Route 28 Summits

2004 Route 28 Summit Participants and Proposals






Adult Neurogenesis and Neuropsychiatric Disorders

04 Summit Topic / 04 Speakers / 04 Schedule / 04 Location / 04 Participants and Proposals

The 2004 Challenges:

Green Teams: “Episodes”

Physical changes in the body can be accompanied by mental changes as well. Medical illnesses such as stroke, heart attack, cancer, Parkinson's disease, and hormonal disorders can cause depressive illness, making the sick person apathetic and unwilling to care for his or her physical needs, thus prolonging the recovery period. Also, a serious personal loss, difficult relationship, financial problem, or any stressful (unwelcome or even desired) change in life patterns can trigger a depressive episode. Sometimes no such trigger is apparent at all. Very often, a combination of genetic, psychological, and environmental factors is involved in the onset of a depressive disorder.

How can one rationalize or explain the “neurogenesis theory” in the context that major depression comes and goes in episodes, often with rather sudden onsets and offsets, as well as life events and/or illness? Design a strategy that links the episodic nature of depression to neural precursor cell activity and find mechanistic commonalities related to potential triggers. You may but do not have to extend this question to bipolar disorders (manic episodes). Your focus should be on de-pression.

Blue Teams : “Genes”

Some types of depression run in families, suggesting that a biological vulnerability can be inherited. This also seems to be the case with bipolar disorders. Studies of families in which members of each generation develop bipolar disorder found that those with the illness have a somewhat different genetic makeup than those who do not get ill. However, the reverse is not true: Not everybody with the genetic makeup that causes vulnerability to bipolar disorder will have the illness. Apparently additional factors, possibly stresses at home, work, or school, are involved in its onset. This is likely to be true for unipolar depression as well.

Design a strategy for identifying the genetic determinants possibly shared by depression and adult neurogenesis and utilize this hypothetical data to determine the relative contributions of ge-netics and or environmental factors in a precursor cell-related predisposition to depressive disor-ders. You may but do not have to include bipolar disorders (manic episodes). Your focus should be on depression.

Yellow Teams: “Remedy”

Depression is a complex, heterogeneous disorder commonly treated with one of three major classes of drugs: 1. monoamine oxidase inhibitors (MAOIs), 2. selective serotonin reuptake inhibitors (SSRIs), and 3. tricyclic antidepressants (TCAs). All three are based on the monoamine hypothesis of depression and function by increasing the bioavailability of monoamines in the brain. Perhaps as complex as the disease they are commandeered to treat, monamines are a pleiotropic bunch playing a role in diverse biological processes including embryogenesis, plasticity, blood flow and neurogenesis. An emerging concept is that these drugs exert their effects by modulating the signaling pathways involved in plasticity or survival of stem cells. Hence modulation of neurogenic pathways may provide a common mechanism for improving or protecting the general well-being of the depressed brain.

Design a strategy to determine the link between the neurogenic effects of existing anti-depression drugs with the treatment of clinical depression. Is it possible to discriminate between the diverse functions of these drugs and a neurogenic mechanism? Consider the evidence that glial and neu-ronal loss exists outside of the accepted “neurogenic zones” of patients. You may but do not have to consider bipolar disorders (manic episodes) in your studies, where TCA’s may adversely affect the progression of the disease.

Team Assignments

Green 1

Blue 1

Yellow 1

Boldizsar Czeh
Artur Czupryn
Joseph Dougherty
Mikko Sairanen
Ariane Santoso

Los Angeles

Günter Höglinger
Theresa Kelly
Claudia Roth-Alpermann
Nicolai Savaskan
Viviana Triaca

Los Angeles

Tomas Olsson
Sophie Scotto-Lomassese
Lori Shoemaker
Ruth-Maximiliane von Laer
Ashwin Woodhoo

Los Angeles
Frankfurt Main


Green 2

Blue 2

Yellow 2

Jens Benninghoff
Divya Chari
Marianne Larsen
Andrew Naylor
Marco Timmer

Cambridg e

Zhale Bandpey
Zoe Bichler
Tod Kippin
Kimberley Maxwell
Sudhirkumar Yanpallewar


Michael Saxe
Elodie Bruel-Jungerman
Golo Kronenberg
Albrecht Kunze
Colin Watts

New York
Orsay (France)


Green 3

Blue 3

Yellow 3

Ratan Bhardwaj
Silviana Chiavegatto
Anke Karl
Mark R Kotter
Harish Babu

Sao Paulo

Mounira Banasr
Helena Frielingsdorf
Flavia Saravia
U. Shivraj Sohur
Yaniv Ziv

San Diego
Buenos Aires

Oleg Butovsky
Siobhan McMahon
Christelle Rochefort
Li-ping Wang
Jennifer Warner

New Haven


The Winning Proposal Abstracts:


Green 1: Boldizsar Cheh, Mikko Sairanen, Artur Czupryn, Ariane Santoso, Joseph Dougherty.

Developing new tools to investigate the relationship between adult hippocampal neurogenesis and depressive episodes.

Human major depression comes in episodes. Frequently the onset of episodes have an outside trigger like a stressful event. Changes in adult neurogenesis in dentate gyrus of hippocampus have also been associated with depression via response to antidepressant treatment, and measures of hippocampal volume in humans and animals. So do changes in neurogenesis correlate with onset of depressive episodes? Our hypothesis is that decreased neurogenesis infers susceptibility to depressive episodes. We have developed two methods to investigate this. First, we describe a non-invasive in vivo imaging method to measure changes in neurogenesis in humans, using PET and the administration of a radioactively labeled BRDU analog, F-18 FRDU. In humans, a decrease in neurogenesis should precede the onset of a major depressive episode. Furthermore, an increase in neurogenesis should precede remission. Second we develop a transgenic monkey model where we can reversibly repress neurogenesis. By stressing these animals we will be able to test the hypothesis that decreased neurogenesis serves as a permissive factor for depressive episodes. We propose that in macaques in which neurogenesis is repressed, stressful life events will cause more and longer-lasting of episodes of depressive symptoms, than in animals with normal neurogenesis. Furthermore, derepression of neurogenesis will expediate the remission of the episode. Animals with reduced neurogenesis, in the absence of major stressors, should not show major depressive symptoms. Results obtained from this study may lead to new avenues for treatment of depressed patients.


Blue 1: Gunter Höglinger, Nicolai Savaskan, Theresa Kelly, Viviana Triaca, Claudia Roth-Alpermann

Genetic Determinants of Neurogenesis and Depression

The goal of our project is to identify the genetic determinants possibly shared by depression and adult neurogenesis. We propose here an independent and therefore unbiased screen of candidate genes involved in the two phenomena of interest, namely depression and adult neurogenesis. Using a subtraction microarray approach we will identify candidate genes that are involved in both adult neurogenesis and depression. We will narrow down this list of genes using a bioinformatics approach followed by in situ hybridization. To test the functional implication of these genes in adult neurogenesis and depression we will overexpress and knock-down the expression of our candidate genes first in a high-throughput in vitro assay and secondly in the brains of living mice. To determine the relative contribution of environment versus genetics on the development of depression we will use these animals in a modified behavioral model of depression allowing a graded administration of the stressing stimulus in a dose-response-approach. This proposal describes an independent identification of genes involved in depression and neurogenesis followed by a successive narrowing of the possible candidate genes and subsequent testing of these genes in an animal model of depression.


Yellow 1: Tomas Olsson, Ruth von Laer, Sophie Scotto-Lomassese, Ashwin Woodhoo, Lori Shoemaker

Numerous antidepressant treatments have been shown to increase hippocampal adult neurogenesis, whereas stress-induced factors-induced depression is known to down regulate it. Based on these correlations, an exciting possibility has recently emerged suggesting that functional recovery mediated by these treatments might be as a result of increased neurogenesis (for review, Malberg et al, 2004). Santarelli et al., (2003) have shown that disrupting antidepressant-induced neurogenesis blocks behavioral responses of antidepressants, but we cannot rule out the possibility of side effects of such aggressive method as irradiation. In this study, the cornerstone of our approach is the maintenance of normal neural architecture, without inducing possible inflammatory responses. We will evaluate the effects on MAO treatment outcome in conditions of modified neurogenesis in the hippocampus. We aim to achieve this by 1) inducing an increase or decrease of the total number of neural stem/progenitor cells, 2) “silencing” the immature granule cell population, 3) encouraging a glial differentiation of stem cells. Finally, we will also try to address the modifications of hippocampal neurogenesis between control and depressed patients by evaluating the incorporation of 14C into the DNA.

It has been suggested that, in an insect model, new neurons are not necessary but they improve learning in an olfactory complex task, suggesting a supportive function for new adult neurons (Scotto-Lomassese et al, 2003). We thus hypothesize that adult neurogenesis is not necessary for the antidepressant drug-induced functional recovery, but rather is supportive of drug action.


Additional Abstracts

04 Summit Topic / 04 Speakers / 04 Schedule / 04 Location / 04 Participants and Proposals


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