Department of Psychiatry and Behavioral Sciences

Laboratory of Molecular Psychobiology 

Director, Noboru Hiroi, Ph.D.

Professor of Psychiatry

Professor of Neuroscience

noboru.hiroi@einstein.yu.edu 

Faculty Bio  

NoboruHiroi 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 and complex 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 different elements of nicotine dependence.  We use diverse behavioral paradigms to examine how specific genes contribute to elements of nicotine dependence and pre-existing 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. 

Scott D, Hiroi N. Deconstructing craving: dissociable cortical control of cue
reactivity in nicotine addiction. Biol Psychiatry. 2011 Mar 21. [Epub]

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.

Hiroi N, Scott D. Constitutional mechanisms of vulnerability and resilience to nicotine dependence. Mol Psychiatry. 2009 Jul;14(7):653-67.

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.

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.

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 (In press) 2013; Nov;18(11):1153-65.

Harper, K.M., Hiramoto, T., Tanigaki, K., Kang, G., Suzuki, G., Trimble, W., Hiroi, N. Alerations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain. Human Molecular Genetics 2012; 21(15): 3489-3499 2012, PMID:22589251

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. Human Molecular Genetics, 20(24):4775-85 2011.

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. 2009b Jul 19. [Epub ahead of print] PubMed PMID: 19617637.

Suzuki G et al. Sept5 deficiency exerts pleiotropic influence on affective behaviors and cognitive functions in mice. Hum Mol Genet. 2009a May 1;18(9):1652-60.

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.

Calendar

Tuesday, December 02, 2014 | 6:30 PM
Research in the Fight for Global Health Justice: Panel Discussion
Forchheimer Medical Science Building, 3rd Fl. Lecture Hall

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Media Spotlight

The Christian Science Monitor interviews Dr. Tia Powell about the ethics and policies around the dying with dignity movement. (Wednesday, Nov 05, 2014)

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