The primary aim of this laboratory is to more fully understand the genetic bases of nicotine
dependence and 22q11 syndrome. Determining the genetic mechanisms of psychiatric
disorders is challenging for two main reasons. First, the diagnostic criteria of
neuropsychiatric disorders are often not based on the underlying mechanisms of the
disorder. Second, individual genes contribute to neuropsychiatric disorders in complex
ways; each gene may affect only select elements of each neuropsychiatric disorder. Partly
due to these reasons, association studies between polymorphisms of single genes and
clinically defined neuropsychiatric disorders have yielded inconsistent results and are
difficult to replicate. Our research aims to overcome these two obstacles in the study of
nicotine dependence and 22q11 syndrome.
Nicotine dependence: Among those who initiate smoking, only one-third develop
dependence and addiction. Individuals who develop dependence often exhibit pre-existing
behavioral traits. There are many genes that likely contribute, in complex ways, to
individual variations in the development of nicotine dependence and pre-existing behavioral
traits. Identification of such genes has been difficult in humans. Nicotine dependence
includes tolerance, withdrawal, cue reactivity, and many other elements. These elements
are likely to have distinct neural and genetic substrates. Additionally, it is thought that
multiple genes affect nicotine dependence in a complex way. Mouse models provide a
unique opportunity to examine the precise ways that individual genes alter the susceptibility
to different elements of nicotine dependence. We use diverse behavioral paradigms to
examine how specific genes contribute to elements of nicotine dependence and preexisting
behavioral traits in genetically engineered mice. Our studies have revealed that
the transcription factor FosB, monoamine oxidase A, and cGMP-dependent protein kinase
(PKG) are required for nicotine cue reactivity and stress-related behavioral traits. We are
currently using lentiviral vectors to identify specific brain regions in which genes mediate
the expression of nicotine cue reactivity.
22q11 and neuropsychiatric disorders: The human genome includes many variations,
ranging from duplications and deletions of full chromosomes to single nucleotide
polymorphisms. Moreover, a large number of kilo- to mega-base copy number variations
(CNVs) are associated with autism spectrum disorders, mental retardation, and
schizophrenia. Human chromosome 22q11.2 is considered one of the hotspots of CNVs.
Children and adolescents with 22q11.2 duplications and deletions consistently exhibit these
neuropsychiatric disorders, along with associated cognitive and intellectual impairments
during development. However, the diagnosis of these neuropsychiatric disorders is
challenged by variations in diverse cognitive and intellectual capacities. Thus, patients with
the same diagnosis may vary greatly in specific symptoms. The role of 22q11 CNVs in the
emergence of specific cognitive impairments remains unclear. Moreover, because
duplications and deletions of 22q11.2 encompass 1.5 Mb or larger regions, it is not
possible to determine whether segments or single genes are responsible for specific
phenotypes in humans. To circumvent these obstacles, our laboratory examines the role of
individual 22q11 genes in distinct aspects of behavior in genetically engineered mice. We
have identified two small human 22q11.2 segments whose over-expression during
development causes behavioral phenotypes consistent with neuropsychiatric disorders.
Our current work examines the role of each of the genes encoded in the segments in
behavioral phenotypes relevant to neuropsychiatric disorders in mice.
Takahashi T, Okabe S, Broin PÓ, Nishi A, Ye K, Beckert MV, Izumi T, Machida A, Kang G, Abe S, Pena JL, Golden A, Kikusui T, Hiroi N. Structure and function of neonatal social communication in a genetic mouse model of autism. Mol Psychiatry. 2016, 21(9):1208-14.
Hishimoto A, Nomaru H, Ye K, Nishi A, Lim J, Aguilan JT, Nieves E, Kang G, Angeletti RH, Hiroi N. Molecular Histochemistry Identifies Peptidomic Organization and Reorganization Along Striatal Projection Units. Biol Psychiatry. 2016, 79(5):415-20.
Boku, S., Toda, H., Nakagawa, S., Kato, A., Inoue, T., Koyama, K., Hiroi, N., Kusumi, I.
Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter Biol Psychiatry 2015;77(4):335-44.
Hiroi N. Small Cracks in the Dam: Rare genetic variants provide opportunities to delve into mechanisms of neuropsychiatric disorders. Biol Psychiatry. 2014 76(2):91-2.
Hiroi, N., Takahashi, T., Hishimoto, A.,Izumi, T., Boku, S., Hiramoto, T. Copy Number Variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. Molecular Psychiatry 2013; Nov;18(11):1153-65.
Harper KM, Hiramoto T, Tanigaki K, Kang G, Suzuki G, Trimble W, Hiroi N. Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain. Hum Mol Genet. 2012;21(15):3489-99.
Yoshida A, Yamamoto N, Kinoshita M, Hiroi N, Hiramoto T, Kang G, Trimble WS, Tanigaki K, Nakagawa T, Ito J. Localization of septin proteins in the mouse cochlea. Hear Res. 2012; 289(1-2):40-51.
Lapidus KA, Nwokafor C, Scott D, Baroni TE, Tenenbaum SA, Hiroi N, Singer RH, Czaplinski K. Transgenic expression of ZBP1 in neurons suppresses cocaine-associated conditioning. Learn Mem. 2012 Jan 12;19(2):35-42.
Hiramoto T, Kang G, Suzuki G, Satoh Y, Kucherlapati R, Watanabe Y, Hiroi N. Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder in a mouse model. Hum Mol Genet. 2011; 20(24):4775-85.
Scott D, Hiroi N. Deconstructing craving: dissociable cortical control of cue reactivity in nicotine addiction. Biol Psychiatry. 2011 Jun 1;69(11):1052-9.
Scott D, Hiroi N.Emergence of dormant conditioned incentive approach by conditioned withdrawal in nicotine addiction. Biol Psychiatry. 2010 Oct 15;68(8):726-32
Suzuki G et al. Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT, and ARVCF developmentally affects incentive learning and working memory in mice. Hum Mol Genet. 2009 Oct 15;18(20):3914-25.
Hiroi N, Scott D. Constitutional mechanisms of vulnerability and resilience to nicotine dependence. Mol Psychiatry. 2009 Jul;14(7):653-67.
Suzuki G et al. Sept5 deficiency exerts pleiotropic influence on affective behaviors and cognitive functions in mice. Hum Mol Genet. 2009 May 1;18(9):1652-60.
Zhu H et al. Pleiotropic impact of constitutive fosB inactivation on nicotine-induced behavioral alterations and stress-related traits in mice. Hum Mol Genet. 2007 Apr 1;16(7):820-36.
Agatsuma S, et al. Monoamine oxidase A knockout mice exhibit impaired nicotine preference but normal responses to novel stimuli. Hum Mol Genet. 2006 Sep 15;15(18):2721-31.
Hiroi N et al. A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice. Proc Natl Acad Sci U SA 2005 Dec 27;102(52):19132-7.
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