Domain-specific contributions of biological sex and sex hormones to what, where and when components of episodic-like memory in adult rats.

Episodic memory involves the integration and recall of discrete events that include information about what happened, where it happened and when it occurred. Episodic memory function is critical to daily life, and its dysfunction is both a first identifiable indicator and an enduring core feature of cognitive decline in ageing and in neuropsychiatric disorders including Alzheimer's disease and schizophrenia. Available evidence from human studies suggests that biological sex and sex hormones modulate episodic memory function in health and disease. However, knowledge of how this occurs is constrained by the limited availability and underutilization of validated animal models in investigating hormone impacts on episodic-like memory function. Here, adult female, adult male and gonadally manipulated adult male rats were tested on the what-where-when episodic-like memory task to determine whether rats model human sex differences in episodic memory and how the hormonal milieu impacts episodic-like memory processes in this species. These studies revealed salient ways in which rats model human sex differences in episodic memory, including a male advantage in spatial episodic memory performance. They also identified domain-specific roles for oestrogens and androgens in modulating what, where and when discriminations in male rats that were unlike those engaged in corresponding novel object recognition and novel object location tasks. These studies thus identify rats and the what-where-when task as suitable for investigating the neuroendocrine bases of episodic-like memory, and provide new information about the unique contributions that sex and sex hormones make to this complex mnemonic process.

Engineered exosomes targeting MYC reverse the proneural-mesenchymal transition and extend survival of glioblastoma.

Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of multiple growth factor and interleukin signaling pathways, triggering a mesenchymal to proneural transition and shifting the cellular landscape of the tumor. These data confirm that Myc is an effective anti-glioma target and that iExo-Myc offers a feasible, readily translational strategy to inhibit challenging oncogene targets for the treatment of brain tumors.

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.

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.