The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors.

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to "open" the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system.

Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aß Metabolism.

Maternal overnutrition has been reported to affect brain plasticity of the offspring by altering gene expression, regulating both synaptic plasticity and adult neurogenesis. However, whether perinatal metabolic stress may influence the accumulation of misfolded proteins and the development of neurodegeneration remains to be clarified. We investigated the impact of maternal high fat diet (HFD) in an experimental model of Alzheimer's disease (AD). The 3xTg-AD mice born to overfed mothers showed an impairment of synaptic plasticity and cognitive deficits earlier than controls. Maternal HFD also altered the expression of genes regulating amyloid-ß-protein (Aß) metabolism (i.e., Bace1, Ern1, Ide and Nicastrin) and enhanced Aß deposition in the hippocampus. Finally, we found an epigenetic derangement and an aberrant recruitment of transcription factors NF-kB and STAT3 and chromatin remodeler HDAC2 on the regulatory sequences of the same genes. Collectively, our data indicate that early life metabolic stress worsens the AD phenotype via epigenetic alteration of genes regulating Aß synthesis and clearance.

High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms.

Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor's diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs.

Hippocampal Estrogen Signaling Mediates Sex Differences in Retroactive Interference.

Despite being a crucial physiological function of the brain, the mechanisms underlying forgetting are still poorly understood. Estrogens play a critical role in different brain functions, including memory. However, the effects of sex hormones on forgetting vulnerabilitymediated by retroactive interference (RI), a phenomenon in which newly acquired information interferes with the retrieval of already stored information, are still poorly understood. The aim of our study was to characterize the sex differences in interference-mediated forgetting and identify the underlying molecular mechanisms. We found that adult male C57bl/6 mice showed a higher susceptibility to RI-dependent memory loss than females. The preference index (PI) in the NOR paradigm was 52.7 ± 5.9% in males and 62.3 ± 13.0% in females. The resistance to RI in female mice was mediated by estrogen signaling involving estrogen receptor α activation in the dorsal hippocampus. Accordingly, following RI, females showed higher phosphorylation levels (+30%) of extracellular signal-regulated kinase1/2 (ERK1/2) in the hippocampus. Pharmacological inhibition of ERK1/2 made female mice prone to RI. The PI was 70.6 ± 11.0% in vehicle-injected mice and 47.4 ± 10.8% following PD98059 administration. Collectively, our data suggest that hippocampal estrogen α receptor-ERK1/2 signaling is critically involved in a pattern separation mechanism that inhibits object-related RI in female mice.

Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche.

Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non-communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on insulin receptor substrate-1 (IRS-1)/ Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS-1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high-fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.

Sexual and ejaculatory function after holmium laser enucleation of the prostate and bipolar transurethral enucleation of the prostate: a single-center experience.

Currently available surgical treatments for Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Obstruction (BPO) are associated with an increased risk of sexual dysfunction. The aim of our study is to compare sexual and ejaculatory function after Holmium Laser Enucleation of the Prostate (HoLEP) and Bipolar Transurethral Enucleation of the Prostate (B-TUEP). We performed a retrospective analysis of data prospectively collected from 62 (44.9%) and 76 (55.1%) patients who underwent HoLEP and B-TUEP, respectively. Erectile function and ejaculation characteristics were assessed with the International Index of Erectile Function-Erectile Function (IIEF-EF) domain and the Male Sexual Health Questionnaire-Ejaculatory function (MSHQ-EJ) questionnaires. Our study recorded no change in erectile function and no significant difference in rates of preserved antegrade ejaculation after both surgeries. One month after surgery, rates of physical pain/discomfort and perceived decreased physical pleasure during ejaculation were higher in HoLEP than B-TUEP patients (all p < 0.03). Moreover, HoLEP patients were more bothered by their ejaculatory difficulties than B-TUEP men (p = 0.03). At 3- and 12-months follow-up, all ejaculation-related differences disappeared. In conclusion, both procedures are valid alternatives for BPO treatment as they offer comparable urinary and sexual outcomes in the long term. However, in the first month after surgery, HoLEP patients present with more ejaculatory difficulties.

Ten-year experience with penile prosthetic surgery for the treatment of erectile dysfunction: outcomes of a tertiary referral center and predictors of early prosthetic infection.

We aimed to evaluate ten-year outcomes of penile prosthesis (PP) implantation for the treatment of erectile dysfunction and to assess predictors of early prosthetic infection (EPI). We identified 549 men who underwent 576 PP placements between 2008 and 2018. Univariate and multivariate analyses were used to identify potential predictors of EPI. An EPI predictive nomogram was developed. Thirty-five (6.1%) cases of EPI were recorded with an explant rate of 3.1%. In terms of satisfaction, 82.0% of the patients defined themselves as "satisfied," while partner's satisfaction was 88.3%. Diabetes (P = 0.012), longer operative time (P = 0.032), and reinterventions (P = 0.048) were associated with EPI risk, while postoperative ciprofloxacin was inversely associated with EPI (P = 0.014). Rifampin/gentamicin-coated 3-piece inflatable PP (r/g-c 3IPP) showed a higher EPI risk (P = 0.019). Multivariate analyses showed a two-fold higher risk of EPI in diabetic patients, redo surgeries, or when a r/g-c 3IPP was used (all P < 0.03). We showed that diabetes, longer operative time, and secondary surgeries were the risk factors for EPI. Postoperative ciprofloxacin was associated with a reduced risk of EPI, while r/g-c 3IPP had higher EPI rates without an increased risk of PP explant. After further validation, the proposed nomogram could be a useful tool for the preoperative counseling of PP implantation.

Development of a Novel Clinical and Radiologic Risk Score to Predict Septic Complications After Urinary Decompression in Patients with Obstructive Uropathy.

Background: Well-defined clinical predictors of sepsis after upper tract drainage for obstructive uropathy are lacking. The study aim is to develop a data-driven score to predict risk of sepsis after decompression of the upper urinary tract. Materials and Methods: Complete clinical and radiologic data from 271 patients entering the emergency department for obstructive uropathy and submitted to stent/nephrostomy tube decompression were evaluated. The Charlson Comorbidity Index (CCI) was used to score comorbidities. The definition of sepsis was an increase in ≥2 Sequential Organ Failure Assessment points (or a postoperative persistently elevated score +1 additional increase) and documented blood or urine cultures. Descriptive statistics and stepwise multivariable logistic regression modeling with receiver operating characteristic analysis were performed to obtain a composite risk score to predict the risk of sepsis after surgery. This study was approved by our local Ethics Commitee (Prot. 25508). Results: Fifty-five (20.3%) patients developed sepsis. At multivariable analysis, CCI ≥2 (odds ratio [OR] 3.10; 95% confidence interval [CI] 1.36-7.04), maximum body temperature ≥38°C (OR 4.35; 95% CI 1.89-9.44), grade III-IV hydronephrosis (OR 2.37; 95% CI 1.10-4.98), HU of the dilated collecting system ≥7.0 (OR 4.47; 95% CI 2.03-9.81), white blood cells ≥15 × 103/mmc (OR 2.77; 95% CI 1.24-6.19), and C-reactive protein ≥10 (OR 3.27; 95% CI 1.41-7.56) were independently associated with sepsis. The positive predictive value of a true sepsis increased incrementally as a function of number of positive variables, ranging from 1.6% to 100.0% among patients with 1 and 6 positive variables, respectively. Conclusion: Our risk score identifies accurately patients with an increased risk of sepsis after urinary decompression for obstructive uropathy, hence improving clinical management.

Spontaneous Upper Urinary Tract Rupture Caused by Ureteric Stones: Clinical Characteristics and Validation of a Radiological Classification System.

BACKGROUND: This study seeks to validate a radiological classification system of spontaneous upper urinary tract rupture (sUUTR) and to analyse its relationship with clinical, laboratory and radiological characteristics of sUUTR. METHODS: We analysed data from 66 patients with a computerised tomography (CT)-proven sUUTR treated with ureteral or nephrostomy catheter positioning. Comorbidities were scored with the Charlson Comorbidity Index (CCI). All CT scans were reviewed by two experienced radiologists and one urologist, who classified sUUTR in (a) local spread, (b) free fluid and (c) urinoma. Interobserver agreement for radiological score was evaluated with the Intraclass Correlation Coefficient (ICC) and Cohen's Kappa analyses. Descriptive statistics and logistic regression models verified the association between clinical variables and sUUTR severity. RESULTS: The interobserver agreement for sUUTR classification was high among radiologists and between the radiologists and the urologist (all Kappa > 0.7), with an overall high interrater reliability (ICC 0.82). Local spread, free fluid and urinoma were found in 24 (36.4%), 39 (59.1%) and 3 (4.5%) cases, respectively. Patients with free fluid/urinoma had higher rate of CCI ≥ 1 than those with local spread (40.5% vs. 16.7%, p = 0.04). Intraoperative absence of urine extravasation was more frequently found in patients with local spread than those with free fluid/urinoma (66.7% vs. 28.6%, p < 0.01). Multivariable logistic regression analysis revealed that local spread (OR 4.5, p < 0.01) was associated with absence of contrast medium extravasation during pyelography, after accounting for stone size, fever and CCI. CONCLUSIONS: The analysed sUUTR classification score had good inter/intra-reader reliability among radiologists and urologists. Absence of urine extravasation was five times more frequent in patients with local spread, making conservative treatment feasible in these cases.

Bipolar Transurethral Enucleation of the Prostate: Is it a size-independent endoscopic treatment option for symptomatic benign prostatic hyperplasia?

BACKGROUND: Bipolar Transurethral Enucleation of the Prostate (B-TUEP) is recommended as a first-choice treatment for benign prostatic obstruction in prostates >80 ml. Differently, B-TUEP is only considered as an alternative option after TURP for smaller prostates (30-80 ml). The aim of our study is to assess the relation between prostate size and surgical outcomes after B-TUEP. METHODS: We performed a retrospective analysis of data collected from 172 patients submitted to B-TUEP. Patients were segregated according to tertiles of prostate volume (PV) (≤60 ml, 61-110 ml, >110 ml). For each group we evaluated enucleation efficacy (enucleated weight/enucleation time), complication rates, urinary and sexual function parameters. Functional and sexual parameters were compared between groups at baseline, 1 and 3 months follow up. Descriptive statistics and linear and logistic regression models tested the association between PV and postoperative complications/outcomes. RESULTS: Operative time and weight of enucleated adenomas increased along with prostate volumes (all p≤0.01). Enucleation efficacy was higher in men with PV >110 ml compared to other groups (p≤0.001). Length of hospital stay, catheterization time and rates of postoperative complications, such as transfusion and clot evacuation rates and bladder neck/urethral strictures, were comparable between groups. Urinary symptoms improved at 1-and 3-months in each group as compared to baseline evaluation (all p<0.01) but they did not differ according to PV. In each group maximum urinary flow and post-void residual volume significantly improved at 3 months compared to baseline (all p≤0.01), without differences according to PV. Sexual symptoms were similar between groups at each follow up assessment. At multivariable linear and logistic regression analysis, prostate volume was not associated with postoperative functional outcomes and complications. Conversely, patient's comorbid status and antiplatelet/anticoagulation use were independently associated with postoperative complications. CONCLUSION: According to our findings, B-TUEP should be considered a "size independent procedure" as it can provide symptom relief in men with prostates of all sizes with the same efficacy and safety profile.

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer's Disease Signatures.

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer's disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

How the COVID-19 Wave Changed Emergency Urology: Results From an Academic Tertiary Referral Hospital in the Epicentre of the Italian Red Zone.

OBJECTIVE: To quantify and characterize the burden of urological patients admitted to emergency department (ED) in Lombardy during Italian COVID-19 outbreak, comparing it to a reference population from 2019. METHODS: We retrospectively analysed all consecutive admissions to ED from 1 January to 9 April in both 2019 and 2020. According to the ED discharge ICD-9-CM code, patients were grouped in urological and respiratory patients. We evaluated the type of access (self-presented/ambulance), discharge priority code, ED discharge (hospitalization, home), need for urological consultation or urgent surgery. RESULTS: The number of urological diagnoses in ED was inversely associated to COVID-19 diagnoses (95% confidence interval -0.41/-0.19; Beta = -0.8; P < .0001). The average access per day was significantly lower after 10 March 2020 (1.5 ± 1.1 vs 6.5 ± 2.6; P < .0001), compared to reference period. From 11 March 2020, the inappropriate admissions to ED were reduced (10/45 vs 96/195; P = .001). Consequently, the patients admitted were generally more demanding, requiring a higher rate of urgent surgeries (4/45 vs 4/195; P = .02). This reflected in an increase of the hospitalization rate from 12.7% to 17.8% (Beta = 0.88; P < .0001) during 2020. CONCLUSION: Urological admissions to ED during lockdown differed from the same period of 2019 both qualitatively and quantitatively. The spectrum of patients seems to be relatively more critical, often requiring an urgent management. These patients may represent a challenge due to the difficult circumstances caused by the pandemic.

Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling.

Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity-related genes and the activation of cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)-derived exosomes (exo-NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo-NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD-related memory impairment and provide evidence of the potential therapeutic effect of exo-NSC against metabolic disease-related cognitive decline.

Hounsfield unit attenuation value can differentiate pyonephrosis from hydronephrosis and predict septic complications in patients with obstructive uropathy.

We aimed to assess the role of computerized tomography attenuation values (Hounsfield unit-HU) for differentiating pyonephrosis from hydronephrosis and for predicting postoperative infectious complications in patients with obstructive uropathy. We analysed data from 122 patients who underwent nephrostomy tube or ureteral catheter placement for obstructive uropathy. A radiologist drew the region of interest for quantitative measurement of the HU values in the hydronephrotic region of the affected kidney. Descriptive statistics and logistic regression models tested the predictive value of HU determination in differentiating pyonephrosis from hydronephrosis and in predicting postoperative sepsis. A HU cut-off value of 6.3 could diagnose the presence of pyonephrosis with 71.6% sensitivity and 71.5% specificity (AUC 0.76; 95%CI: 0.66-0.85). At multivariable logistic regression analysis HU ≥ 6.3 (p ≤ 0.001) was independently associated with pyonephrosis. Patients who developed sepsis had higher HU values (p ≤ 0.001) than those without sepsis. A HU cut-off value of 7.3 could diagnose the presence of sepsis with 76.5% sensitivity and 74.3% specificity (AUC 0.79; 95%CI: 0.71-0.90). At multivariable logistic regression analysis, HU ≥ 7.3 (p ≤ 0.001) was independently associated with sepsis, after accounting for clinical and laboratory parameters. Measuring HU values of the fluid of the dilated collecting system may be useful to differentiate pyonephrosis from hydronephrosis and to predict septic complications in patients with obstructive uropathy.

Glucose Overload Inhibits Glutamatergic Synaptic Transmission: A Novel Role for CREB-Mediated Regulation of Synaptotagmins 2 and 4.

Glucose metabolism derangement is critically involved in the age-related memory loss but the underlying molecular mechanisms are still poorly understood. In a mouse model of type 1 diabetes we found memory impairment associated with inhibition of the transcription factor CREB and alteration of pre- and post-synaptic protein expression in the hippocampus. Accordingly, glucose excess negatively affected activity-dependent CREB phosphorylation and CREB-mediated mRNA expression of synaptic proteins in hippocampal primary neurons. Specifically, glucose excess inhibited the activity-dependent recruitment of CREB on the regulatory sequences of synaptotagmin (SYT) 2 and 4 promoters and the expression of SYT4 protein. As a result, high glucose affected both the frequency of miniature excitatory postsynaptic currents and NMDA receptor-mediated currents in autaptic hippocampal neuronal cultures. Collectively, our findings highlight novel mechanisms underlying hyperglycaemia-related memory loss, including CREB-dependent downregulation of synaptotagmin expression.

Endoscopic repair of a vesicouterine fistula with the injection of microfragmented autologous adipose tissue (Lipogems®).

Vesicouterine fistula (VUF) is a rare extra-anatomical communication developing between the uterus or cervix and the urinary bladder, most commonly after an iatrogenic injury during a cesarean section. Patients with VUF may have various clinical presentations, ranging from Youssef's syndrome (vaginal urine leakage, amenorrhea, and menouria) to urinary tract infection and infertility. Quality of life for patients having this pathology is strongly affected owing to the psychological burden. Treatment is surgery based because low success rates have been reported for conservative or minimally invasive approaches. Herein, we present a case of a 35-year-old woman successfully treated by a minimally invasive endoscopic repair procedure with the injection of microfragmented autologous adipose tissue (Lipogems®).

Brain insulin resistance impairs hippocampal plasticity.

Nutrient-related signals have been demonstrated to influence brain development and cognitive functions. In particular, insulin signaling has been shown to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Alteration of brain insulin signaling interferes with the maintenance of neural stem cell niche and neuronal activity in the hippocampus. Brain insulin resistance is also emerging as key factor causing the cognitive impairment observed in metabolic and neurodegenerative diseases. Here, we review the molecular mechanisms involved in the insulin modulation of both adult neurogenesis and synaptic activity in the hippocampus. We also summarize the effects of altered insulin sensitivity on hippocampal plasticity. Finally, we reassume the experimental and epidemiological evidence highlighting the critical role of brain insulin resistance at the crossroad between type 2 diabetes and Alzheimer's disease.

Life-threatening Double-J stent migration with helicoidal appearance: Length matters.

BACKGROUND: The Double-J stent is one of the most commonly used devices in urologic practice. Due to its widespread use, numerous common complications have been reported, such as irritative symptoms, infection, and encrustation. More rare complications have also been described, such as up or downward migration and displacement outside the urinary tract. We present a rare case of downward migration of a Double-J stent in a 21-year-old Caucasian female. CASE PRESENTATION: A 21-year-old female with a solitary kidney presented to the emergency department with acute renal failure, left flank pain, and fever. She had undergone left Double-J stenting 1 week earlier in her homeland for left renal colic and anuria. A kidney-ureter-bladder X-ray revealed a 10-mm lumbar ureteral stone and the proximal coil of the Double-J stent making multiple loops along the ureter, resulting in a helical appearance. She underwent surgery to remove the previous stent and to place a new one. She was discharged 2 days later and her renal function had returned to normal values at her 1-week follow-up. CONCLUSIONS: Double-J Stent placement is a common procedure in the management of urinary tract diseases but is not devoid of life-threatening complications. Regular follow-up of stents and on-time evaluation of clinical complaints are mandatory for an aggressive treatment of complications.

Enhancing Plasticity Mechanisms in the Mouse Motor Cortex by Anodal Transcranial Direct-Current Stimulation: The Contribution of Nitric Oxide Signaling.

Consistent body of evidence shows that transcranial direct-current stimulation (tDCS) over the primary motor cortex (M1) facilitates motor learning and promotes recovery after stroke. However, the knowledge of molecular mechanisms behind tDCS effects needs to be deepened for a more rational use of this technique in clinical settings. Here we characterized the effects of anodal tDCS of M1, focusing on its impact on glutamatergic synaptic transmission and plasticity. Mice subjected to tDCS displayed increased long-term potentiation (LTP) and enhanced basal synaptic transmission at layer II/III horizontal connections. They performed better than sham-stimulated mice in the single-pellet reaching task and exhibited increased forelimb strength. Dendritic spine density of layer II/III pyramidal neurons was also increased by tDCS. At molecular level, tDCS enhanced: 1) BDNF expression, 2) phosphorylation of CREB, CaMKII, and GluA1, and 3) S-nitrosylation of GluA1 and HDAC2. Blockade of nitric oxide synthesis by L-NAME prevented the tDCS-induced enhancement of GluA1 phosphorylation at Ser831 and BDNF levels, as well as of miniature excitatory postsynaptic current (mEPSC) frequency, LTP and reaching performance. Collectively, these findings demonstrate that anodal tDCS engages plasticity mechanisms in the M1 and highlight a role for nitric oxide (NO) as a novel mediator of tDCS effects.

Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms.

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.