety, prompting us to explore the role of TACR3 in anxiety.

Our research involved studying where TACR3 is found in the rat brain, how its expression changes during growth, and how sex hormones influence its presence in the hippocampus. We also examined the effects of drugs that can modulate TACR3 on synaptic plasticity. Additionally, we cloned the tacr3 gene to overexpress it in our neurons.

In our research, we harnessed the power of two innovative tools, both of which were meticulously crafted within our laboratory. The first tool, known as FORTIS, boasts the remarkable ability to detect alterations in surface AMPA receptors within living neurons. Through the utilization of FORTIS, we successfully demonstrated that the TACR3 receptor antagonist Osanetant yields a profound increase in surface AMPA receptors while concurrently thwarting the process of Long-Term Potentiation (LTP).

Our second pioneering tool involves the ingenious application of cross-correlation as a metric for assessing connectivity among neurons. This invaluable instrument played a pivotal role in uncovering the substantial impact of TACR3 manipulations on neural connectivity. Importantly, it revealed that deficiencies arising from an inactive TACR3 can be effectively rectified through the administration of testosterone.

What We Discovered:

Among our findings, one discovery shone brightly: we uncovered that sex hormones, particularly testosterone, have a remarkable ability to influence the expression of TACR3 in the hippocampus. This dynamic interplay between TACR3 and sex hormones holds profound implications for anxiety-like behaviors in living organisms.

As we delved deeper into our exploration, we stumbled upon another intriguing observation. Rats with heightened anxiety levels were missing a crucial element in their hippocampus-long-term potentiation (LTP). LTP is a phenomenon that signifies the strengthening of neural connections, crucial for learning and memory. However, in severely anxious rats lacking TACR3, something remarkable occurred. Connectivity became more robust, preventing further strengthening in the form of LTP. We also discovered that modulating TACR3, either through drugs or molecular tools, profoundly affected synaptic plasticity. This revelation adds a new layer of understanding to the intricate relationship between TACR3, anxiety, and neural connectivity.

What makes this discovery even more exciting is the potential for testosterone treatment to counteract these plasticity changes, offering hope for innovative approaches to address anxiety-related challenges.

Beyond Anxiety:

Our research goes beyond anxiety dynamics. It also sheds light on non-syndromic normosmic congenital hypogonadotropic hypogonadism - a condition linked to mutations in TACR3 or TAC3 genes, resulting in reduced gonadal hormone production and lower testosterone levels. These findings hold promise for individuals dealing with sexual dysfunction, depression, and heightened anxiety, emphasizing the potential of testosterone treatments to enhance their quality of life.

Our Conclusion:

In summary, our study positions TACR3 as a pivotal link connecting anxiety and testosterone. We've unraveled the intricate mechanisms behind anxiety and opened the door to innovative treatments involving testosterone and the modulation of synaptic plasticity. Our findings provide valuable insights into the complexity of anxiety and offer hope for future therapeutic approaches.

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Life Sciences > Biological Sciences > Neuroscience
Life Sciences > Health Sciences > Clinical Medicine > Psychiatry
Behavioral Neuroscience
Life Sciences > Biological Sciences > Neuroscience > Behavioral Neuroscience
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Psychiatric Disorder > Anxiety
Synaptic plasticity
Life Sciences > Biological Sciences > Physiology > Neurophysiology > Synaptic plasticity
Life Sciences > Health Sciences > Clinical Medicine > Endocrinology