Sex differences distinguish performance in four object recognition-based memory tasks in the Pink1-/- rat model of Parkinson's disease.

Male more than female patients with Parkinson's disease (PD) experience early, sometimes prodromal non-motor deficits involving cognition and memory. These so-called mild impairments predict future risk of freezing, falls and developing PD-related dementia. Moreover, because most treatments are ineffective, these symptoms often persist and progressively worsen. Thus, there are urgent needs to better understand and better treat these signs. The work presented here highlights new ways in which rats with knockout of PTEN-induced putative kinase 1 gene (Pink1-/-) can serve as models that emulate PD's mild cognitive deficits and their sex differences. Specifically, longitudinal behavioral testing confirmed that male Pink1-/- rats developed significant deficits in Novel Object Recognition and Novel Object Location tasks by 5 months old, but that female Pink1-/- were unimpaired in these and in the Object-in-Place task through testing at 12 months of age. Further, What, Where, When Episodic-like Memory testing showed that deficits in all three memory domains were present in Pink1-/- males by 3 months of age. However, in Pink1-/- females, non-significant episodic memory impairments were first observed at 7 months of age which progressed to significant deficits in 'What', 'Where' and 'When' domains by the time female rats were 12 months old. Together, these data show that Pink1-/- rats model the greater vulnerability of male PD patients to cognitive and memory deficits; the increasing risk for higher-order deficits in female PD patients with age; and other features including the early/earliest onset that distinguishes episodic memory impairments from other at-risk cognitive operations in this disorder.