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- 1. Maternal Separation and Its Effect on Parvalbumin-Expressing Interneuron Development and Behavior Joey Low1,2, Shawn Tan Pang Hao2, Shawn Je Hyunsoo2 1School of Biological Sciences, Nanyang Technological University, Singapore 637551 2Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857 www.sbs.ntu.edu.sg 1. Introduction Early life stress induces vulnerability to psychiatric disorders in humans, but the underlying neurobiology remains unclear. Parvalbumin (PV)-interneurons are a subtype of inhibitory interneurons in the neural circuits of the brain that are implicated in behavioral disorders such as attention-deficit hyperactive disorder (ADHD), schizophrenia, and autism. Using maternal separation (MS) in a reporter mice line as a model to study stress-induced psychiatric disorders in humans, we hypothesized that early life stress leads to dysfunctional development of PV-interneurons, hence resulting in altered behavior. MS MC Crawley Box Fear Conditioning Tail Suspension Behavioral Assays PND 02 14 28 49 50 71 Weaning General health check Behavioral Assays PND 0 28 49 50 71 Separation of pups from dam 3 hours daily Weaning General health check PV Stop tdTomato LoxPLoxP Cre Recombinase A. Experiment timeline. Behavioral assays were carried out in the order shown. B. Two mice lines respectively carrying a PV-Cre and Rosa26tdTomato (RTM) construct were crossed to generate a PV-Cre RTM reporter mice line used for PV-interneuron quantification. Any changes in PV-interneuron numbers in MS mice could then be correlated with changes in behavior. A B 3. Results 3.1. MS Mice display Novelty-Induced Hyperlocomotion in the Open Field Test 3.2. MS Mice show Impulsivity and are More Likely to make Transitions in the Light/Dark Box 3.3. MS Mice show Stronger Learning and Retention of Fear Memory in the Contextual Fear Conditioning Test 3.4. MS Mice exhibit Depression-Like Behavior and show Less Struggling in the Tail Suspension Test 3.5. PV-Cre RTM Mice show Specific Staining for PV but not for Other Interneuron Markers DAPI tdTomato PV Composite DAPI tdTomato Calretinin Composite DAPI tdTomato SST Composite 3.6. Interneuron Quantification shows No Change in Hippocampal PV-Interneuron Numbers in MS Mice 4. Conclusion Fig 3.3.1 Day One fear conditioning Fig 3.3.2 Day Two contextual fear recall Our maternal separation paradigm produces a phenotype in mice resembling that of ADHD and depression in humans, as well as stronger fear memory and response. However, no change in PV-interneurons is observed possibly because interneuron dysfunction is more subtle. Further characterization of potential functional changes in PV-interneurons of MS mice needs to be done to explain the behavioral changes. Elevated Zero Maze Open Field Light Dark Box 1, 2, 3 FSohal, V.S., Zhang, F., Yizhar, O., Deisseroth, K., 2009. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698-702. Gandal, M.J., Nesbitt, A.M., McCurdy, R.M., Alter, M.D., 2012. Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bipolar disorder. PLoS ONE 7. Karch, S., Segmiller, F., Hantschk, I., Cerovecki, A., Opgen-Rhein, M., Hock, B., Dargel, S., Leicht, G., Hennig-Fast, K., Riedel, M., Pogarell, O., 2012. Increased gamma oscillations during voluntary selection processes in adult patients with attention defi- cit/hyperactivity disorder. J Psychiatr Res 46, 1515-1523. 1 2 3 x 2. Methodology Behavioral Assays PV-Interneuron Quantification