Indirect feedback inhibition from hilar mossy cells enhances the sparse activation of dentate granule cells and frequency-dependent pattern separation

The discrimination of similar episodes and places and their representation as distinct memories depend on a process called pattern separation that is performed by the circuitry of the hippocampal dentate gyrus (hDG). Excitatory hilar mossy cells (MCs) support pattern separation through their connections with different inhibitory interneuron (INT) populations that provide feedback inhibition to granule cells (GCs). In this study, we investigated how MCs and their synaptic connections with cholecystokinin-expressing interneurons (CCKIs) and parvalbumin-expressing interneurons (PVIs) influence the dynamics of hDG circuitry by using pharmacological agents to reduce neurotransmission from MCs or different INTs, genetically modified (GM) mice to selectively remove MCs from hDG circuitry and optogenetics to manipulate INT activity during GC whole cell/field recordings (age 8-10 weeks, n=5-18 animals/group). In addition, we used computational models to simulate hDG circuit dynamics. Our results showed that the net influence of MCs on GC activity is frequency-dependent and inhibitory, likely through the recruitment of INTs, since (i) GC responses to 20Hz and 50Hz stimulation of the medial perforant pathway (MPP) were less depressed in GM mice (that lacked MCs) compared with WT, but not at 5Hz; (ii) GC responses to 20Hz and 50Hz stimulations of the MPP were less depressed in the presence of GABAA receptor antagonist picrotoxin (PTX) in WT animals but not to 5Hz; (iii) GC responses to 20Hz and 50Hz stimulation of the MPP were less depressed, compared to controls, by pharmacologically reducing (40.9%±2.2%) MC-GC synaptic transmission with the type 1 cannabinoid receptor agonist WIN 55,212-2 (WIN). Secondly, our preliminary results confirmed that CCKIs and PVIs provide feedback inhibition of GCs at different stimulation frequencies: (i) GC responses to 10Hz and 20Hz stimulation of MPP were increased by blocking CCKI-GC synaptic transmission using the N-type voltage-gated calcium channel inhibitor ω-Conotoxin GVIA in WT hippocampal slices; (ii) GC responses to 5Hz and 10Hz stimulation of MPP were restored by activating ChR2-expressing PVIs in GM animals. Finally, our computational model showed that the removal of MCs from DG circuitry led to the disinhibition of GC activity through their indirect MC-basket cell-GC connections. Together, these findings suggest that the net inhibitory influence of MCs on GC activity is frequency-dependent due to the recruitment of CCKIs and PVIs at different stimulation frequencies

The causes and consequences of Alzheimer's disease: phenome-wide evidence from Mendelian randomization

Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease

Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM. Methods: PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m2, and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH2O with lung RM, or PEEP of 5 cmH2O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion: PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery. Trial registration: The trial was registered in clinicaltrials.gov (NCT02963025) on 15 November 2016