Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

Abstract

Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and psychiatric diseases. Specifically, thyroid state alterations in the adult are related to psychological changes and mood disorders as depression. The dentate gyrus of the hippocampal formation undergoes neurogenesis in adult mammals including humans. Recent evidence suggests that depressive disorders and their treatment are tightly related to the number of newly born neurons in the dentate gyrus. We have studied the effect of thyroid hormones (TH) on hippocampal neurogenesis in adult rats in vivo. A short period of adultonset hypothyroidism impaired normal neurogenesis in the subgranular zone of the dentate gyrus with a 30% reduction in the number of proliferating cells. Hypothyroidism also reduced the number of newborn neuroblasts and immature neurons (doublecortin (DCX) immunopositive cells) which had a severely hypoplastic dendritic arborization. To correlate these changes with hippocampal function, we subjected the rats to the forced swimming and novel object recognition tests. Hypothyroid rats showed normal memory in object recognition, but displayed abnormal behavior in the forced swimming test, indicating a depressive-like disorder. Chronic treatment of hypothyroid rats with TH not only normalized the abnormal behavior but also restored the number of proliferative and DCX-positive cells, and induced growth of their dendritic trees. Therefore, hypothyroidism induced a reversible depressive-like disorder, which correlated to changes in neurogenesis. Our results indicate that TH are essential for adult hippocampal neurogenesis and suggest that mood disorders related to adult-onset hypothyroidism in humans could be due, in part, to impaired neurogenesis.

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

“…For example, agomelatine, a new antidepressant that acts as a melatonin agonist, also stimulates neurogenesis in rat hippocampus, 87 as do thyroid hormones, which have been used in the treatment of depression. 47 Psychotropic drugs that do not have antidepressant activity, such as haloperidol, have no effect on neurogenesis. 85 Thus, the induction of adult neurogenesis might represent a common final target for different classes of antidepressants.…”

“…46 Corticosteroids were the first hormones found to have an affect on hippocampal neurogenesis. 41 Activation of hypothalamic-pituitary-adrenal axis and sustained elevation of glucocorticoids can lead to chronic inhibition of neurogenesis, 47 whereas adrenalectomy leads to an increase in the number of neurons in the adult rat hippocampus. 48 Thyroid hormones also stimulate neurogenesis.…”

“…48 Thyroid hormones also stimulate neurogenesis. 47 Inflammation, which gives rise to microglial activation in the area where the new neurons are born, strongly impairs hippocampal neurogenesis in rodents. 49,50 Inflammation does not affect precursor cell proliferation, but it reduces neuronal differentiation and survival, effects likely due to microglia-derived interleukin-6 (IL-6).…”

Effects of adult dysthyroidism on the morphology of hippocampal neurons

“…However, only in CA1 the total 50 number of pyramidal neurons was reduced by adult hypothy-51 roidism [26]. Nevertheless, Alva-Sánchez et al [27] found that short-term adult-onset hypothyroidism impairs 56 dendritic arborization of immature neurons.…”

Major Depressive Disorder: Pathophysiology and Clinical Management.

“…Thyroid hormones: Thyroid hormones (TH) imbalances are implicated in the pathophysiology of neurodegenerative and psychiatric conditions. These hormones are very essential for brain development, maturation and have been shown to promote neurogenesis, in particular, in the hippocampus [59]. Hypothyroidism has been linked to depressive -like behavior in that it impaired hippocampal neurogenesis which resolved with hormone replacement.…”