No abstract

Thyroid hormone receptors are encoded by the TR␣ (NR1A1) and TR␤ (NR1A2) loci. These genes are transcribed into multiple variants whose functions are unclear. Analysis by gene inactivation in mice has provided new insights into the functional complexity of these products. Different strategies designed to modify the TR␣ locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, we generated mice devoid of all known isoforms produced from the TR␣ locus (TR␣ 0/0 ). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TR␣ 0 and TR␤ ؊ mutations produces viable TR␣ 0/0 ␤ ؊/؊ mice, which display a more severe linear growth reduction and a more profound hypothermia as well as impaired hearing. A striking phenotypic difference is observed between TR␣ 0/0 and the previously described TR␣ ؊/؊ mice, which retain truncated TR⌬␣ isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TR␣ ؊/؊ mice are rescued in TR␣ 0/0 animals. We demonstrate that the TR⌬␣ protein isoforms, which are natural products of the TR␣ locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TR␣ locus in vertebrate postnatal development and homeostasis.

Multiple-unit threshold curves (MTCs) were obtained from inferior colliculus (IC) neurons across much of the (approximately 2-2.5 yr) life-span of two inbred mouse strains: the C57BL/6, which undergoes progressive age-related sensorineural hearing loss; and the CBA, which maintains good sensitivity until well into the second year of life. Tonotopic organization (the orderly dorsoventral arrangement of frequency sensitivity) is disrupted in the IC central nucleus (ICC) of aging C57 mice. Dorsal (low-frequency) MTCs change little during the first year of life, but in more ventral (high-frequency) regions high-frequency portions of MTCs are eliminated, best frequencies become lower, and low-frequency thresholds are reduced. These changes make the curves more similar to one another along the dorsoventral axis. During the second year of life, all thresholds become greatly elevated with neurons throughout the IC responding only to middle frequencies at very high intensities. In C57 mice, Q10 ratios (a measure of MTC tip sharpness) decline after 7 mo. The decline of Q10 with aging is associated with the age-related lowering of best frequencies and elevation of thresholds, both of which are positively correlated with smaller Q10s. The frequency range of C57 MTCs begins to decrease at 14 mo of age, when hearing loss is quite severe at all frequencies. In CBA mice, the above changes are minimal or do not occur even in 22 mo olds, which have moderate loss of sensitivity across all frequencies. Even in young mice (prior to demonstrable cochlear pathology in C57 mice), there are differences in MTCs between the two strains employed, with sensitivity of CBA mice being "shifted" toward higher frequencies. Age-related changes in MTC properties depend on the pattern of hearing loss (e.g., high frequency vs. flat) and the dorsoventral location of neurons within the ICC.

No abstract

The representation of frequency was mapped in the primary auditory cortex (AI) of C57BL/6J (C57) mice during young adulthood (1.5-2 months) when hearing is optimal, and at 3, 6, and 12 months of age, a period during which progressive, high frequency, sensorineural hearing loss occurs in this strain. Maps were also obtained from CBA/CaJ mice which retain good hearing as they age. In AI of young adult C57 mice and CBA mice, characteristic frequencies (CFs) of multiple-unit clusters were easily identified with extracellular recordings, and a general tonotopic organization was observed from dorsal (high frequency) to ventral and caudal (low frequency). In individual cases there appeared to be deviations from the above tonotopic organization, despite the fact that inbred mice are genetically invariant. As progressive loss of high frequency sensitivity ensued peripherally, a substantially increased representation of middle frequencies was observed in AI. There was no apparent change in the surface area of the auditory cortex despite the elimination of high frequencies, and virtually the entire auditory cortex became devoted to the middle frequencies (especially 10-13 kHz) for which sensitivity remained high. Similar age-related changes were not observed in normal-hearing CBA mice. These findings indicate that plasticity in the representation of frequency in AI is associated with high frequency hearing loss in C57 mice.