Impaired Brain Energy Metabolism: Involvement in Depression and Hypothyroidism

Abstract

Although hypothyroidism appears to be an important factor in the pathogenesis of depression, the impact of thyroid hormones on the bioenergetics of the adult brain is still poorly known. Since metabolic changes are reported to be a key player in the manifestation of depressive disorder, we investigated whether there are differences in selected metabolic markers in the frontal cortex and hippocampus of Wistar Kyoto rats (WKY; an animal model of depression) compared to those of control Wistar rats and whether the induction of hypothyroidism by propylthiouracil (PTU) elicits similar effects in these animals or intensifies some parameters in the WKY rats. In our study, we used WKY rats as a model of depression since this strain exhibits lower levels of monoamines in the brain than control rats and exhibits behavioral and hormonal alterations resembling those of depression, including increased reactivity to stress. The findings indicate a decrease in glycolysis intensity in both brain structures in the WKY rats as well as in both strains under hypothyroidism conditions. Furthermore, hypothyroidism disrupted the connection between glycolysis and the Krebs cycle in the frontal cortex and hippocampus in the depression model used in this study. Decreased thyroid hormone action was also shown to attenuate oxidative phosphorylation, and this change was greater in the WKY rats. Our results suggest that both the depression and hypothyroidism models are characterized by similar impairments in brain energy metabolism and mitochondrial function and, additionally, that the co-occurrence of hypothyroidism and depression may exacerbate some of the metabolic changes observed in depression.

Contribution of Hypothyroidism to Cognitive Impairment and Hippocampal Synaptic Plasticity Regulation in an Animal Model of Depression

“…The anxiety-like behavior examined in our study with the use of the elevated plus maze test is often observed in addition to depression-like behavior in various animal models of depression, including the WKY rats [ 18 ]. Abnormalities in learning and memory processes in WKY rats have been shown previously in the Morris water maze [ 19 ] and novel object recognition test [ 12 ]. These data are in agreement with our findings that spatial memory impairment, as assayed in the novel object location (NOL) test, also occurred in this rat strain.…”

“…Experimental studies have demonstrated that hypothyroidism impairs learning, short-term and long-term memory, induces changes in neurotransmitters and signaling molecules, and disrupts synaptic plasticity [ 10 , 11 ]. As we have shown in previous studies, thyroid hormone deficiency also leads to metabolic disturbances in the brain both in control animals and in a depression model [ 12 ].…”

“…As a control group, Wistar rats were used because these strains have similar genetic backgrounds, but differ in their susceptibility to stress [ 14 , 17 ]. Hypothyroidism was induced in the Wistar and WKY rats via administration of PTU in the drinking water for three weeks; as we have previously shown, this dosage lowers fT3 and fT4 and increases plasma TSH levels [ 12 ]. Since brain thyroid hormone levels do not correlate with their concentration in the blood, we previously determined the thyroid hormone content in the hippocampus and found that the level of T3 was decreased in Wistar rats receiving PTU and was even more substantially decreased in WKY rats [ 12 ].…”

“…The function of thyroid hormones in the periphery is mainly related to metabolism, but the present research reveals that these hormones, not only in the pre- and early postnatal periods, but also in the adult brain, affect metabolic processes and synaptic plasticity. In our previous studies, we found that in WKY rats, as well as in Wistar and WKY rats treated with PTU, glycolysis was reduced, and in a model of the coexistence of depression and hypothyroidism (WKY + PTU), the efficiency of mitochondrial respiration was impaired [ 12 ]. The increase in glycogen synthase expression observed in the present study, together with the lack of changes in glycogen phosphorylase in WKY animals with and without PTU treatment, suggests a shift in the balance towards glycogen synthesis and limiting the process of glycogenolysis.…”

“…The procedure was performed as described previously [ 12 ]. Briefly, total RNA was extracted using a Total RNA Mini Kit (A&A Biotechnology, Gdynia, Poland) following the manufacturer’s instructions.…”