Summary: A new study identified a crucial link between anxiety disorders and the brain receptor TACR3, as well as testosterone. This groundbreaking research found that rodents with high anxiety had low TACR3 levels in the hippocampus, a key area for learning and memory.
Notably, the study showed that testosterone deficiency-related anxiety could be addressed by targeting TACR3. This discovery opens new therapeutic possibilities for treating anxiety disorders, especially in individuals with hypogonadism.
Key Facts:
- The research found a significant correlation between low levels of TACR3 in the hippocampus and heightened anxiety in male rodents.
- TACR3 deficiency and low testosterone levels are closely linked, suggesting a potential pathway for treating anxiety disorders.
- The study employed innovative tools like FORTIS and cross-correlation in multi-electrode arrays, advancing understanding of synaptic plasticity and its role in anxiety.
Source: Ben-Gurion University
A groundbreaking study has unveiled a significant link between anxiety disorders and a brain receptor known as TACR3, as well as testosterone.
Prof. Shira Knafo, head of the Molecular Cognitive Lab at Ben-Gurion University, led the research published last month in the journal Molecular Psychiatry.
Anxiety is a common response to stress, but for those dealing with anxiety disorders, it can significantly impact daily life. 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.
Prof. 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 piqued the researchers’ curiosity and was the foundation for an in-depth investigation into the link between 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. Subsequently, their hippocampi were 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 reduced sex hormone production, 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.
Prof. Knafo and her team were aided 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 utilizing FORTIS, 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 employed was a novel application of cross-correlation to measure neuronal connectivity within a multi-electrode array system. This tool played a pivotal role in uncovering the profound impact of TACR3 manipulations on synaptic plasticity.
Synaptic plasticity 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 address challenges related to anxiety associated with testosterone deficiency.
TACR3 is seemingly a central player in bridging anxiety and testosterone. The researchers have unraveled the complex mechanisms behind anxiety and opened avenues for novel therapies, including testosterone treatments, that could improve the quality of life for individuals grappling with sexual development disorders and associated anxiety and depression.
Prof. Knafo is a member of the Department of Physiology and Cell Biology in the Faculty of Health Sciences as well as The National Institute for Biotechnology in the Negev.
Funding:
The research was supported by the Israel Science Foundation (Grant no. 536/19).
About this anxiety research news
Author: Ehud Zion Waldoks
Source: Ben-Gurion University
Contact: Ehud Zion Waldoks – Ben Gurion University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity” by Shira Knafo et al. Molecular Psychiatry
Abstract
Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity
Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to neurokinin B (NKB), its high-affinity ligand. Dysfunctional TACR3 has been associated with pubertal failure and anxiety, yet the mechanisms underlying this remain unclear. Hence, we have investigated the relationship between TACR3 expression, anxiety, sex hormones, and synaptic plasticity in a rat model, which indicated that severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus.
TACR3 expression in female rats fluctuates during the estrous cycle, reflecting sensitivity to sex hormones. Indeed, in males, sexual development is associated with a substantial increase in hippocampal TACR3 expression, coinciding with elevated serum testosterone and a significant reduction in anxiety. TACR3 is predominantly expressed in the cell membrane, including the presynaptic compartment, and its modulation significantly influences synaptic activity.
Inhibition of TACR3 activity provokes hyperactivation of CaMKII and enhanced AMPA receptor phosphorylation, associated with an increase in spine density. Using a multielectrode array, stronger cross-correlation of firing was evident among neurons following TACR3 inhibition, indicating enhanced connectivity.
Deficient TACR3 activity in rats led to lower serum testosterone levels, as well as increased spine density and impaired long-term potentiation (LTP) in the dentate gyrus. Remarkably, aberrant expression of functional TACR3 in spines results in spine shrinkage and pruning, while expression of defective TACR3 increases spine density, size, and the magnitude of cross-correlation.
The firing pattern in response to LTP induction was inadequate in neurons expressing defective TACR3, which could be rectified by treatment with testosterone. In conclusion, our study provides valuable insights into the intricate interplay between TACR3, sex hormones, anxiety, and synaptic plasticity.
These findings highlight potential targets for therapeutic interventions to alleviate anxiety in individuals with TACR3 dysfunction and the implications of TACR3 in anxiety-related neural changes provide an avenue for future research in the field.
