Anxiety is a common response to stress, but for those dealing with anxiety disorders, it can significantly impact daily life. Now, a groundbreaking rat study has unveiled a significant link between anxiety disorders and a brain receptor known as Tachykinin receptor 3 (TACR3), as well as testosterone.
Prof. Shira Knafo, head of the molecular cognitive lab at Ben-Gurion University of the Negev (BGU) in Beersheba led the research. It has just been published in the journal Molecular Psychiatry under the title “Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity.”
Clinical evidence has hinted at a close connection between low testosterone levels and anxiety, particularly in men with hypogonadism, a condition characterized by reduced sexual function. However, the precise nature of this relationship has remained unclear until now.
The role of testosterone
Testosterone is an androgen found in both men and women. In female bodies, testosterone is converted quickly into estrogen, while in men, it remains mostly as testosterone. In women, testosterone plays a role in reproduction, growth, and general health.
Knafo discovered male rodents exhibiting exceedingly high anxiety levels had notably lower levels of a specific receptor called TACR3 in their hippocampus. The hippocampus is a brain region closely associated with learning and memory processes. TACR3 is part of the tachykinin receptor family and responds to a substance known as neurokinin. This observation aroused the researchers’ curiosity and was the basis for an in-depth investigation into the link among TACR3 deficiency, sex hormones, anxiety, and synaptic plasticity.
The rodents were classified based on their behavior in a standard elevated plus maze-test measuring anxiety levels. Their hippocampi were then isolated and underwent gene expression analysis to identify genes with varying expressions between rodents with extremely low anxiety and those with severe anxiety.
One gene that stood out was TACR3. Previous research had revealed that mutations in genes associated with TACR3 led to a condition known as “congenital hypogonadism,” resulting in lower production of sex hormones, including testosterone. Notably, young men with low testosterone often experienced delayed sexual development, accompanied by depression and heightened anxiety. This pairing led researchers to investigate the role of TACR3 further.
Knafo and her team were helped in their research by two innovative tools they crafted themselves. The first, known as FORTIS, detects changes in receptors critical for neuronal communication within living neurons. By using this tool, they demonstrated that inhibiting TACR3 resulted in a sharp increase in these receptors on the cell surface, blocking the parallel process of long-term synaptic strengthening, known as LTP.
The second pioneering tool was a novel application of cross-correlation to measure neuronal connectivity within a multi-electrode array system. It played a pivotal role in uncovering the profound impact of TACR3 manipulations on synaptic plasticity.
This term refers to the ability of synapses, the connections between brain cells, to change their strength and efficiency. This dynamic process is fundamental for the brain’s adaptation to the environment. Through synaptic plasticity, the brain can reorganize its neural circuitry in response to new experiences. This flexibility allows for the modification of synaptic connections, enabling neurons to strengthen or weaken their communication over time. Essentially, synaptic plasticity is a key mechanism by which the brain encodes and stores information, adapting continuously to the ever-changing external stimuli and internal states. Importantly, it revealed that deficiencies stemming from TACR3 inactivity could be efficiently rectified through testosterone administration, offering hope for novel approaches to cope with challenges related to anxiety associated with testosterone deficiency.