We propose to use behavioral and genetic mouse models to identify the neural mechanisms by which serotonin transporter (5-HTT) function modulates sensorimotor gating deficits and perseverative behaviors. Sensorimotor gating is a neural mechanism that filters excessive sensory, cognitive, and motor information, permitting mental and behavioral integration. Prepulse inhibition (PPI) is a form of startle plasticity that provides an operational measure of sensorimotor gating. Recent findings have implicated gain-of-function mutations in 5-HTT, and hypersensitivity of 5-HT1DP (homologous to mouse 5-HT1B) receptors, in two disorders characterized by deficient PPI and perseverative behaviors: obsessive-compulsive disorder (OCD) and autistic disorders. Only antidepressant drugs that potently block the reuptake of serotonin provide effective treatment for these disorders. Our recent findings in mice have identified a functional interaction between 5-HTT and 5-HT1B receptors in modulating PPI and perseverative behaviors. We found that the PPI deficits and perseverative behaviors induced by acute 5-HT1B agonist challenge are absent in 5-HTT knockout mice. We also found that the behavioral deficits induced by 5-HT1B agonists are absent in mice treated chronically, but not subchronically, with the selective serotonin reuptake inhibitor fluoxetine. Thus, we hypothesize that reducing 5-HTT function, genetically or pharmacologically, prevents the PPI deficits and perseverative behaviors induced by 5-HT1B receptor activation by desensitizing these receptors. We also hypothesize that increasing 5-HTT function, genetically or pharmacologically, will exacerbate the behavioral deficits induced by 5-HT1B receptor activation by sensitizing these receptors. Here, we propose to identify the mechanisms by which 5-HTT and 5-HT1B receptors interact to modulate these behaviors. First, we will test the hypothesis that potent blockade of 5-HTT is required to prevent 5-HT1B agonist-induced behavioral deficits by comparing the ability of different classes of antidepressants to reverse these effects. Second, we will assess 5-HT1B receptor expression and functional coupling to localize the brain regions in which 5-HT1B receptors are desensitized by antidepressant treatments. Third, we will generate two inducible transgenic mouse strains with increased 5-HTT function. One strain will overexpress mouse 5-HTT to evaluate the effects of increased 5-HTT availability, which may model the consequences of specific 5-HTT gene-linked polymorphic region (5-HTTLPR) alleles recently linked to OCD. The other strain will express human 5-HTT containing an uncommon mutation, Ne425Val, which renders 5-HTT constitutively active and was recently linked to OCD and autism. We hypothesize that both mouse strains will exhibit PPI deficits and perseverative behaviors, and increased behavioral responses to 5-HT1B agonists. Our unique approach could lead to novel animal models of the sensorimotor gating deficits and perseverative behaviors in OCD and autism.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Opal, M D; Klenotich, S C; Morais, M et al. (2014) Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry 19:1106-14
Jiao, J; Opal, M D; Dulawa, S C (2013) Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene. Mol Psychiatry 18:1273-80
Woehrle, Nancy S; Klenotich, Stephanie J; Jamnia, Naseem et al. (2013) Effects of chronic fluoxetine treatment on serotonin 1B receptor-induced deficits in delayed alternation. Psychopharmacology (Berl) 227:545-51
Distler, Margaret G; Opal, Mark D; Dulawa, Stephanie C et al. (2012) Assessment of behaviors modeling aspects of schizophrenia in Csmd1 mutant mice. PLoS One 7:e51235
Klenotich, Stephanie J; Dulawa, Stephanie C (2012) The activity-based anorexia mouse model. Methods Mol Biol 829:377-93
Klenotich, Stephanie J; Seiglie, Mariel P; McMurray, Matthew S et al. (2012) Olanzapine, but not fluoxetine, treatment increases survival in activity-based anorexia in mice. Neuropsychopharmacology 37:1620-31
Shanahan, Nancy A; Velez, Lady P; Masten, Virginia L et al. (2011) Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice. Biol Psychiatry 70:1039-48
Jiao, Jianwei; Nitzke, Angela M; Doukas, Demetrios G et al. (2011) Antidepressant response to chronic citalopram treatment in eight inbred mouse strains. Psychopharmacology (Berl) 213:509-20
Wang, Li; Jiao, Jianwei; Dulawa, Stephanie C (2011) Infant maternal separation impairs adult cognitive performance in BALB/cJ mice. Psychopharmacology (Berl) 216:207-18
Savic, Daniel; Distler, Margaret G; Sokoloff, Greta et al. (2011) Modulation ofTcf7l2 expression alters behavior in mice. PLoS One 6:e26897

Showing the most recent 10 out of 13 publications