Biological Sex and Sex Hormone Impacts on Deficits in Episodic-Like Memory in a Rat Model of Early, Pre-motor Stages of Parkinson's Disease

Abstract

Episodic memory deficits are among the earliest appearing and most commonly occurring examples of cognitive impairment in Parkinson's disease (PD). These enduring features can also predict a clinical course of rapid motor decline, significant cognitive deterioration, and the development of PD-related dementia. The lack of effective means to treat these deficits underscores the need to better understand their neurobiological bases. The prominent sex differences that characterize episodic memory in health, aging and in schizophrenia and Alzheimer's disease suggest that neuroendocrine factors may also influence episodic memory dysfunction in PD. However, while sex differences have been well-documented for many facets of PD, sex differences in, and sex hormone influences on associated episodic memory impairments have been less extensively studied and have never been examined in preclinical PD models. Accordingly, we paired bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesions with behavioral testing using the What-Where-When Episodic-Like Memory (ELM) Task in adult rats to first determine whether episodic-like memory is impaired in this model. We further compared outcomes in gonadally intact female and male subjects, and in male rats that had undergone gonadectomy-with and without hormone replacement, to determine whether biological sex and/or sex hormones influenced the expression of dopamine lesioned-induced memory deficits. These studies showed that 6-OHDA lesions profoundly impaired recall for all memory domains in male and female rats. They also showed that in males, circulating gonadal hormones powerfully modulated the negative impacts of 6-OHDA lesions on What, Where, and When discriminations in domain-specific ways. Specifically, the absence of androgens was shown to fully attenuate 6-OHDA lesion-induced deficits in ELM for "Where" and to partially protect against lesion-induced deficits in ELM for "What." In sum, these findings show that 6-OHDA lesions in rats recapitulate the vulnerability of episodic memory seen in early PD. Together with similar evidence recently obtained for spatial working memory, the present findings also showed that diminished androgen levels provide powerful, highly selective protections against the harmful effects that 6-OHDA lesions have on memory functions in male rats.

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

“…This provisionally identifies the perirhinal cortex as a/the critical substrate in conferring male vulnerability and female sparing of NOP performance in preclinical rodent models of PD models. This idea gains further traction from findings from this lab showing that 6-OHDA lesions sex-specifically impair performance in the OiP task (present study) but impair performance on the WWWhen ELM task equally in males and females [57]. While both tasks engage hippocampal and medial prefrontal circuits, only the OiP task is additionally linked to perirhinal cortex [99,113].…”

“…WWWhen behaviors-which are estrogen sensitive behaviors for which active hormone can be fully accounted for by testosterone metabolism [57]. This suggests that the benefits of estrogen replacement in malesat least in this 6-OHDA lesion PD model, may be limited to those aspects of cognition or memory that are sensitive to exogenous more so or rather than endogenous estrogen stimulation.…”

“…Barnes maze [56] and WWWhen ELM [57] tasks. Both studies showed that 6-OHDA lesions impaired performance in males and in females and that in males, androgen-sensitive behaviors were selectively spared from lesion-induced deficits in subjects where circulating androgen levels were decreased [56,57].…”

“…Cryoprotected brains were rapidly frozen in powdered dry ice and were serially sectioned (40 μm) on a freezing microtome. Immunohistochemistry for the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) was performed on a 1 in 6 series of sections from sham- or 6-OHDA-lesioned animal as previously described[57] using an anti-TH mouse monoclonal antibody (LNC1 clone, EMD Millipore, Burlingame, MA, USA). Briefly, sections were rinsed in 0.1M PB, treated with 1% H 2 O 2 in 0.1M PB, and incubated in heated sodium citrate buffer, pH 8.5 prior to a blocking step in tris-buffered saline (TBS), pH 7.4 containing 10% normal swine serum (NSS).…”

“…In addition, studies in female rats in which 6-hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine lesions were combined with ovariectomy found that dietary exposures to estrogen agonists or phytoestrogens (genistein, soy) improved spatial cognition in Morris water maze tasks [54,55]. Previous studies in this laboratory have also assessed executive and episodic memory functions using Barnes maze testing [56] and the What Where When episodic-like memory (WWWhen ELM) task, respectively, in male rats where neostriatal 6-OHDA lesions were combined with gonadectomy (GDX) or with GDX paired with hormone replacement [57]. For both tasks, 6-OHDA-induced deficits in behaviors previously identified as androgen-sensitive were spared in lesioned rats where androgen levels were diminished.…”