Many of our actions feel automatic. Driving a familiar route to work 'on autopilot'is a common experience - as is taking a wrong turn when today's goal differs from the norm. This is an example of habit learning - a pattern of associations between stimuli and responses, or between patterns of thought, that is acquired over time and, once acquired, become stereotyped and requires effort to overcome. Dysregulation of such habit learning, and of the basal ganglia circuitry that underlies it, is central to obsessive-compulsive disorder, Tourette's syndrome, and related disorders. The mechanisms of habit learning may be of importance to more than one psychiatric disorder. Unfortunately, our knowledge of the mechanisms of information processing and storage in the basal ganglia during striatum-dependent learning remains rudimentary. Targeted genetic manipulations in mice have been a useful tool in the analysis of other forms of learning. We have recently shown regulation by the transcription factor CREB to be critical in normal striatum- dependent learning, using transgenic mice in which CREB's function is specifically disrupted in the striatum. This study represents the first time, to our knowledge, that such specific targeting of the striatum in genetically modified mice has been used to probe the mechanisms of striatum-dependent learning. We now propose to build on this preliminary study through more refined behavioral assays, targeting subregions of the striatum using viral vectors, and characterizing downstream genes important in striatal information processing and storage. This approach takes advantage of my experience in the generation and behavioral analysis of genetically modified mice as well as other experimental approaches in which expertise exists in the Yale community. Clinical expertise in the Yale OCD Research Clinic and Child Study Center allows for a clinically informed research program that will aid me in my development towards independence as a researcher while advancing our understanding of psychiatric disorders in which maladaptive habits wreak havoc in patient's lives. This understanding will pave the way for therapies of the future.

Public Health Relevance

Obsessive-compulsive disorder is the fourth most common psychiatric disorder and a major cause of disability in America and worldwide. The neural circuitry that underlies it is involved in normal habit learning. We seek to understand the mechanisms of this habit learning and of OCD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH081190-05
Application #
8305989
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Rosemond, Erica K
Project Start
2008-05-15
Project End
2013-05-30
Budget Start
2012-05-01
Budget End
2013-05-30
Support Year
5
Fiscal Year
2012
Total Cost
$177,272
Indirect Cost
$13,131
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Pittenger, Christopher; Adams Jr, Thomas G; Gallezot, Jean-Dominique et al. (2016) OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding. J Affect Disord 196:87-96
Xu, M; Li, L; Pittenger, C (2016) Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming. Neuroscience 324:321-9
Kelmendi, Benjamin; Adams Jr, Thomas; Jakubovski, Ewgeni et al. (2016) Probing Implicit Learning in Obsessive-Compulsive Disorder: Moderating Role of Medication on the Weather Prediction Task. J Obsessive Compuls Relat Disord 9:90-95
Pittenger, Christopher; Bloch, Michael H; Wasylink, Suzanne et al. (2015) Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial. J Clin Psychiatry 76:1075-84
Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh et al. (2015) Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A 112:893-8
Pittenger, Christopher (2015) Glutamatergic agents for OCD and related disorders. Curr Treat Options Psychiatry 2:271-283
Anticevic, Alan; Hu, Sien; Zhang, Sheng et al. (2014) Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biol Psychiatry 75:595-605
Bloch, M H; Bartley, C A; Zipperer, L et al. (2014) Meta-analysis: hoarding symptoms associated with poor treatment outcome in obsessive-compulsive disorder. Mol Psychiatry 19:1025-30
Castellan Baldan, Lissandra; Williams, Kyle A; Gallezot, Jean-Dominique et al. (2014) Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron 81:77-90
Panza, Kaitlyn E; Pittenger, Christopher; Bloch, Michael H (2013) Age and gender correlates of pulling in pediatric trichotillomania. J Am Acad Child Adolesc Psychiatry 52:241-9

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