Hypothyroidism increases Fos immunoreactivity in cholinergic neurons of brain medullary dorsal vagal complex in rats

Abstract

Hypo-or hyperthyroidism is associated with autonomic disorders. We studied Fos expression in the medullary dorsal motor nucleus of the vagus (DMV), nucleus tractus solitarii (NTS), and area postrema (AP) in four groups of rats with different thyroid states induced by a combination of drinking water and daily intraperitoneal injection for 1-4 wk: 1) tap water and vehicle; 2) 0.1% propylthiouracil (PTU) and vehicle; 3) PTU and thyroxine (T 4; 2 g/100 g); and 4) tap water and T 4 (10 g/100 g). The numbers of Fos immunoreactive (IR) positive neurons in the DMV, NTS, and AP were low in euthyroid rats but significantly higher in the 4-wk duration in hypothyroid rats, which were prevented by simultaneous T4 replacement. Hyperthyroidism had no effect on Fos expression in these areas. There were significant negative correlations between T4 levels and the numbers of Fos-IRpositive neurons in the DMV (r ϭ Ϫ0.6388, P Ͻ 0.008), NTS (r ϭ Ϫ0.6741, P Ͻ 0.003), and AP (r ϭ Ϫ0.5622, P Ͻ 0.004). Double staining showed that Fos immunoreactivity in the DMV of hypothyroid rats was mostly localized in choline acetyltransferase-containing neurons. Thyroid hormone receptors ␣1 and ␤2 were localized in the observed nuclei. These results indicate that thyroid hormone influences the DMV/NTS/AP neuronal activity, which may contribute to the vagal-related visceral disorders observed in hypothyroidism. thyroid hormone; dorsal motor nucleus of the vagus; nucleus tractus solitarii; vagus nerve; area postrema HYPOTHYROIDISM IS A PREVALENT DISEASE worldwide and has a high incidence in elderly patients with nonthyroidal disease (3, 39). Extensive cardiovascular, gastrointestinal (GI), and metabolic disorders, such as sinus bradycardia, altered GI secretion and motility, and hyperlipidemia are the main clinical symptoms of hypothyroidism. These symptoms indicate autonomic dysfunction with a relative vagal dominance (43, 44) and correlate to increased mortality from cardiovascular and cerebrovascular diseases in those with a history of overt or subclinical thyroid disorders (29, 39). How thyroid hormone regulates vagal activities, particularly the central mechanism, is still poorly understood.On the basis of solidly established physiological role of medullary thyrotropin-releasing hormone (TRH)-containing vagal regulatory pathways in the central regulation of GI functions (47), we recently revealed that feedback regulation of TRH gene expression by thyroid hormone in the medullary raphe pallidus (Rpa), raphe obscurus (Rob), and parapyramidal region (PPR) may contribute to hypothyroidism-induced autonomic disorders (49 -52). TRH-containing projections arising from these nuclei innervate the dorsal vagal complex (DVC) (20) and the sympathetic motor neurons in the intermediolateral cell column of the spinal cord (40). Our previous studies showed that hypothyroidism increases TRH mRNA levels in the Rpa, Rob, and PPR and induces Fos expression, a widely accepted parameter indicating brain neuronal activation, in the TRH-synthesizing neurons in these nucl...

Central Thyrotropin-Releasing Hormone Infusion Opposes Cardiovascular and Metabolic Suppression during Caloric Restriction

“…TRH appears to inhibit vagal tone [14,36,37,38]. In the present study, we found additional support for the hypothesis that TRH reduces vagal tone.…”

Adult‐onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage‐gated potassium channel downregulation in male mice

“…The limitation of this model is that the possible direct effects of PTU in the neurons cannot be excluded, although there is no report investigating the direct effects of PTU on the neuron or axon. However, there were several reports showing that the TH replacement rescued the effect by PTU administration in the cholinergic neurons in the brain (Yuan & Yang, 2005) or in the sympathetic neuron in the heart (Whitsett et al., 1982). These can be considered to be the indirect evidence that the PTU affect neurons only by mediating the TH status.…”

Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats

“…For example, brainstem TRH is involved in the strong sympathovagal activation during acute cold exposure, resulting in gastric ulceration and in the autonomic disorders presenting in hypo-and hyperthyroidism. [31][32][33][34] We recently established a role for disrupted autonomic responses to brainstem TRH receptor activation in diabetic pathophysiology, by demonstrating that an unbalanced 'sympathetic-over-vagal' excitation by brainstem TRH is responsible for the impaired insulin response to glucose in the Goto-Kakizaki (GK) rat, 17,25 an inbred polygenetic model of spontaneous non-obese T2D with a wide range of abnormalities directly relevant to components of the cardiometabolic syndrome and diabetes complications. [35][36][37] The objective of the present study was to test the hypothesis that in T2D, brainstem TRH evokes exaggerated sympathetic activation that is responsible for the increased cardiovascular morbidity.…”