potassium-perchlorate and Disease-Models--Animal

Alterations in motor functions are well-characterized features observed in humans and experimental animals with thyroid hormone dysfunctions during development. We have previously suggested the implication of the endocannabinoid system in the hyperlocomotor phenotype observed in developmentally induced hypothyroidism in rats. In this work we have further analyzed the implication of endocannabinoids in the effect of hypothyroidism on locomotor activity. To this end, we evaluated the locomotor activity in adult mice lacking the cannabinoid receptor type 1 (CB1R

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Brain; Cannabinoid Receptor Agonists; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Dronabinol; Haloperidol; Hypothyroidism; Imidazoles; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Perchlorates; Phenotype; Potassium Compounds; Receptor, Cannabinoid, CB1; Receptors, Dopamine D1; Receptors, Dopamine D2

Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner.

Topics: Acetylcholinesterase; Age of Onset; Animals; Anxiety; Avoidance Learning; Brain; Disease Models, Animal; Fear; Hypothyroidism; Isoenzymes; Male; Memory Disorders; Mice, Inbred BALB C; Motor Activity; Perchlorates; Potassium Compounds; Random Allocation

Thyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice.. HT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated γ-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins.. These results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.

Topics: Animals; Disease Models, Animal; Excitatory Postsynaptic Potentials; Gyrus Cinguli; Hyperalgesia; Hypothyroidism; In Vitro Techniques; Male; Methimazole; Mice; Mice, Inbred C57BL; Pain Threshold; Perchlorates; Potassium Compounds; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Thyroxine; Triiodothyronine; Up-Regulation

Although adult-onset hypothyroidism (AOH) has been connected to neural activity alterations, including movement, behavioral, and mental dysfunctions, the underlying changes in brain metabolic physiology have not been investigated in a systemic and systematic way. The current knowledge remains fragmented, referring to different experimental setups and recovered from various brain regions. In this study, we developed and applied a gas chromatography-mass spectrometry (GC-MS) metabolomics protocol to obtain a holistic view of the cerebellar metabolic physiology in a Balb/cJ mouse model of prolonged adult-onset hypothyroidism induced by a 64-day treatment with 1% potassium perchlorate in the drinking water of the animals. The high-throughput analysis enabled the correlation between multiple parallel-occurring metabolic phenomena; some have been previously related to AOH, while others implicated new pathways, designating new directions for further research. Specifically, an overall decline in the metabolic activity of the hypothyroid compared to the euthyroid cerebellum was observed, characteristically manifested in energy metabolism, glutamate/glutamine metabolism, osmolytic/antioxidant capacity, and protein/lipid synthesis. These alterations provide strong evidence that the mammalian cerebellum is metabolically responsive to AOH. In light of the cerebellum core functions and its increasingly recognized role in neurocognition, these findings further support the known phenotypic manifestations of AOH into movement and cognitive dysfunctions.

Topics: Animals; Body Weight; Cerebellum; Cluster Analysis; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Hypothyroidism; Male; Metabolic Networks and Pathways; Metabolome; Metabolomics; Mice; Mice, Inbred BALB C; Microarray Analysis; Perchlorates; Potassium Compounds; Principal Component Analysis; Reproducibility of Results