Tuning brain networks: The emerging role of transcranial direct current stimulation on structural plasticity

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique (NIBS) that has been proven to promote beneficial effects in a range of neurological and psychiatric disorders. Unfortunately, although has been widely investigated, the mechanism comprehension around tDCS effects presents still some gaps. Therefore, scientists are still trying to uncover the cellular and molecular mechanisms behind its positive effects to permit a more suitable application. Experimental models have provided converging evidence that tDCS elicits improvements in learning and memory by modulating both excitability and synaptic plasticity in neurons. Recently, among tDCS neurobiological effects, neural synchronization and dendritic structural changes have been reported in physiological and pathological conditions, suggesting possible effects at the neuronal circuit level. In this review, we bring in to focus the emerging effects of tDCS on the structural plasticity changes and neuronal rewiring, with the intent to match these two aspects with the underpinning molecular mechanisms identified so far, providing a new perspective to work on to unveil novel tDCS therapeutic use to treat brain dysfunctions

Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic Decompensation—Comparing Biological Models and Gaining New Insights into Molecular and Cellular Mechanisms

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets

Brain complexity in stroke recovery after bihemispheric transcranial direct current stimulation in mice

Stroke is one of the leading causes of disability worldwide. There are many different rehabilitation approaches aimed at improving clinical outcomes for stroke survivors. One of the latest therapeutic techniques is the non-invasive brain stimulation. Among non-invasive brain stimulation, transcranial direct current stimulation has shown promising results in enhancing motor and cognitive recovery both in animal models of stroke and stroke survivors. In this framework, one of the most innovative methods is the bihemispheric transcranial direct current stimulation that simultaneously increases excitability in one hemisphere and decreases excitability in the contralateral one. As bihemispheric transcranial direct current stimulation can create a more balanced modulation of brain activity, this approach may be particularly useful in counteracting imbalanced brain activity, such as in stroke. Given these premises, the aim of the current study has been to explore the recovery after stroke in mice that underwent a bihemispheric transcranial direct current stimulation treatment, by recording their electric brain activity with local field potential and by measuring behavioural outcomes of Grip Strength test. An innovative parameter that explores the complexity of signals, namely the Entropy, recently adopted to describe brain activity in physiopathological states, was evaluated to analyse local field potential data. Results showed that stroke mice had higher values of Entropy compared to healthy mice, indicating an increase in brain complexity and signal disorder due to the stroke. Additionally, the bihemispheric transcranial direct current stimulation reduced Entropy in both healthy and stroke mice compared to sham stimulated mice, with a greater effect in stroke mice. Moreover, correlation analysis showed a negative correlation between Entropy and Grip Strength values, indicating that higher Entropy values resulted in lower Grip Strength engagement. Concluding, the current evidence suggests that the Entropy index of brain complexity characterizes stroke pathology and recovery. Together with this, bihemispheric transcranial direct current stimulation can modulate brain rhythms in animal models of stroke, providing potentially new avenues for rehabilitation in humans.Miraglia et al. demonstrated-in a stroke mouse model-that brain activity changes, measured by Entropy index, correlate with stroke. They also demonstrated that transcranial direct current stimulation ameliorates post-stroke deficits and Entropy correlates with functional recovery. The authors concluded that Entropy could characterize stroke pathology and predict stroke outcomes.Graphical Abstrac

Sildenafil normalizes MALAT1 level in diabetic cardiomyopathy

Introduction A large body of evidence recently highlighted the involvement of long non-coding RNAs (lncRNAs) in cardiovascular disease [1] and some dysregulated lncRNAs have been associated with diabetic cardiomyopathy [2\u20135]. Among them, a higher expression of the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been observed in diabetic cardiomyopathy [6, 7]. However, a clear understanding of the molecular mechanisms leading to pathological regulation of lncRNAs in diabetic cardiomyopathy is still missing. Our prior work by Barbati et al. [8], established that, in the presence of high glucose, nitric oxide (NO) signaling derangement might alter the epigenetic landscape of cardiac cells, both in vitro and in vivo, via transcription factor CREM activation. Aim The present study is aimed at investigating the role of high glucose (HG) and NO pathway in the regulation of MALAT1 in the heart of mice after 6 months of prolonged hyperglycemia and in two cellular models of cardiomyocytes exposed to HG

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 NSPC

Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression

The effects of transcranial direct current stimulation (tDCS) on brain functions and the underlying molecular mechanisms are yet largely unknown. Here we report that mice subjected to 20-min anodal tDCS exhibited one-week lasting increases in hippocampal LTP, learning and memory. These effects were associated with enhanced: i) acetylation of brain-derived neurotrophic factor (Bdnf) promoter I; ii) expression of Bdnf exons I and IX; iii) Bdnf protein levels. The hippocampi of stimulated mice also exhibited enhanced CREB phosphorylation, pCREB binding to Bdnf promoter I and recruitment of CBP on the same regulatory sequence. Inhibition of acetylation and blockade of TrkB receptors hindered tDCS effects at molecular, electrophysiological and behavioral levels. Collectively, our findings suggest that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene, and support the therapeutic potential of tDCS for brain diseases associated with impaired neuroplasticity

Transcranial Direct Current Stimulation Enhances Neuroplasticity and Accelerates Motor Recovery in a Stroke Mouse Model

BACKGROUND: More effective strategies are needed to promote poststroke functional recovery. Here, we evaluated the impact of bihemispheric transcranial direct current stimulation (tDCS) on forelimb motor function recovery and the underlying mechanisms in mice subjected to focal ischemia of the motor cortex. METHODS: Photothrombotic stroke was induced in the forelimb brain motor area, and tDCS was applied once per day for 3 consecutive days, starting 72 hours after stroke. Grid-walking, single pellet reaching, and grip strength tests were conducted to assess motor function. Local field potentials were recorded to evaluate brain connectivity. Western immunoblotting, ELISA, quantitative real-time polymerase chain reaction, and Golgi-Cox staining were used to uncover tDCS-mediated stroke recovery mechanisms. RESULTS: Among our results, tDCS increased the rate of motor recovery, anticipating it at the early subacute stage. In this window, tDCS enhanced BDNF (brain-derived neurotrophic factor) expression and dendritic spine density in the peri-infarct motor cortex, along with increasing functional connectivity between motor and somatosensory cortices. Treatment with the BDNF TrkB (tropomyosin-related tyrosine kinase B) receptor inhibitor, ANA-12, prevented tDCS effects on motor recovery and connectivity as well as the increase of spine density, pERK (phosphorylated extracellular signal-regulated kinase), pCaMKII (phosphorylated calcium/calmodulindependent protein kinase II), pMEF (phosphorylated myocyte-enhancer factor), and PSD (postsynaptic density)-95. The tDCSpromoted rescue was paralleled by enhanced plasma BDNF level, suggesting its potential role as circulating prognostic biomarker. CONCLUSIONS: The rate of motor recovery is accelerated by tDCS applied in the subacute phase of stroke. Anticipation of motor recovery via vicariate pathways or neural reserve recruitment would potentially enhance the efficacy of standard treatments, such as physical therapy, which is often delayed to a later stage when plastic responses are progressively lower

Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction

A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability

Summary: Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis. : Using a combination of in vitro and in vivo studies, Fusco et al. find that excess glucose impairs the self-renewal capacity of neural stem cells through a molecular circuit that involves the transcription factor CREB and Sirtuin 1. The authors suggest that this circuitry may link nutrient excess with neurodegeneration and brain aging. Keywords: neural stem cells, adult neurogenesis, CREB, Sirt-1, nutrients, metabolism, diabete