Decreased anxiety- and depression-like behaviors and hyperactivity in a type 3 deiodinase-deficient mouse showing brain thyrotoxicosis and peripheral hypothyroidism
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Abstract
<p class="first" id="P2">Hypo- and hyperthyroid states, as well as functional abnormalities
in the hypothalamic-pituitary-thyroid
axis have been associated with psychiatric conditions like anxiety and depression.
However, the nature of this relationship is poorly understood since it is difficult
to ascertain the thyroid status of the brain in humans. Data from animal models indicate
that the brain exhibits efficient homeostatic mechanisms that maintain local levels
of the active thyroid hormone, triiodothyronine (T3) within a narrow range. To better
understand the consequences of peripheral and central thyroid status for mood-related
behaviors, we used a mouse model of type 3 deiodinase (DIO3) deficiency (Dio3 −/−
mouse). This enzyme inactivates thyroid hormone and is highly expressed in the adult
central nervous system. Adult Dio3 −/− mice exhibit elevated levels of T3-dependent
gene expression in the brain, despite peripheral hypothyroidism as indicated by low
circulating levels of thyroxine and T3. Dio3 −/− mice of both sexes exhibit hyperactivity
and significantly decreased anxiety-like behavior, as measured by longer time spent
in the open arms of the elevated plus maze and in the light area of the light/dark
box. During the tail suspension, they stayed immobile for a significantly shorter
time than their wild-type littermates, suggesting decreased depression-like behavior.
These results indicate that increased thyroid hormone in the brain, not necessarily
in peripheral tissues, correlates with hyperactivity and with decreases in anxiety
and depression-like behaviors. Our results also underscore the importance of DIO3
as a determinant of behavior by locally regulating the brain levels of thyroid hormone.
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