title: Aberrant Monoaminergic System in Thyroid Hormone Receptor-β Deficient Mice as a Model of Attention-Deficit/Hyperactivity Disorder.
abstract: BACKGROUND
  Thyroid hormone receptors are divided into 2 functional types: TRα and TRβ. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans.
  
  
  METHODS
  Here we examined behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupted (TRα (0/0) ) and TRβ-deficient (TRβ (-/-) ) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured.
  
  
  RESULTS
  TRβ (-/-) mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TRα (0/0) mice showed normal exploratory activity. The biochemical profiles of dopamine and 5-hydroxytryptamine showed significantly low dopamine metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-hydroxytryptamine metabolic rates in TRβ (-/-) mice, but not in TRα (0/0) mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TRβ (-/-) mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system.
  
  
  CONCLUSIONS
  These findings suggest that TRβ deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Masanori
authors.initials: M
authors.lastname: Ookubo
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Miyuki
authors.initials: M
authors.lastname: Sadamatsu
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Satoru
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai). h-kanai@nagahama.jrc.or.jp.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Kanai
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism* / Q000523:psychology*; D001522:Behavior, Animal; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D005106:Exploratory Behavior; D006185:Habituation, Psychophysiologic; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008032:Limbic System / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000378:metabolism; D011699:Putamen / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics*
chemical_list: D015306:Biogenic Monoamines; D006657:Histones; D037042:Thyroid Hormone Receptors beta; D012701:Serotonin; D006655:Histone Deacetylases; D004298:Dopamine
keywords: ADHD; dopamine; histone deacetylase; reward system; serotonin