title: Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model.
abstract: Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset.
authors.affiliation: Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: McCarthy
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Bell
authors.forename: Elisa N
authors.initials: EN
authors.lastname: Cannon
authors.forename: Kaly A
authors.initials: KA
authors.lastname: Mueller
authors.forename: Megan N
authors.initials: MN
authors.lastname: Huizenga
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Debra A
authors.initials: DA
authors.lastname: Fadool
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D003042:Cocaine