## 1 Introduction  
Rod and cone photoreceptors play a central role in vision. Rods are responsible for dim light vision, whereas cones are responsible for bright light, color vision, and visual acuity. Rods and cones degenerate in a variety of pathological conditions, including inherited retinal degenerative diseases such as retinitis pigmentosa, Leber congenital amaurosis (LCA), and cone-rod dystrophies and age-related retinal degeneration such as age-related macular degeneration (AMD) and diabetic retinopathy. Inherited retinal degenerative diseases affect approximately 1 in 3000 individuals worldwide, whereas AMD is the leading cause of blindness among the older population.  
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism [1, 2, 3]. TH has also been associated with cell death/survival. TH signaling is the main driving force in apoptotic tissue remodeling during anuran metamorphosis [4; 5]. TH signaling is associated with the apoptosis of a variety of human cells, including lymphocytes [6], breast cancer cells [7], HeLa cells [8], and pituitary tumor cells [9]. Excessive TH signaling has been shown to induce auditory defects/cochlear degeneration [10] and cerebellum degeneration [11] in mice. TH signaling abnormality has also been linked to neurodegenerative conditions/dementia in elderly individuals [12; 13; 14], including human cone/retinal diseases. Clinical studies show that an elevated TH level in circulation is associated with an increased incidence of AMD [15; 16; 17; 18; 19; 20; 21; 22; 23; 24]. In line with this, an optical coherence tomography evaluation has shown macular thinning in patients with thyroid-associated ophthalmopathy [25; 26].  
In the retina, TH signaling is well known for its regulation in cone opsin expression/patterning and cone development. It suppresses the expression of S-opsin (short-wave-sensitive opsin 1), induces the expression of M-opsin (medium-wave-sensitive opsin 1) [27; 28; 29], and controls the dorsal-ventral gradient expression of cone opsins [27]. TH signaling also regulates cone survival/viability. The suppression of TH signaling by antihyroid treatment [30]; the inhibition of Dio2 [31; 32], the enzyme responsible for converting the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3); the overexpression of Dio3 [32; 33], the enzyme responsible for degrading T3; or the deletion of the TH receptor [34] reduces cone degeneration in mouse models of LCA and cone dystrophy/achromatopsia and a chemically induced mouse model of AMD [35; 36]. In contrast, stimulating TH signaling by T3 treatment [30; 37; 38] or the deletion of Dio3 [38] induces cone death in mice, accompanied with cellular oxidative stress, necroptosis, and inflammation. Moreover, cone degenerating retinas show an increased expression of the TH receptor [35] and iodothyronic deiodinases [32], suggesting that TH signaling activity is locally elevated and may play a role in disease progression.  
The present work investigated the genes/transcriptomic alterations that might be involved in TH-induced cone degeneration in mice using single-cell RNA sequencing (scRNAseq) and a subsequent ingenuity pathway analysis (IPA). We found that cone cluster transcriptomes were at the top after T3 treatment. The IPA revealed that treatment with T3 suppressed phototransduction and oxidative phosphorylation, accompanied with mitochondrial dysfunction, and induced cellular stress/death pathways. This work, using a mouse model of hyperhyroidism, provides an insight into how excessive TH signaling induces cone degeneration.