title: The impact of biological sex and sex hormones on cognition in a rat model of early, pre-motor Parkinson's disease.
abstract: Parkinson's disease (PD) is well known for motor deficits such as bradykinesia. However, patients often experience additional deficits in working memory, behavioral selection, decision-making and other executive functions. Like other features of PD, the incidence and severity of these cognitive symptoms differ in males and females. However, preclinical models have not been used to systematically investigate the roles that sex or sex hormones may play in these complex signs. To address this, we used a Barnes maze spatial memory paradigm to compare the effects of a bilateral nigrostriatal dopamine lesion model of early PD on cognitive behaviors in adult male and female rats and in adult male rats that were gonadectomized or gonadectomized and supplemented with testosterone or estradiol. We found that dopamine lesions produced deficits in working memory and other executive operations, albeit only in male rats where circulating androgen levels were physiological. In males where androgen levels were depleted, lesions produced no additional Barnes maze deficits and attenuated those previously linked to androgen deprivation. We also found that while most measures of Barnes maze performance were unaffected by dopamine lesions in the females, lesions did induce dramatic shifts from their preferred use of thigmotactic navigation to the use of spatially guided place strategies similar to those normally preferred by males. These and other sex- and sex hormone-specific differences in the effects of nigrostriatal dopamine lesions on executive function highlight the potential of gonadal steroids as protective and/or therapeutic for the cognitive symptoms of PD. However, their complexity also indicates the need for a more thorough understanding of androgen and estrogen effects in guiding the development of hormone therapies that might effectively address these non-motor signs.
authors.affiliation: School of Medicine, Stony Brook University, Stony Brook, New York 11794-5230, United States.
authors.forename: Erika
authors.initials: E
authors.lastname: Betancourt
authors.affiliation: School of Medicine, Stony Brook University, Stony Brook, New York 11794-5230, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wachtel
authors.affiliation: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794-5230, United States.
authors.forename: Michalis
authors.initials: M
authors.lastname: Michaelos
authors.affiliation: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794-5230, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Haggerty
authors.affiliation: Northport High School, 154 Laurel Hill Road, Northport, NY 11768, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Conforti
authors.affiliation: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794-5230, United States. Electronic address: mary.kritzer@stonybrook.edu.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Kritzer
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009919:Orchiectomy; D010052:Ovariectomy; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000503:physiopathology* / Q000523:psychology*; D062706:Prodromal Symptoms; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D065852:Spatial Memory / Q000502:physiology; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D013739:Testosterone; D004958:Estradiol; D016627:Oxidopamine
keywords: 6-OHDA; Barnes maze; androgen; estrogen; executive function; working memory