Division of Integrative Neuroscience - Columbia University Medical ...

Division of Integrative Neuroscience
Rene Hen, PhD, Division Chief
Department of Psychiatry, Columbia University
College of Physicians and Surgeons
New York State Psychiatric Institute
April 1, 2010 - March 31, 2011
Overview
The Division of Integrative Neuroscience is a research division aimed at understanding
the pathophysiology underlying psychiatric illnesses using approaches that span
multiple levels of neurobiological analysis. Accordingly, we combine molecular and
cellular neurobiological and behavioral techniques with analyses of neural circuits and
neural systems in order to fully understand animal models of psychiatric illnesses such
as anxiety disorders, depression and schizophrenia. Consisting of laboratories led by
Dr. Rene Hen, Dr. Holly Moore, Dr. Joshua Gordon, Dr. Karen Duff, Dr. Andreas
Kottmann, Dr. Peter Balsam and Drs. E. David Leonardo and Alex Dranovsky and
several additional faculty members and fellows, Integrative Neuroscience maintains
close ties with the Department of Neuroscience and various other neuroscience
laboratories at Columbia University.
Faculty and Staff
René Hen, PhD Professor Research Scientist VII
Peter Balsam, MD, PhD Professor Research Scientist
Karen Duff, PhD Professor Research Scientist
Joshua Gordon, MD, PhD Assistant Professor Research Scientist
Andreas Kottmann, PhD Assistant Professor Research Scientist
Kathleen Taylor, PhD Assistant Professor
E. David Leonardo, MD, PhD Assistant Professor/Psychiatrist Research Scientist
Holly Moore, PhD Assistant Professor Research Scientist
Alex Dranovsky, MD, PhD Assistant Professor Research Scientist
Mark Opler, PhD Assistant Professor
Amar Sahay, PhD Research Scientist
Liam Drew, PhD Research Scientist
Susanne Ahmari, MD, PhD Research Fellow
Nesha Burghardt, PhD Research Scientist
Ryan Ward, PhD Research Fellow
Salomao Segal, PhD Research Fellow
Benjamin Samuels, PhD Research Fellow
Torfi Sigursson, PhD Research Fellow Research Scientist
Katya Likhtik, PhD Research Fellow
Mazen Kheirbek, PhD Research Fellow
Melody Wu, PhD Research Fellow
Zoe Donaldson, PhD Research Fellow
Eero Castren, MD, PhD Assistant Professor
Andrew Rosen, PhD Research Fellow
2011 Annual Report 1 7/1/11

Hen Lab
René Hen’s research is focused on the contribution of serotonin (5-HT) receptors to
pathological states such as depression and anxiety. Pharmacological studies and
molecular cloning have identified several subtypes of receptors with distinct properties,
signaling systems, and tissue distributions. However, the study of the function of
individual serotonin receptor subtypes has been hampered by the lack of specific drugs.
In addition, a number of the serotonergic drugs that are active in the treatment of
neuropsychiatric disorders influence the whole serotonergic system. For example,
antidepressants such as fluoxetine are 5-HT uptake blockers and potentiate the action
of 5-HT at multiple post-synaptic sites. To dissect the contributions of individual
serotonin receptors to physiology and behavior, mouse mutants lacking individual
receptor subtypes were created in his laboratory, providing genetic models for a number
of human behavioral traits such as impulsiveness, depression, and anxiety. Tissue
specific and conditional knockouts are currently being used to identify the neural circuits
underlying these traits. Recently his lab has also been investigating the function of the
ventral hippocampus and the contribution of hippocampal neurogenesis to mood and
cognition. Specifically, they have shown that antidepressants stimulate the division of
neuronal progenitor cells in the dentate gyrus, which in turn results in an increase in the
number of immature neurons in the adult hippocampus. Furthermore, using various
ablation strategies they have shown that hippocampal neurogenesis is required for
some of the behavioral effects of antidepressants. Novel antidepressant therapies
aimed at targeting directly hippocampal stem cells are currently under investigation.
Gordon Lab
The Gordon lab studies mouse genetic models of psychiatric diseases from an
integrative neuroscience perspective, focused on understanding how a given disease
mutation leads to a behavioral phenotype in disease-related mouse models. A major
effort in the laboratory is aimed at identifying the effects of a deletion in the serotonin
1A-receptor (5-HT1AR) that lead to a phenotype of increased anxiety-related behavior.
We have previously identified functional abnormalities in the hippocampus of 5-HT1AR
knockouts suggesting that hippocampal dysfunction plays a role in the anxiety-related
phenotype in 5-HT1AR-deficient mice. Recently we have extended these findings to
include analysis of the communication between the hippocampus and the medial
prefrontal cortex in both wild-type and 5-HT1AR knockouts, demonstrating that this
pathway plays a role in anxiety. A paper describing these results has been submitted. In
addition, in collaboration with Dr. Lorna Role, we have begun to examine ventral striatal
activity in neuregulin-1 (NRG-1) heterozygote animals. NRG-1 has been identified as a
schizophrenia-predisposition gene in several independent studies, and mice lacking a
single copy of the gene have several behavioral hallmarks of schizophrenia. We have
identified abnormal patterns of activity in the ventral striatum of these mice, and are
currently characterizing this activity and attempting to determine its behavioral
relevance. Finally, in a collaboration with Drs. Joseph Gogos and Maria Karayiorgou,
we have begun to examine hippocampal and medial prefrontal cortex activity in mice
carrying a genetic deletion homologous to one which causes schizophrenia in humans.
Moore Lab
The hippocampal complex, parahippocampal cortex, and prefrontal cortex form multiple
circuits with “limbic-related” regions of the basal forebrain and midbrain. These circuits
interact extensively, and disruption of these interactions underlies the psychopathology
2011 Annual Report 2 7/1/11

of most psychiatric disorders. Moreover, many disorders, including anxiety, addiction
disorders and schizophrenia, emerge in most individuals during adolescence or early
adulthood. Thus, it is imperative to understand 1) how these corticolimbic circuits are
changing as the individual matures from early adolescence to adulthood, and 2) how
development of these circuits is altered by genetic alterations or environmental
exposures known to increase the risk for specific psychiatric disorders. Along these
lines, the Moore laboratory conducts research on 1) developmental changes in cerebral
cortical regulation of limbic basal forebrain and ascending monoaminergic systems
during adolescence, 2) modeling in rodents the neural and behavioral consequences of
disruptions of neurodevelopment relevant to schizophrenia, and 3) limbic circuit
mechanisms relevant to specific therapeutic, diagnostic or research procedures used in
psychiatric patients. To pursue these lines of research, we use anatomical, in vivo
neurochemical and neurophysiological and behavioral techniques. Description of the
progress made during the 2008-2009 year is as follows:
Ontogeny of corticolimbic circuits. The Moore lab has recently submitted
for publication two studies uncovering significant changes in the structure
of corticolimbic circuits occurring during adolescence the rat. The first
study characterizes changes in prefrontal cortical inputs to the amygdala
during early and late adolescence (Cressman et al., submitted). The
second study describes postnatal development of the morphology of
neurons in the CA1 and subiculum regions of the hippocampal complex.
This study focused on the projection neurons in these regions, assessing
changes in dendritic branching and the density and distribution of dendritic
spines on these neurons (Cressman et al., submitted). A third set of
developmental studies, conducted in collaboration with the Division of
Developmental Neuroscience, has characterized the neural and
pharmacological substrates of infant vocalization in the rat, particularly
vocalizations modulated by recent social experience (Muller et al., 2008;
Muller et al., 2009; Shair et al., 2009). Taken together, the above studies
provide information on normative development of circuits that mediate the
emotional and cognitive processes affected in a number of psychiatric
disorders.
Rodent models of the pathophysiology of schizophrenia. Dr. Moore’s
studies have determined a specific window around embryonic day 17 in
the rodent, during which methylation (specifically, abnormal alkylation) of
nucleic acids causes altered development of the cortical and thalamic
subregions that are particularly relevant to schizophrenia (Moore et al,
Biological Psychiatry, 2006). Importantly, this model also features
abnormal behavioral and neurochemical changes occurring during the
transition from puberty to adulthood that may model the “peripubertal”
period of risk. We have recently submitted a manuscript showing that the
projection neurons in the ventral subiculum of the MAM E17 model show
morphological abnormalities in dendritic compartments that receive
glutamatergic excitatory inputs, a neuropathological profile also reported in
the subiculum of patients with schizophrenia. There is also convergent
evidence for abnormal glutamate and/or energy metabolism in the
hippocampal complex (including subiculum) in the MAM E17 model.
These abnormalities in activity of the hippocampal complex may model an
important mechanism contributing to psychosis in schizophrenia, a link
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illustrated in a recent publication by our collaborators Schobel et al.
(2009). Conversely, “capping” glutamate transmission may be protective
against the psychotic symptoms. This hypothesis has gained support from
a recent collaborative study among several laboratories at NYSPI showing
that in a mouse model with a deficit in glutamate synthesis, both
hippocampal activity and the response to psychostimulants are blunted
(Gaisler-Solomon et al., 2009).
The Moore laboratory has also continued its collaboration with the
laboratories of M. Elizabeth Ross and Stewart Anderson at Weill Medical
College, Cornell University, to characterize models of cerebral cortical
interneuron pathology relevant to schizophrenia. Their studies have shown
that signaling pathways mediated by cyclin D2 and sonic hedgehog in the
medial ganglionic eminence of the embryonic forebrain are important for
the determination of the parvalbumin (PV)-expressing interneurons in the
cortex (Xu et al., submitted). Current experiments in these models are
aimed at characterizing the deficit in GABAergic inhibitory transmission in
limbic cortical circuits and its ultimate effect on seizure susceptibility,
affective behaviors and the response to psychostimulants. Other projects
related modeling disruptions of brain development that increases
susceptibility to psychiatric disorders include a study examining the effects
of early juvenile hypoglycemia on the post-natal development of emotional
regulation and stress responses in the rat (Moore et al., submitted) and a
study modeling the effect of an excess in stress hormones during very
early pregnancy on the postnatal development of schizophrenia-related
behaviors in the offspring (Kleinhaus et al., in press). The laboratory has
also collaborated with a number of NYSPI and Columbia Psychiatry
investigators in phenotyping genetic mouse models relevant to
schizophrenia (Chen et al., 2008; Kvajo et al., 2008).
Dranovsky and Leonardo Lab
Alex Dranovsky and David Leonardo have embarked on a collaboration to develop
novel tools in using the mouse as a model to study the neuro-circuitry of psychiatric
disease. They are using molecular biology techniques to generate inducible transgenic
mice that will allow manipulations such as reversible inactivation of genetically defined
populations of neurons in transgenic mice. These animals will be used to disrupt
genetically defined circuits that have been implicated in psychiatric disease and study
how altering brain circuits affect behaviors in animal models of illness. There are two
major areas of emphasis at this time:
Using circuit inactivation techniques they are investigating the regional aspects
of hippocampal function with the hypothesis that dorsal connections help the
brain compute cognitive information, while ventral connections compute
emotional information.
Studying the contribution of adult hippocampal neurogenesis to hippocampal
structure and function with the hypothesis that adult-born neurons integrate into
hippocampal circuitry, change hippocampal connectivity, and ultimately help the
hippocampus compute emotional and cognitive information.
Duff Lab
The main focus of Dr. Duff’s work is to examine mechanisms involved in the
development of neurodegenerative diseases (Alzheimer’s, Tauopathies, Parkinson’s)
2011 Annual Report 4 7/1/11

and to test therapeutic approaches that may attenuate disease progression. Over the
last 20 years, Dr. Duff has used genetic engineering technology to create several
mouse models for neurodegenerative diseases. There are currently three major areas
of research ongoing in the lab:
Examination of the spread of Abeta/amyloid and tau/tangle pathology from the
entorhinal cortex – an area of the brain first affected by pathology in AD- to areas
of the brain usually affected later to assess whether pathology or dysfunction
propagates, and if so, if propagation occurs by transynaptic spread. This project
uses regionally-restricted expression of APP or tau transgenes to initiate
pathology in the EC which is then followed longitudinally both by
immunohistochemistry to identify pathological forms of Abeta or tau, and by fMRI
detected change in cerebral blood volume, a measure of metabolic activity. In
parallel, cellular studies are being undertaken to examine the mechanism by
which pathogenic tau or abeta can spread form cell to cell.
A second project aims to understand the role of autophagy in disease
progression (tauopathy) and to identify new drugs that could upregulate
autophagy and attenuate disease.
A third project aims to better understand the impact of inheritance of a genetic
variant in the Apolipoprotein E gene (ApoE4) in susceptibility to AD. This study
aims to profile gene expression changes in affected region brain cell populations
(stellate neurons from EC) vs. resistant region cell populations (neurons from
primary visual cortex) from humans without disease (ages 20-50), with
susceptible (ApoE4 /E3) vs. non-susceptible gene variants (ApoE3 /3). Other
projects have examined the utility of drugs that have potential for treating AD or
tauopathy in our mouse models, and also the effect of AD risk factors such as
hypoperfusion on AD phenotypes in a rat model of the disease.
Balsam Lab
The lab is studying the mechanisms of adaptive behavior and how they might be altered
in animal models of psychiatric disorders. In an NIMH funded project the lab studies
how animals learn about time and use it to guide behavior. Additionally, this project
examines how temporal information processing is changed by alterations in
dopaminergic function. One project along these lines being done in collaboration with
the labs of Drs. Eric Kandel and Christoph Kellendonk of Columbia University is
analyzing and seeking to remediate the timing and motivational deficits found in a
transgenic mouse line that like schizophrenic patients, exhibits an increased level of
dopamine D2 receptor activity in the striatum. In a related NIDA funded project we are
studying how dopaminergic function changes over the course of learning in
collaboration with Dr. Jon Horvitz (City College) and Dr. Mark West (Rutgers University).
We have also begun collaborating on studies of motivation and cognition in animal
models with Drs. Jonathan Javitch, Holly Moore and Mark Ansorge at the NYSPI as well
as a collaboration with the Columbia Genome Center on the molecular bases of habit
learning. Additionally, we collaborate with William Fifer on NICHD funded studies
demonstrating that newborn infants learn during sleep as well as with Stephen Rayport
on his NIMH funded project on glutamate signaling in schizophrenia.
Kottmann Lab
The Kottmann laboratory employs a variety of molecular, pharmacological, cellular and
genetic loss and gain of function strategies in mice to define the neuronal contribution
2011 Annual Report 5 7/1/11

towards the regulation of stem cell maintenance and/or differentiation in the adult
forebrain. Recently the lab has demonstrated that the induction of physiological cell
stress in cholinergic cell populations in the striatum causes alterations in cell fate
determination in the neurogenic niche of the SVZ. Using a combination of temporally
and spatially controlled genetic gene ablation with gain of function approaches we
showed that differential expression of sonic hedgehog (SHH), a morphogen well known
from its involvement in the differentiation of the CNS during development, causes the
observed alterations in SVZ neurogenesis. Further experimentation revealed that Shh
expression in mesencephalic dopamine neurons is upregulated by physiological cell
stress in cholinergic neurons which are monosynaptically connected with dopamine
neurons. Mesencephalically expressed Shh acts thereby as a sentinel for basal ganglia
dysfunction and at the same time alters qualitative outcome of SVZ neurogenesis
causing an altered cyto-architecture of the olfactory bulb. Current efforts are directed to
understanding whether altered Shh signaling from dopamine neurons to the SVZ
causes the production of distinct cholinergic and dopaminergic neuronal identities in
addition to neurons that migrate into the olfactory bulb. These studies might guide us to
novel approaches to stimulate in vivo resident stem cells to give rise to particular cell
identities for which a physiological need exists in particular psychiatric and
neurodegenerative conditions.
In the course of these studies the Kottmann Lab produced two novel models of
neurodegenerative diseases in mice: The genetic ablation of Wolframin 1, a cell
physiological stress response factor expressed in basal brain structures and
hippocampus, yielded a progressive, genetic model of Wolfram Syndrome, a fatal
neurodegenerative disease associated with severe psychiatric complications. Haploid
insufficiency for wolframin1, which is associated with increased risk for depression in
humans, causes habituation deficits in the absence of overt neurodegeneration in mice.
The conditional ablation of Shh from differentiated mesencephalic dopamine neurons
yielded a model for progressive loss of cholinergic neurons in the striatum and
dopamine neurons in the substantia nigra and ventral tegmental area. Both mouse lines
are being made available by Columbia University for drug screening and validation
efforts that aim for the identification of neuroprotective agents.
In collaboration with Dr. Stuart Firestein’s lab (Department of Biology, Columbia
University) we have begun to analyze olfactory acuity in our mutant animals
hypothesizing that Shh dysregulation could cause the olfactory dysfunction that is a
preclinical sign in many neurodegenerative and psychiatric diseases. The Kottmann Lab
collaborates with the lab of Dr. Serge Przedborski to determine whether Shh signaling
renders mesencephalic dopamine neurons more resistant to dopaminergic neurotoxins
like MPTP and 6-OHDA. Finally, the Kottmann Lab maintains close ties with the Center
for Motor Neuron Biology and Disease and investigates whether differential expression
of Shh by cranial somatic motor neurons distinguishes motor neurons that resist
degeneration in Amyotrophic lateral sclerosis (ALS) from such that succumb to the
disease.
Education and Training
Neurobehavioral Sciences Research Postdoctoral T32 MH015174 - Rene Hen, Director
2011 Annual Report 6 7/1/11

Translational Workshop Series – a series of workshops in which a basic neuroscientist
and clinical psychiatrist or psychologist are invited to lead discussion on translational
approaches in research and treatment for a psychiatric disorder.
Highlights
Dr. Eero Castren - Winner of the Schaefer Research Scholars for 2011
Dr. René Hen HDRF Grant NYSDOH 2011 – 2012
“Characterization of affective circuits in a genetic and an environmental model of
depression and of antidepressant response.”
Dr. Holly Moore Grant from NIMH 1P50MH086404-01 7/1/10-6/30/15
CCNMD: “Dopamine (DA) dysfunction in schizophrenia”
Dr. Joshua Gordon received the International Mental Health Research Organization
Rising Star Award and a Hope for Depression Research Grant, “Neurophysiological
characterization of affective circuits and their role in depression.”
Dr. Karen Duff
NIHR01 (3/2011-2/2016) $2,408,107
“Spatio-temporal relationship of pathology and functional decline with tauopathy.
NIHR01 (7/2011-6/2016) $2,235,790 Autophagic Clearance of Aberrant Tau:
Biochemical and Therapeutic Implications”
NIHR21 (9/2010-6/2012) $269,667 Profiling Pathologically Normal ApoE Variants
to Identify Pathways for AD.
Dr. E. David Leonardo - 2010 1 RO1MH091427-01, “A Late sensitive period for the
Development of Anxiety disorders.”
Dr. Ryan Ward received an NIH post-doctoral fellowship for “Dopamine D2 receptor
overexpression, adenosine A2A receptors, and motivation.”
Dr. Peter Balsam participated in the NIMH CNTRCS meeting on how to measure
cognition in animal models of schizophrenia and gave keynote addresses at the annual
meetings of the Eastern Psychological Association and the Society for the Quantitative
Analysis of Behavior.
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2011 Annual Report 7 7/1/11

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