Distinct behavioral phenotypes in male mice lacking the thyroid hormone receptor α1 or β isoforms

Abstract

Thyroid hormones influence both neuronal development and anxiety via the thyroid hormone receptors (TRs). The TRs are encoded by two different genes, TRα and TRβ. The loss of TRα1 is implicated in increased anxiety in males, possibly via a hippocampal increase in GABAergic activity. We compared both social behaviors and two underlying and related non-social behaviors, state anxiety and responses to acoustic and tactile startle in the gonadally intact TRα1 knockout (α1KO) and TRβ (βKO) male mice to their wild-type counterparts. For the first time, we show an opposing effect of the two TR isoforms, TRα1 and TRβ, in the regulation of state anxiety, with α1 knockout animals (α1KO) showing higher levels of anxiety and βKO males showing less anxiety compared to respective wild-type mice. At odds with the increased anxiety in non-social environments, α1KO males also show lower levels of responsiveness to acoustic and tactile startle stimuli. Consistent with the data that T4 is inhibitory to lordosis in female mice, we show subtly increased sex behavior in α1KO male mice. These behaviors support the idea that TRα1 could be inhibitory to ERα driven transcription that ultimately impacts ERα driven behaviors such as lordosis. The behavioral phenotypes point to novel roles for the TRs, particularly in non-social behaviors such as state anxiety and startle.

Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats

“…The kisspeptin system has been studied in the amygdala in the context of estrogen signaling in males (Stephens et al, 2016) and in sexual behavior (Gresham et al, 2016). Another gene, Thra , to our knowledge has not bee studied in the BnST of males, but knockout mice exhibit increased anxiety, as well as facilitated sexual behavior, with decreased mount and intromission latencies (Vasudevan et al, 2013). Thra has also been shown to interfere with ER-mediated transcription of other genes, such as Oxtr (Vasudevan et al, 2001).…”

Critical Period Regulation by Thyroid Hormones: Potential Mechanisms and Sex-Specific Aspects

“…In rodents, low levels of TH lead to altered locomotion (Sadamatsu et al, 2006; van Wijk et al, 2008), impaired spatial memory (Sadamatsu et al, 2006) and reduced anxiety (Darbra et al, 1995). Genetic ablation of THrα and ß modify anxiety- and fear-related behaviors (Guadaño-Ferraz et al, 2003; Vasudevan et al, 2013). Interestingly, neonatal induced hypothyroidism also increases the number audiogenic seizures in adulthood (Yasuda et al, 2000), suggesting that TH deficits early in life may trigger a long-term imbalance between excitatory and inhibitory transmission.…”

Progesterone-facilitated lordosis of estradiol-primed mice is attenuated by knocking down expression of membrane progestin receptors in the midbrain

“…Differences in behavioral phenotypes have been noted for other steroid receptor subtypes, such as estrogen receptors [32,33] and, even more recently, thyroid hormone receptors α and β [34], for reproductive and non-reproductive behaviors. A consideration for future investigations is divergence in downstream effectors of mPR isoforms for steroids’ functional effects.…”