Laboratory of Mouse Genetics and Behavior

In our group, we use a systems approach to better understand normal and abnormal brain function. In particular, we study the mechanisms that underlie neuropsychiatric disorders such as schizophrenia, depression, and anxiety disorders. We are interested in understanding how genetic and epigenetic factors affect behavior and intervening systems such as circuitry, anatomy, and physiology. To address these questions, we exploit our ability to genetically modify mice--either to mimic known human susceptibility factors or to use conditional gene modifications (temporal and spatial) to further investigate our hypotheses regarding circuitry and physiology.

Towards these ends, we currently are pursuing several lines of research related to the role of serotonin signaling in the cortex. These studies have demonstrated an important role for cortical influence on behaviors related to schizophrenia and anxiety. We also have an active program examining the role of serotonin on the development of brain circuits that modulate affective and anxiety states. To examine epigenetic factors, we have developed a mouse model of paternal age on behavior and brain function. These lines of research have opened several avenues of inquiry that we are actively exploring.

Selected publications:

Weisstaub NV, Zhou M, Lira A, Lambe E, González-Maeso J , Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA (2006) Cortical 5-HT 2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice. In press, Science

Gingrich JA (2005): Oxidative stress is the new stress. Nat Med 11:1281-2.

Popa D, Lena C, Fabre V, Prenat, C, Gingrich JA, Escourrou, P, Hamon, M, Adrien, J (2005): Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci 25:11231-8.

Villalobos C, Beique JC, Gingrich JA, Andrade R (2005): Serotonergic regulation of calcium-activated potassium currents in rodent prefrontal cortex. Eur J Neurosci 22:1120-6.

Zhuang X, Masson J, Gingrich JA, Rayport S, Hen R (2005): Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J Neurosci Methods 143:27-32.

Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich JA, Dumuis A, Brunner D, Bockaert J, Hen R (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knockout mice. J. Neurosci. 24: 412-419.

Lira, A., Zhou, M., Castanon, N., Ansorge, M. S., Gordon, J. A., Francis, J. H., Bradley-Moore, M., Lira, J., Underwood, M. D., Arango, V, Hofer, MA., Hen, R., Gingrich, J.A. (2003). Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54: 960-971.

Gingrich J.A., Ansorge MS, Merker R, Weisstaub N, Zhou M (2003): New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders. CNS Spectr 8: 572-7.

Gingrich J.A. (2003): Sharing genes? How mice can help us understand our biology. CNS Spectr 8: 571.

Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmback, E., Lira, A., Zhou, M., Weisstaub, N., Hen, R., Gingrich, J.A., Sealfon, SC (2003): Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23: 8836-43.

Gingrich, J.A. (2002): Mutational analysis of the serotonergic system: recent findings using knockout mice. Curr Drug Target CNS Neurol Disord 1: 449-65.

Fiorica-Howells E, Hen R, Gingrich J.A., Li Z, Gershon MD (2002): 5-HT(2A) receptors: location and functional analysis in intestines of wild-type and 5-HT(2A) knockout mice. Am J Physiol Gastrointest Liver Physiol 282: G877-93.

Gingrich, J.A. and Hen, R. (2001) Dissecting the role of the serotonergic system in neuropsychiatric disorders using transgenic mice. Psychopharmacology 155: 1-10.

Gingrich, J.A., Hen, R. (2000) Using Transgenic Mice to Probe the Role of Specific Genes in Behavior In Current Concepts in Psychiatry. Volume 1, Chapter 5. Henn, F. ed. Springer, Hamburg.

Gingrich, J.A. and Hen, R. (2000) The Broken Mouse: Interpreting phenotypic changes in knockout mice. Current Opinions in Neurobiology 10: 146-152.


Current Funding Sources:

NIMH(RO1-MH076026-01) (Gingrich)
Gene - Environment Interactions in 5-HTT Deficient Mice.
This study examines the environmental factors that contribute to the worsening or amelioration of the depressive phenotype that have been described in the 5HTT knockout mice.

NIMH (R21 MH073794-01) (Gingrich)
Epigenetic mechanisms: Paternal Age and Disease
2 year project to investigate the role of aberrant sperm methylation as a mechanism for the risk advanced paternal age poses for their offspring to several diseases, including schizophrenia.

NIMH (P50MH066171-01A1) Conte Center for Schizophrenia Research (Lieberman)
Our component of this Center uses mice partially deficient in neuregulin-1 as an animal model of schizophrenia

NIMH (2 P50 MH062185-06) Conte Center for the Neuroscience of Mental Disorders
The Neurobiology of Suicidal Behavior (Mann)
Project 6- Genetic Modulation Of Serotonin During Development: Models Of Aggression, Impulsivity And Depression (PI: Underwood) Our component of this Center Animal Project (7) examines the development of behavior in SERT and MAOA KO mice to understand the divergent effects of each genotype on behavior.

Whitehall Foundation (Gingrich)
Role of Cortical 5-HT2A receptor expression in hallucinogen function.
3 year project to identify the role of cortical 5-HT2A receptors in the mechanism of action of LSD-like hallucinogens.

American Foundation For Suicide Prevention (Gingrich)
Role of Cortical 5-HT2A receptors in impulsivity and aggression.
To examine the role of serotonin 5-HT2A receptors as possible mediators of impulsivity and aggression with the goal of identifying medications that may reduce these characteristics in susceptible individuals.

NARSAD (Ansorge)
Consequences of SERT Inhibition during Development on Adult Behavior and Neurophysiology.
2 year project to investigate the disruption of SERT function during critical developmental periods may alter the trajectory of the central nervous system development in ways that influences affective function later in life.
Role on project: Postdoctoral Mentor



Lab Members:

Mark Ansorge, PhD (Postdoctoral Fellow) Projects: The impact of early-life disruption of serotonin transporter function on behavior, physiology, and behavior The role of 5-HT7 receptor function in normal and abnormal behavior. From Berlin , Mark was a “promoter jock” before becoming a consummate behaviorist.
Robert Merker, PhD ( Postdoctoral Fellow) Projects: Spatial control of gene expression using Cre recombinase. Reduced genetic expression of Neuregulin1 as a mouse model of schizophrenia. Rob received his PhD at NYU.
Maria Milekic, PhD (Postdoctoral Fellow) Projects: Effect of advanced paternal age on sperm DNA methylation and offspring behavior Role of 5-HT2A receptor signaling in psychostimulant and NMDA antagonist effects. Maria received her PhD at Mt. Sinai with Cristina Alberini. She calls Sweden home.
Noelia Weisstaub, MS (Graduate Student) Projects: Role of 5-HT2A signaling in anxiety and cognition. Role of 5-HT2A receptor signaling in the mechanism of action of LSD-like hallucinogens Graduate student in the Department of Biology, Noelia hails from Buenos Aires .
Joshko Ivica, (Veterinary Assistant) Responsible for breeding, weaning, genotyping the Gingrich Lab colony of genetically-modified mice. The foundation upon which our research is built… He trained in Croatia before he joined our group.
Zulaika Velazquez, *Research Associate) After many years in the lab, now effectively acts as lab manager. She is the organizational and emotional glue that binds the lab. If that was not enough… she is a Julliard graduate with a breathtaking operatic voice. A future Carmen??
Emanuela Morelli, MS (Research Associate). Assists in behavioral assessments of genetically and pharmacologically manipulated mice with Dr. Ansorge. “Manu” has come to our group from Rome to learn more basic neuroscience and complement her background in human psychology. She plans to apply to Graduate programs in neuroscience.
Students: Rebecca Balter, ( Columbia Undergraduate student) . Dentate neurogenesis in response to genetic manipulation of the serotonin transporter and 5-HT7-receptor gene manipulations. Rebecca has been doing research for credit in our group. Rebecca plans to apply to Graduate Programs in Neuroscience after graduation.
Kevin Kumar, (Cornell Undergraduate Student) Kevin studies the role of paternal age in offspring behavior. He came to the “other” Ivy League university in NY to learn more about basic research. Kevin is trying his hand at basic research before heading off to medical school.
Alison O'Neill, ( Columbia Undergraduate Student) Trying to understand the function that 5-HT2A receptor signaling plays in anxiety, cognition, and schizophrenia. Alison joins us for a second year, yet claims she is not a masochist.
Cindy Parra, ( Columbia Undergraduate Student) Cindy joins the group to work with Mark Ansorge in order to quantify the neural substrates of emotional function that are abnormal in serotonin transporter knockout mice. She joins our group to perform her senior thesis research before applying to medical school or combined MD-PhD programs.
Jackie Tinsley ( Columbia Undergraduate Student) Jackie joins our lab for her senior thesis in order to study the effect of paternal age on DNA methylation. Unfortunately, we did not have a photo at press time.
Distinguished Gingrich Lab Alumni (DGLA):
Mingming Zhou, PhD, distinguished Gingrich Lab Alumnus. Was instrumental in the engineering of targeting constructs for the serotonin transporter knockout mice, 5-HT2A knockout mice, 5-HT4 knockout mice, among others. She also had a deftness for inserting these constructs into ES cells that went germline. She is missed! She is shown (left) with her son and Maria Bradley-Moore at our annual lab outing in Fort Tryon Park. She has recently taken a position with Paul Greengard at The Rockefeller University.
Alena Lira , MD , distinguished Gingrich Lab Alumnus. Made important contributions to our understanding of serotonin transporter function in development and 5-HT2A receptor function in atypical antipsychotics. After her tenure in the lab, she attended SUNY Downstate Medical School . Currently pursing her passion in medical understanding of deep sea diving physiology.
Maria Bradley-Moore, MD, distinguished Gingrich Lab Alumnus. Made important contributions to our understanding of paternal age on offspring behavior. After her brilliant work in our group, she attended Columbia University Medical School . Currently, applying to psychiatry residency programs. The DGLA group is a work in progress. There are many other distinguished alumni for whom we do not have photos. Please send your photo and a current address and you will be included the next time around.