Summary: A new study identifies a critical connection between anxiety disorders and the brain receptor TACR3, as well as circulating testosterone levels. Researchers found that male rodents with pronounced anxiety showed reduced TACR3 expression in the ventral hippocampus, a brain region important for learning, memory, and emotional regulation.
The work indicates that anxiety linked to testosterone deficiency can be alleviated by modulating TACR3 signaling, suggesting new therapeutic opportunities for anxiety, particularly in people with hypogonadism.
Key Facts:
- Low TACR3 expression in the hippocampus correlates with elevated anxiety-like behavior in male rodents.
- TACR3 deficiency is closely associated with reduced testosterone, pointing to an interaction between sex hormones and anxiety-related brain mechanisms.
- Researchers used novel tools, including the live-neuron receptor sensor FORTIS and cross-correlation analysis on multi-electrode arrays, to explore TACR3’s role in synaptic plasticity and neuronal connectivity.
Source: Ben-Gurion University
A breakthrough study links TACR3, testosterone, and anxiety-related synaptic changes
Led by Prof. Shira Knafo of the Molecular Cognitive Lab at Ben-Gurion University, the study—published in the journal Molecular Psychiatry—investigates how TACR3, a tachykinin receptor, interacts with systemic testosterone to influence anxiety and synaptic plasticity.
While anxiety is a normal stress response, persistent or excessive anxiety is a disabling condition for many. Previous clinical observations have suggested a relationship between low testosterone and increased anxiety in men, especially those with hypogonadism, but the underlying mechanisms remained unclear. This research provides experimental evidence linking reduced TACR3 in the hippocampus with both anxiety and altered testosterone levels.
The team identified rodents with markedly different anxiety profiles using the elevated plus maze, a standard behavioral assay. After separating animals with low versus high anxiety, the researchers analyzed gene expression in the ventral hippocampus and found TACR3 expression was substantially lower in the highly anxious group. TACR3 belongs to the tachykinin receptor family and is activated by neurokinin B.
Genetic and clinical data previously associated TACR3 mutations with congenital hypogonadism, a disorder that impairs sexual development and reduces sex hormone production, including testosterone. Those clinical links, together with the new experimental findings, motivated a focused investigation into how TACR3, sex hormones, and synaptic function interact to influence anxiety.
To probe TACR3 function in living neurons, the researchers developed and applied two innovative experimental tools. The first, FORTIS, is a live-neuron assay that monitors receptor dynamics at the cell surface. Using FORTIS, they showed that pharmacological inhibition of TACR3 increased surface expression of certain synaptic receptors while preventing the normal induction of long-term potentiation (LTP), a cellular model of learning and memory.
The second technique adapted cross-correlation analysis to a multielectrode array system, enabling quantification of functional connectivity across neuronal networks. Following TACR3 inhibition, neurons exhibited stronger cross-correlated firing, reflecting altered connectivity and synaptic organization.
Synaptic plasticity—the capacity of synapses to change their strength and structure—is central to how the brain adapts, learns, and stores information. The study found that defective TACR3 signaling increased spine density and AMPA receptor phosphorylation, activated CaMKII, and produced connectivity changes that impaired LTP in the dentate gyrus. Remarkably, administering testosterone reversed these deficits, restoring more typical synaptic function and firing responses.
Together, the results position TACR3 as a molecular bridge between testosterone levels and anxiety-related synaptic changes. The findings suggest that targeting TACR3 signaling, possibly alongside hormone-based approaches, could offer new strategies to treat anxiety symptoms associated with testosterone deficiency or TACR3 dysfunction.
Prof. Knafo is a faculty member in the Department of Physiology and Cell Biology, Faculty of Health Sciences, and is affiliated with The National Institute for Biotechnology in the Negev.
Funding: The research received support from 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 credit: 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), a G protein–coupled receptor responsive to neurokinin B, has been implicated in pubertal development and anxiety, yet the mechanisms linking TACR3 function to emotional regulation are not well defined. Using a rat model, the study found that severe anxiety is associated with reduced TACR3 expression in the ventral hippocampus. TACR3 levels vary with sex hormone status—fluctuating across the female estrous cycle and rising in males during sexual maturation, which coincides with higher serum testosterone and reduced anxiety-like behavior.
TACR3 is enriched at the cell membrane and presynaptic sites, where its modulation profoundly affects synaptic activity. Inhibition of TACR3 led to CaMKII hyperactivation, increased AMPA receptor phosphorylation, and higher spine density. Multielectrode recordings showed greater cross-correlation of neuronal firing after TACR3 inhibition, indicating stronger but maladaptive connectivity. TACR3 deficiency produced lower serum testosterone, increased spine size and number, and impaired long-term potentiation in the dentate gyrus. Introducing functional TACR3 into spines caused spine shrinkage and pruning, while defective TACR3 promoted spine enlargement and increased connectivity; impaired firing responses to LTP induction in neurons expressing defective TACR3 were reversed by testosterone treatment.
These findings delineate an interaction between TACR3, systemic testosterone, and synaptic plasticity in anxiety regulation, highlighting candidate targets for therapeutic intervention in conditions linked to TACR3 dysfunction and testosterone deficiency.