Developing Topics.

Background: Aging and the decline in sex steroid hormone (e.g., estrogen) are associated with a potential loss of its neuroprotective effects on the female brain.

The impact of sex on memory during aging and Alzheimer's disease progression: Epigenetic mechanisms.

Alzheimer's disease (AD) is a leading cause of dementia, disability, and death in the elderly. While the etiology of AD is unknown, there are several established risk factors for the disease including, aging, female sex, and genetics. However, specific genetic mutations only account for a small percentage (1-5%) of AD cases and the much more common sporadic form of the disease has no causative genetic basis, although certain risk factor genes have been identified.

Parabrachial nucleus Vglut2 expressing neurons projection to the extended amygdala involved in the regulation of wakefulness during sevoflurane anesthesia in mice.

Aims: The parabrachial nucleus (PBN) promotes wakefulness states under general anesthesia. Recent studies have shown that glutamatergic neurons within the PBN play a crucial role in facilitating emergence from anesthesia. Our previous study indicates that vesicular glutamate transporter 2 (vglut2) expression neurons of the PBN extend into the extended amygdala (EA).

Class 1 histone deacetylases differentially modulate memory and synaptic genes in a spatial and temporal manner in aged and APP/PS1 mice.

Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, using 3-, 12- and 18- month-old APP/PS1 mice and age matched WT littermates, we conducted a series of memory tests, measured synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters in the hippocampus and prefrontal cortex (PFC). Our results showed impaired recognition and long-term spatial memory in 18-month-old WT mice and impaired recognition, short-term working, and long-term spatial reference memory in 12-and 18- month-old APP/PS1 mice.

Unique transcriptional signatures correlate with behavioral and psychological symptom domains in Alzheimer's disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues.

Distinguishing features of depression in dementia from primary psychiatric disease.

Depression is a common and devastating neuropsychiatric symptom in the elderly and in patients with dementia. In particular, nearly 80% of patients with Alzheimer's Disease dementia experience depression during disease development and progression. However, it is unknown whether the depression in patients with dementia shares the same molecular mechanisms as depression presenting as primary psychiatric disease or occurs and persists through alternative mechanisms.

Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice.

Rationale: Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear.

Objective: In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice.

Histone deacetylase 1 regulates haloperidol-induced motor side effects in aged mice.

Background: Antipsychotic drugs prescribed to elderly patients with neuropsychiatric disorders often experience severe extrapyramidal side effects. Previous studies from our group suggest that changes in histone modifications during aging increase the risk for antipsychotic drug side effects, because co-administration of antipsychotics with class 1 histone deacetylase (HDAC) inhibitors could mitigate the severity of motor side effects in aged mice. However, which HDAC subtype contributes to the age-related sensitivity to antipsychotic drug side effects is unknown.

Unique Transcriptional Signatures Correlate with Behavioral and Psychological Symptom Domains in Alzheimer's Disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our sample: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissue.

Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimer's disease.

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice.

Sex-dependent sensitivity to positive allosteric modulation of GABA action in an APP knock-in mouse model of Alzheimer's disease: Potential epigenetic regulation.

Conflicting evidence suggest that perturbations of GABAergic neurotransmission play crucial roles in disrupting cortical neuronal network oscillations, memory, and cognitive deficits in Alzheimer's disease (AD). However, the role and impact of sex differences on GABAergic transmission in AD are not well understood. Using an APP knock-in mouse model of AD, APP mice, we studied the effects of acute diazepam administration on memory and anxiety-like behavior to unveil sex-dependent dysregulation of GABAergic neurotransmission.

Population-attributable fractions of risk factors for all-cause dementia in China rural and urban areas: a cross-sectional study.

Background: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce.

Methods: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis.

Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice.

Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown.

DNA Barcoding Mushroom Spawn Using EF-1α Barcodes: A Case Study in Oyster Mushrooms ().

Oyster mushrooms (genus ) are widespread and comprise the most commonly cultivated edible mushrooms in the world. Species identification of oyster mushroom spawn based on cultural, morphological, and cultivated characteristics is time consuming and can be extraordinarily difficult, which has impeded mushroom breeding and caused economic loss for mushroom growers. To explore a precise and concise approach for species identification, the nuclear ribosomal internal transcribed spacer (ITS), 28S rDNA, and the widely used protein-coding marker translation elongation factor 1α (EF-1α) gene were evaluated as candidate DNA barcode markers to investigate their feasibility in identifying 13 oyster mushroom species.

An autophagy-related protein Becn2 regulates cocaine reward behaviors in the dopaminergic system.

Drug abuse is a foremost public health problem. Cocaine is a widely abused drug worldwide that produces various reward-related behaviors. The mechanisms that underlie cocaine-induced disorders are unresolved, and effective treatments are lacking.

Comparison of memory, affective behavior, and neuropathology in APP knock-in mice to 5xFAD and APP/PS1 mice.

Transgenic mouse models of Aβ amyloidosis generated by knock-in of a humanized Aβ sequence can offer some advantages over the transgenic models that overexpress amyloid precursor protein (APP). However, systematic comparison of memory, behavioral, and neuropathological phenotypes between these models has not been well documented. In this study, we compared memory and affective behavior in APP mice, an APP knock-in model, to two widely used mouse models of Alzheimer's disease, 5xFAD and APP/PS1 mice, at 10 months of age.

Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice.

Background: The role of microglia in Alzheimer's disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging.

Brain Aromatase and the Regulation of Sexual Activity in Male Mice.

The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice. Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear.

Sex differences in CRF1, CRF, and CRFBP expression in C57BL/6J mouse brain across the lifespan and in response to acute stress.

Signaling pathways mediated by corticotropin-releasing factor and its receptor 1 (CRF1) play a central role in stress responses. Dysfunction of the CRF system has been associated with neuropsychiatric disorders. However, dynamic changes in the CRF system during brain development and aging are not well investigated.

Sex differences in hypothalamic-pituitary-adrenal axis regulation after chronic unpredictable stress.

Introduction: Exposure to stress, mediated through the hypothalamic-pituitary-adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex-specific factors that confer resilience or vulnerability to stress and stress-associated psychiatric disorders remain largely unknown. The evident sex differences in stress-related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation.

Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.

Approximately two-thirds of those suffering with Alzheimer's disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models.

Protein-protein interactions underlying the behavioral and psychological symptoms of dementia (BPSD) and Alzheimer's disease.

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known.

The link between chronic pain and Alzheimer's disease.

Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer's disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies.