How do molecular and circuit changes in the brain cause psychiatric illness? And how can we leverage the inherent plasticity of the brain to treat psychiatric disorders? Our laboratory is currently addressing these questions by investigating communication between prefrontal cortex and the basal ganglia, with a specific focus on dissecting the pathophysiology of perseverative and compulsive behaviors. These disabling and notoriously treatment-resistant symptoms are prominent in multiple severe psychiatric disorders including Obsessive Compulsive Disorder, autism, and addiction. Ongoing projects in the lab include identification of molecular changes and plasticity mechanisms linked with the onset, persistence, and treatment of compulsive behaviors. We are also exploring the molecular and circuit mechanisms underlying anxiety, and the relationship between stress, anxiety, and the development of compulsive behaviors. To investigate these questions, we test hypotheses from human clinical studies in mouse models of disease, using a variety of techniques for analysis and manipulation of neural circuits including optogenetics, in vivo electrophysiology, novel transgenic tools, in vivo microscopy, viral tract tracing, and rodent behavioral analysis. The ultimate goal of our work is to develop new treatment approaches for these devastating illnesses.
Cazorla, M., Delmondes de Carvalho, F., Shegda, M., Chuhma, N., Rayport, S., Ahmari, S.E. and Kellendonk, C. Striatal D2 receptors regulate the anatomical balance of basal ganglia circuitry. In press. Neuron.
Corbit VL, Manning EE, Gittis AH, andAhmari SE*. Strengthened M2 inputs to central striatum in the Sapap3-KO mouse model of compulsive behavior. (2019) Journal of Neuroscience. 39: 2965-2975. PMID: 30737313
Khierbek, M.A., Drew, L.J., Constantini, D.O., Burghardt, N.S., Tannenholz, L., Ahmari, S.E., Zeng, H., Fenton, A.A. and Hen, R. Differential control of learning and anxiety along the dorso-ventral axis of the dentate gyrus. Neuron. 77: 955-968, 2013.
Ahmari, S.E., Spellman, T., Douglass, N.L., Khierbek, M.A., Gordon, J., Deisseroth, K. and Hen, R. Repeated cortico-striatal stimulation generates chronic OCD-like behavior. Science. 7: 1234-1239, 2013.
Tanaka, K., Ahmari, S.E., Leonardo, E.D., Richardson-Jones, J.W., Budreck, E.C., Scheiffele, P., Inamura, N., Ikenaka, K. and Hen, R. Flexible Accelerated STOP-tetO knockin (FAST): a versatile new gene modulating system. Biological Psychiatry. 67: 770-773, 2010.
Ahmari, S.E., Risbrough, V., Geyer, M. and Simpson, H.B. Impaired sensorimotor gating in unmedicated adults with obsessive compulsive disorder. Neuropsychopharmacology. 37: 1216-1223, 2012.
Ahmari SE. Using Mice to Model Obsessive Compulsive Disorder: From Genes to Circuits. (2015) Neuroscience. 321: 121-137. PMID: 26562431.
Zike ID, Chohan MO, Kopelman JM, Krasnow E, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood GD, Tanaka KF, Moore H, *Ahmari SE, *Veenstra-VanderWeele J. OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. (2017) PNAS. 114: 5719-5724. PMID: 28507136.
Manning EE, Dombrovski AY, Torregrossa MM, and Ahmari SE*. Impaired instrumental reversal learning is associated with increased mPFC activity in Sapap3-KO mouse model of compulsive behavior”. (2018) Neuropsychopharmacology. 44: 1494-1504. PMID: 3058785129.
Piantadosi SC, Chamberlain B, Glausier JR, Lewis DA, and Ahmari SE*. Decreases in excitatory synaptic gene expression in orbitofrontal cortex and striatum of subjects with obsessive compulsive disorder. (2019) Molecular Psychiatry. epub ahead of print. PMID: 31168067