RESUMO
The primary auditory cortex (ACtx) is critically involved in the association of sensory information with specific behavioral outcomes. Such sensory-guided behaviors are necessarily brain-wide endeavors, requiring a plethora of distinct brain areas, including those that are involved in aspects of decision making, motor planning, motor initiation, and reward prediction. ACtx comprises a number of distinct excitatory cell-types that allow for the brain-wide propagation of behaviorally-relevant sensory information. Exactly how ACtx involvement changes as a function of learning, as well as the functional role of distinct excitatory cell-types is unclear. Here, we addressed these questions by designing a two-choice auditory task in which water-restricted, head-fixed mice were trained to categorize the temporal rate of a sinusoidal amplitude modulated (sAM) noise burst and used transient cell-type specific optogenetics to probe ACtx necessity across the duration of learning. Our data demonstrate that ACtx is necessary for the ability to categorize the rate of sAM noise, and this necessity grows across learning. ACtx silencing substantially altered the behavioral strategies used to solve the task by introducing a fluctuating choice bias and increasing dependence on prior decisions. Furthermore, ACtx silencing did not impact the animal's motor report, suggesting that ACtx is necessary for the conversion of sensation to action. Targeted inhibition of extratelencephalic projections on just 20% of trials had a minimal effect on task performance, but significantly degraded learning. Taken together, our data suggest that distinct cortical cell-types synergistically control auditory-guided behavior and that extratelencephalic neurons play a critical role in learning and plasticity.
RESUMO
Preserving optimal mitochondrial function is critical in the heart, which is the most ATP-avid organ in the body. Recently, we showed that global deficiency of the nuclear receptor RORα in the "staggerer" mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. However, the mechanisms underlying these observations have not been defined previously. Here, we used pharmacological and genetic gain- and loss-of-function tools to demonstrate that RORα regulates cardiomyocyte mitophagy to preserve mitochondrial abundance and function. We found that cardiomyocyte mitochondria in staggerer mice with lack of functional RORα were less numerous and exhibited fewer mitophagy events than those in WT controls. The hearts of our novel cardiomyocyte-specific RORα KO mouse line demonstrated impaired contractile function, enhanced oxidative stress, increased apoptosis, and reduced autophagic flux relative to Cre(-) littermates. We found that cardiomyocyte mitochondria in "staggerer" mice with lack of functional RORα were upregulated by hypoxia, a classical inducer of mitophagy. The loss of RORα blunted mitophagy and broadly compromised mitochondrial function in normoxic and hypoxic conditions in vivo and in vitro. We also show that RORα is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that enhanced expression of RORα increases caveolin-3 abundance and enhances mitophagy. Finally, knockdown of RORα impairs cardiomyocyte mitophagy, compromises mitochondrial function, and induces apoptosis, but these defects could be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for RORα in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying RORα-mediated cardioprotection.
