Inferring connection proximity in networks of electrically coupled cells by subthreshold frequency response analysis

Electrical synapses continuously transfer signals bi-directionally from one cell to another, directly or indirectly via intermediate cells. Electrical synapses are common in many brain structures such as the inferior olive, the subcoeruleus nucleus and the neocortex, between neurons and between glial cells. In the cortex, interneurons have been shown to be electrically coupled and proposed to participate in large, continuous cortical syncytia, as opposed to smaller spatial domains of electrically coupled cells. However, to explore the significance of these findings it is imperative to map the electrical synaptic microcircuits, in analogy with in vitro studies on monosynaptic and disynaptic chemical coupling. Since "walking” from cell to cell over large distances with a glass pipette is challenging, microinjection of (fluorescent) dyes diffusing through gap-junctions remains so far the only method available to decipher such microcircuits even though technical limitations exist. Based on circuit theory, we derive analytical descriptions of the AC electrical coupling in networks of isopotential cells. We then suggest an operative electrophysiological protocol to distinguish between direct electrical connections and connections involving one or more intermediate cells. This method allows inferring the number of intermediate cells, generalizing the conventional coupling coefficient, which provides limited information. We validate our method through computer simulations, theoretical and numerical methods and electrophysiological paired recording

Antagonistic negative and positive neurons of the basolateral amygdala

The basolateral amygdala (BLA) is a site of convergence of negative and positive stimuli and is critical for emotional behaviors and associations. However, the neural substrate for negative and positive behaviors and relationship between negative and positive representations in the basolateral amygdala are unknown. Here we identify two genetically distinct, spatially segregated populations of excitatory neurons in the mouse BLA that participate in valence-specific behaviors and are connected through mutual inhibition. These results identify a genetically defined neural circuit for the antagonistic control of emotional behaviors and memories.National Institutes of Health (U.S.) (Grant T32GM007287

Engram cells retain memory under retrograde amnesia

Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor–induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell–specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.RIKEN Brain Science InstituteHoward Hughes Medical InstituteJPB Foundatio

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.RIKEN Brain Science InstituteHoward Hughes Medical InstituteJPB Foundatio

Endovascular management of giant visceral artery aneurysms

Endovascular management of small visceral artery aneurysms is an established treatment with satisfactory outcomes. However, when size exceeds 5 cm visceral aneurysms are considered as “giant” (giant visceral artery aneurysms or GVAAs) and management is significantly more complex. Between August 2007 and June 2019 eleven cases of GVAAs that were endovascularly treated were retrospectively reviewed and included in this single center study. Mean size was 80 mm (± 26.3 mm) x 46 mm (+ -11.8 mm). Nine of the lesions were true aneurysms, and two were pseudoaneurysms. In 8 patients, the lesion was causing compression symptoms in the surrounding organs, one patient developed a contained rupture while 2 patients were completely asymptomatic. However, all patients were hemodynamically stable at the time of treatment. Technical success was defined as immediate complete exclusion of the aneurysmal sac, and clinical success as complete relief from clinical symptoms. Follow-up was performed with CT angiography, ultrasound and clinical examination. Mean follow-up was 45 months (range 6–84). Technical and clinical success were both 91%. Complications were one lack of control of contained rupture that was subsequently operated, one case of self-limiting non-target spleen embolization and one case of splenic abscess. Three patients died, one due to the contained rupture 15 days after procedure, the other two for other causes and occurred during the long-term follow-up. This series suggests that endovascular treatment of giant visceral artery aneurysms and pseudoaneuryms is a valid minimally invasive solution with very satisfactory immediate and long-term outcomes unless the aneurysm is already ruptured. A variety of endovascular tools may be required for successful treatment

Mid-term safety and effectiveness of macular peeling one month after intravitreal dexamethasone implant for tractional diabetic macular edema

Macular peeling combined or followed by intravitreal dexamethasone implant (DEX-i) was recommended as an efficacy approach for tractional diabetic macular edema (tDME). Knowing the synergistic effect of cataract surgery and DEX-i one month earlier in eyes with DME, we compared Epiretinal Membrane/Inner Limiting Membrane (ERM/ILM) peeling preceded by DEX-i one month before versus ERM/ILM peeling alone for the treatment of tDME. A retrospective study on patients affected by tDME who underwent ERM/ILM peeling one month after DEX-i (n = 11; Group A) or ERM/ILM peeling alone (n = 10; Group B) was performed. Longitudinal comparison of best-correct visual acuity (BCVA), central retinal thickness (CRT), and intraocular pressure (IOP) between the time of surgery (T0) and each time point (months 1,3,5,6) within and among the groups were assessed. To evaluate the repeated measurements of BCVA, CRT, and IOP, a linear mixed-effects model was used. In Group A, DEX-i significantly improved mean BCVA and CRT (P < 0.001) just after 1 month (T0). After ERM/ILM peeling, mean BCVA and CRT significantly improved from month 1 in Group A and month 3 in Group B. Mixed model revealed a significant difference in BCVA (P ≤ 0.0001) and CRT (P ≤ 0.02) at different time-points among the groups with better results in Group A. Neither complications nor uncontrolled IOP increase was detected. ERM/ILM peeling confirmed its effectiveness in treating tDME. DEX-i performed one month before surgery seemed to be a safe approach and ensured a greater and faster recovery considering functional and tomographic parameters

Prevalence of Different Subtypes of Serrated Polyps and Risk of Synchronous Advanced Colorectal Neoplasia in Average-Risk Population Undergoing First-Time Colonoscopy

OBJECTIVES: A growing body of evidence indicates that patients with sessile serrated adenoma/polyp (SSA/P) and traditional serrated adenoma (TSA) are at risk for subsequent malignancy. Despite increasing knowledge on histological categorization of serrated polyps (SPs) data are lacking on the actual prevalence and the association of each SP subtype with advanced colorectal neoplasia. METHODS: We prospectively determined the prevalence of different SP subtypes and evaluate the association with synchronous advanced neoplasia in asymptomatic average-risk subjects undergoing first-time colonoscopy. All retrieved polyps were examined by two independent pathologists. Serrated lesions were classified into hyperplastic polyps (HP), SSA/P (without and with cytological dysplasia, SSA/P/DIS), and TSA, and were screened for BRAF and K-ras mutations. RESULTS: Among 258 polyps detected in 985 subjects, the proportion of SSA/P and TSA was 8.9% and 1.9% with an overall prevalence of 2.3% and 0.6%, respectively. SSA/Ps were small without significant difference in their location between proximal and distal colon; TSA were predominantly left-sided. BRAF mutation was common in SSA/Ps and K-ras mutation was present in all TSA. Independent predictors of advanced neoplasia were male sex (odds ratio (OR)=2.0, 95% confidence interval (CI) 1.0-4.0), increasing age (OR=4.5, 95% CI 1.5-13.4 for 50-69 years and OR=9.9, 95% CI 3.1-31.5 for >70 years), current smoking (OR=2.0, 95% CI 1.3-6.8), >3 tubular adenoma (OR=3.6, 95% CI 1.9-6.4), and SSA/P (OR=6.0, 95% CI 1.9-19.5). CONCLUSIONS: The substantial prevalence of BRAF-mutated SSA/P and the independent association with synchronous advanced colorectal neoplasia in asymptomatic average-risk subjects support the overall impact of the serrated pathway on colorectal cancer (CRC) risk in general population. The endoscopic characteristics of SSA/P emphasize the need of high-quality colonoscopy as a key factor for an effective CRC screening progra

Technical and Commercial Challenges of Proton-Exchange Membrane (PEM) Fuel Cells

This review critically evaluates the latest trends in fuel cell development for portable and stationary fuel cell applications and their integration into the automotive industry. Fast start-up, high efficiency, no toxic emissions into the atmosphere and good modularity are the key advantages of fuel cell applications. Despite the merits associated with fuel cells, the high cost of the technology remains a key factor impeding its widespread commercialization. Therefore, this review presents detailed information into the best operating conditions that yield maximum fuel cell performance. The paper recommends future research geared towards robust fuel cell geometry designs, as this determines the cell losses, and material characterization of the various cell components. When this is done properly, it will support a total reduction in the cost of the cell which in effect will reduce the total cost of the system. Despite the strides made by the fuel cell research community, there is a need for public sensitization as some people have reservations regarding the safety of the technology. This hurdle can be overcome if there is a well-documented risk assessment, which also needs to be considered in future research activities

Anti-vascular endothelial growth factor monotherapy or combined with verteporfin photodynamic therapy for retinal angiomatous proliferation: a systematic review with meta-analysis

: Purpose: To assess functional and anatomical outcomes of intravitreal anti-Vascular Endothelial Growth Factor (anti-VEGF) monotherapy versus combined with verteporfin Photodynamic Therapy (PDT) for Retinal Angiomatous Proliferation (RAP). Methods: Studies reporting outcomes of intravitreal anti-VEGF monotherapy and/or in combination with verteporfin PDT in RAP eyes with a follow-up ≥ 12 months were searched. The primary outcome was the mean change in best corrected visual acuity (BCVA) at 12 months. Mean change in central macular thickness (CMT) and mean number of injections were considered as secondary outcomes. The mean difference (MD) between pre- and post-treatment values was calculated along with 95% Confidence Interval (95% CI). Meta-regressions were performed to assess the influence of anti-VEGF number of injections on BCVA and CMT outcomes. Results: Thirty-four studies were included. A mean gain of 5.16 letters (95% CI = 3.30-7.01) and 10.38 letters (95% CI = 8.02-12.75) was shown in the anti-VEGF group and combined group, respectively (anti-VEGF group vs. combined group, p < 0.01). A mean CMT reduction of 132.45 µm (95% CI = from -154.99 to -109.90) and 213.93 µm (95% CI = from -280.04 to -147.83) was shown in the anti-VEGF group and combined group, respectively (anti-VEGF group vs. combined group, p < 0.02). A mean of 4.9 injections (95% CI = 4.2-5.6) and 2.8 injections (95% CI = 1.3-4.4) were administered over a 12-month period in the anti-VEGF group and combined group, respectively. Meta-regression analyses showed no influence of injection number on visual and CMT outcomes. High heterogeneity was found across studies for both functional and anatomical outcomes. Conclusion: A combined approach with anti-VEGF and PDT could provide better functional and anatomical outcomes in RAP eyes compared with anti-VEGF monotherapy

What is memory? The present state of the engram

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today