Hepatic soluble epoxide hydrolase activity regulates cerebral Aß metabolism and the pathogenesis of Alzheimer's disease in mice.

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-ß (Aß) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aß metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aß is essential for preventing Aß deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.

A thalamic-primary auditory cortex circuit mediates resilience to stress.

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity.

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex-entorhinal cortex-hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

[Inpatient Care Expenditure of Terminally Ill Patients in the Geriatric Ward of Peking Union Medical College Hospital].

Objective To describe the inpatient care expenditure of the terminally ill patients in the geriatric ward of Peking Union Medical College Hospital and facilitate future research on the economic outcomes of hospice and palliative care.Methods The histories of patients admitted to the Department of Geriatrics of Peking Union Medical College Hospital during 2018 were reviewed by trained doctors.According to the diagnosis and overall health state,terminally ill patients were selected and enrolled in the study.Demographics,health and disease information,prescriptions,and expenditure details were retrieved from the HIS system.Results In 2018,35 patients were terminally ill and eligible for hospice care,including 20 males and 15 females,with the average age of(78±8)years(59-91 years),the average age-adjusted Charlson Comorbidity Index of 10±3,and the median Barthel index of 40(10,70).These patients had malignant tumor(23 cases),heart failure(4 cases),end-stage renal disease(1 case),end-stage liver disease(2 cases),dementia(4 cases)and other severe diseases(3 cases).The patients received standard care within the scope of internal medicine and geriatrics.Finally,8 patients died during hospitalization,and 27 were discharged alive.The 35 patients had the median length of stay of 15(12,23)days,the median inpatient expenditure of CNY 21 500(13 800,37 600),and the median daily expenditure of CNY 1425(970,2503).The percentage of expenditure was(28.5±12.3)% for medication,(33.2±18.0)% for tests and examinations,and 11.5%(6.4%,15.8%)for accommodation and medical services.The medications for symptom control costed CNY(77±58)per day on average,accounting for(5.2±3.5)% of the total expenditure.Conclusions The inpatient expenditure for terminally ill patients in the tertiary grade A hospital was higher than that reported in community hospitals providing hospice care.In terms of expenditure constitution,the money spent on medications and tests/examinations were similar,and the percentage of expenditure on medications for symptom control was low.There is a need for further research on the economic impact of hospice and palliative care among terminally ill patients in China.