Genetic variation that alters activity-dependent circuit formation may contribute to an experience-dependent imbalance in circuit development. Brain derived neurotrophic factor (BDNF) is a neurotrophic factor involved in developmental maturation of neural processes and cell survival. 20-30% of Caucasians carry a polymorphism in the BDNF gene, where codon 66 is altered from a valine to methionine (Shimizu et al., 2004), a change which has been shown to alter activity regulated release of BDNF (Chen et al., 2006). The BDNF val66met polymorphism has been linked to anxiety and depression (although not without controversy), with stronger correlation in persons who have had the greatest amount of early life stress (Gatt et al., 2009). We hypothesize that individuals possessing the met66 allele of BDNF have weakened parahippocampal inputs to the cingulated and that early life stress enhances amygdala inputs to the cingulated. We hypothesize an imbalance in projections to the frontal cortex biases emotional experience and behaviors. In our animal model of this process, underdevelopment of the (parahippocampal) perirhinal (PRH) cingulated afferents enable enhanced, competitive development of the basolateral amygdala (BLA) cingulated afferents leading to abnormal dominance of harm avoidance information in frontal circuits involved in action selection and cognitive control. We propose a PRH:BLA cingulated projection imbalance, with diverse causes, may underlie a range of disorders in the spectrum of anxiety and novelty seeking. We will test the hypothesis that BDNF met66 variant mice which show enhance anxiety (Chen et al. 2006) also show unbalanced development of PRH and BLA inputs to the cingulated cortex. To pursue this putative endophenotype of anxiety, we will use state of the art longitudinal in vivo imaging of synapse formation (Aim 1) and optogenetic tools (Aim 2) to probe the adolescent development of long range afferents from the PRH and BLA to the cingulated cortex in BDNF val66met knocking mice (Chen et al., 2006). Specific measures will include in vivo cingulated spine and PRH and BLA bouton turnover and density (Aim 1), the ratio of excitatory and inhibitory currents driven by the BLA and PRH afferents in the cingulated, and the average PRH- and BLA-cingulated AMPA:NMDA ratio (Aim 2). We will also investigate the effects adolescent stress and cognitive training on plasticity (Aim 1) and connectivity (Aim 2) of PRH and BLA afferents. We predict that cognitive training in tasks that engage the PRH and the cingulated together will protect against the development of PRH:BLA imbalance and reduce anxiety behavior. Our experiments will inform understanding of the developmental etiology of disorders of anxiety and harm avoidance, provide an endophenotype that may be transferred to human studies, and test forms of cognitive therapy to rebalance circuit development.

Public Health Relevance

Excess anxiety or its opposite, low harm avoidance, can profoundly disrupt human lives. In our model, abnormal juvenile development leads to a lack of balance in inputs that relay information about safety and danger to the frontal cortex adversely affecting decision making. We will test this model to illuminate the developmental causes of disorders of anxiety and harm avoidance, provide a biological measure that can be transferred to human studies, and test forms of cognitive therapy to repair an imbalance in these circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH087542-05
Application #
8641983
Study Section
Special Emphasis Panel (ZMH1-ERB-L (06))
Program Officer
Panchision, David M
Project Start
2009-09-16
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$371,844
Indirect Cost
$134,244
Name
University of California Berkeley
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Johnson, Carolyn; Wilbrecht, Linda (2011) Juvenile mice show greater flexibility in multiple choice reversal learning than adults. Dev Cogn Neurosci 1:540-51