Task-specific effects of biological sex and sex hormones on object recognition memories in a 6-hydroxydopamine-lesion model of Parkinson’s disease in adult male and female rats

Abstract

ABSTRACTMany patients with Parkinson’s disease (PD) experience impairments in cognition and memory with few therapeutic options currently available to mitigate them. This has fueled interest in determining how factors including biological sex and sex hormones might modulate higher order function in PD. Previous studies have investigated this in female rats and in gonadally intact and gonadectomized males, with and without hormone replacement, that received bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesions to model PD. Barnes maze and What Where When Episodic-like memory testing showed that 6-OHDA lesions disrupted spatial working and episodic memory functions in both sexes, and that in males, androgen-sensitive behaviors could be rescued in subjects where circulating androgen levels were diminished. Here we tested similar animal groups using the Novel Object Preference (NOP) and Object-in-Place (OiP) tasks. This revealed two entirely different patterns of sex and sex hormone influence. First, for both tasks, 6-ODHA lesions impaired object discrimination in males but not females. Further, for the NOP task, 6-OHDA lesions disrupted discrimination in males rats independently of hormone status. And finally, 6-OHDA lesions impaired OiP performance in males regardless of whether androgen levels were high or low but had no effect on discrimination in gonadectomized rats given 17β-estradiol. Together with previous findings, these data identify the impacts of sex and sex hormones on cognition and memory in PD as behavioral task/behavioral domain specific. This specificity could explain why a cohesive clinical picture of endocrine impacts on higher order function in PD has remained elusive.HIGHLIGHTS6-OHDA lesions impair Novel Object performance in male but not female rats.6-OHDA lesions impair Object-in-Place performance in male but not female rats.Gonadectomy has no effect on 6-OHDA-induced deficits in Novel Object Preference.Estrogen replacement prevents 6-OHDA-induced Object-in-Place deficits in males.