Opposite-sex effects of the Tac2 pathway blockade in fear memory consolidation: implications for fear-related disorders

Abstract

Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impairs fear memory in male mice. Surprisingly, we demonstrate here a totally opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3β/β-Catenin signaling in both mediate the opposite-sex differential Tac2 pathway regulation of fear memory. This study may have implications beyond memory functioning in fear-related disorders, including fields related to behavior where opposite-sex effects have not been studied in-depth or at all.

Limbic Neuropeptidergic Modulators of Emotion and Their Therapeutic Potential for Anxiety and Post-Traumatic Stress Disorder

“…This is not surprising, given numerous previous reports that the Tac2 pathway modulates sex hormones in both male (Danzer et al, 1999) and female rodents (Sahu and Kalra, 1992). Notably, a new study shows that, whereas osanetant impairs fear memory in male mice, it enhances the memory in females (Florido et al, 2020).…”