Mechanisms Of Neuronal Plasticity Research Articles

Advanced neuroimaging of the trigeminal nerve and the whole brain in trigeminal neuralgia: a systematic review.

For trigeminal neuralgia (TN), a major role of imaging is to identify the causes, but recent studies demonstrated structural and microstructural changes in the affected nerve. Moreover, an increasing number of studies have reported central nervous system involvement in TN. In this systematic review, recent quantitative magnetic resonance imaging (MRI) studies of the trigeminal nerve and the brain in patients with TN were compiled, organized, and discussed, particularly emphasizing the possible background mechanisms and the interpretation of the results. A systematic search of quantitative MRI studies of the trigeminal nerve and the brain in patients with TN was conducted using PubMed. We included the studies of the primary TN published during 2013 to 2023, conducted for the assessment of the structural and microstructural analysis of the trigeminal nerve, and the structural, diffusion, and functional MRI analysis of the brain. Quantitative MRI studies of the affected trigeminal nerves and the trigeminal pathway demonstrated structural/microstructural alterations and treatment-related changes, which differentiated responders from nonresponders. Quantitative analysis of the brain revealed changes in the brain areas associated with pain processing/modulation and emotional networks. Studies of the affected nerve demonstrated evidence of demyelination and axonal damage, compatible with pathological findings, and have shown its potential value as a tool to assess treatment outcomes. Quantitative MRI has also revealed the possibility of dynamic microstructural, structural, and functional neuronal plasticity of the brain. Further studies are needed to understand these complex mechanisms of neuronal plasticity and to achieve a consensus on the clinical use of quantitative MRI in TN.

Upper Limb Electromyographic Responses to Motor Imagery and Action Observation in Acquired Brain Injury.

Acquired Brain Injuries are one of the leading causes of mortality and disability worldwide. One of the most frequent sequelae is motor impairment of the upper limbs, which affects people's functionality and quality of life. Following the discovery of mirror neurons, new techniques were developed based on the mechanisms of neuronal plasticity, such as motor imagery (MI) and action observation (AO). We propose a protocol using electromyographic recordings of forearm muscles in people who have suffered a stroke during an MI task and an AO task. Three different experimental conditions will be studied during the electromyographic recordings: control recording, recording during MI, and recording during AO. Understanding the muscle activation in each technique will allow us to develop future protocols and intervention plans, improving the quality of care for people who have suffered a stroke.

Restoring of Interhemispheric Symmetry in Patients With Stroke Following Bilateral or Unilateral Robot-Assisted Upper-Limb Rehabilitation: A Pilot Randomized Controlled Trial.

Bilateral robotic rehabilitation has proven helpful in the recovery of upper limb motor function in patients with stroke, but its effects on the cortical reorganization mechanisms underlying recovery are still unclear. This pilot Randomized Controlled Trial (RCT) aimed to evaluate the effects on the interhemispheric balance of unilateral or bilateral robotic treatments in patients with subacute stroke, using Quantitative Electroencephalography (qEEG). 19 patients with ischemic stroke underwent a 30-session upper limb neurorehabilitation intervention using a bilateral upper limb exoskeleton. Each patient was randomly assigned to the bilateral (BG, n=10) or unilateral treatment group (UG, n=9). EEG evaluations were performed before (T0) and right after (T [Formula: see text] the first treatment session, after 30 treatment sessions (T1), and at 1-week follow-up (T2), in both eyes open and eyes closed conditions. From the acquired EEG data, the pairwise-derived Brain Symmetry Index (pdBSI) was computed. In addition, clinical evaluation was performed at T0 and T1 with validated clinical scales. After the treatment, a significant improvement in clinical and EEG evaluations was observed for both groups, but only the BG showed reduced pdBSI in delta and theta bands. In the cluster of sensorimotor channels, there was no significant difference between groups. The observed changes were not maintained at follow-up. No significant changes were observed in the pdBSI after a single rehabilitation session. Results suggest that balancing of interhemispheric symmetry comes along with a clinical improvement in the upper extremity and that the pdBSI can be used to investigate the mechanisms of neuronal plasticity involved in robotic rehabilitation after stroke.

Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.

Neuronal plasticity contributes to postictal death

Repeated generalized tonic-clonic seizures (GTCSs) are the most critical risk factor for sudden unexpected death in epilepsy (SUDEP). GTCSs can cause fatal apnea. We investigated neuronal plasticity mechanisms that precipitate postictal apnea and seizure-induced death. Repeated seizures worsened behavior, precipitated apnea, and enlarged active neuronal circuits, recruiting more neurons in such brainstem nuclei as periaqueductal gray (PAG) and dorsal raphe, indicative of brainstem plasticity. Seizure-activated neurons are more excitable and have enhanced AMPA-mediated excitatory transmission after a seizure. Global deletion of the GluA1 subunit of AMPA receptors abolishes postictal apnea and seizure-induced death. Treatment with a drug that blocks Ca2+-permeable AMPA receptors also renders mice apnea-free with five-fold better survival than untreated mice. Repeated seizures traffic the GluA1 subunit-containing AMPA receptors to synapses, and blocking this mechanism decreases the probability of postictal apnea and seizure-induced death.

Dendritogenic Potential of the Ethanol Extract from Lippia alba Leaves in Rat Cortical Neurons.

A reduced dendritic complexity, especially in regions such as the hippocampus and the prefrontal cortex, has been linked to the pathophysiology of some neuropsychiatric disorders, in which synaptic plasticity and functions such as emotional and cognitive processing are compromised. For this reason, the identification of new therapeutic strategies would be enriched by the search for metabolites that promote structural plasticity. The present study evaluated the dendritogenic potential of the ethanol extract of Lippia alba, an aromatic plant rich in flavonoids and terpenes, which has been widely used in traditional medicine for its presumed analgesic, anxiolytic, and antidepressant potential. An in vitro model of rat cortical neurons was used to determine the kinetics of the plant's effect at different time intervals. Changes in morphological parameters of the neurons were determined, as well as the dendritic complexity, by Sholl analysis. The extract promotes the outgrowth of dendritic branching in a rapid and sustained fashion, without being cytotoxic to the cells. We found that this effect could be mediated by the phosphatidylinositol 3-kinase pathway, which is involved in mechanisms of neuronal plasticity, differentiation, and survival. The evidence presented in this study provides a basis for further research that, through in vivo models, can delve into the plant's therapeutic potential.

MicroRNA-dependent regulation of gene expression in GABAergic interneurons.

Information processing within neuronal circuits relies on their proper development and a balanced interplay between principal and local inhibitory interneurons within those circuits. Gamma-aminobutyric acid (GABA)ergic inhibitory interneurons are a remarkably heterogeneous population, comprising subclasses based on their morphological, electrophysiological, and molecular features, with differential connectivity and activity patterns. microRNA (miRNA)-dependent post-transcriptional control of gene expression represents an important regulatory mechanism for neuronal development and plasticity. miRNAs are a large group of small non-coding RNAs (21-24 nucleotides) acting as negative regulators of mRNA translation and stability. However, while miRNA-dependent gene regulation in principal neurons has been described heretofore in several studies, an understanding of the role of miRNAs in inhibitory interneurons is only beginning to emerge. Recent research demonstrated that miRNAs are differentially expressed in interneuron subclasses, are vitally important for migration, maturation, and survival of interneurons during embryonic development and are crucial for cognitive function and memory formation. In this review, we discuss recent progress in understanding miRNA-dependent regulation of gene expression in interneuron development and function. We aim to shed light onto mechanisms by which miRNAs in GABAergic interneurons contribute to sculpting neuronal circuits, and how their dysregulation may underlie the emergence of numerous neurodevelopmental and neuropsychiatric disorders.

Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling

Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but its exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of rat spinal neurons with computational modeling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a homomeric channels. A computational model of WDR neuron supplemented with different ASIC1a channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using the Texas coral snake ASIC-activating toxin (MitTx) and calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin). This study supports a dual contribution to windup of calcium permeable ASIC1a channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.

The molecular diversity of plasticity mechanisms underlying memory: An evolutionary perspective.

Experience triggers molecular cascades in organisms (learning) that lead to alterations (memory) to allow the organism to change its behavior based on experience. Understanding the molecular mechanisms underlying memory, particularly in the nervous system of animals, has been an exciting scientific challenge for neuroscience. We review what is known about forms of neuronal plasticity that underlie memory highlighting important issues in the field: (1) the importance of being able to measure how neurons are activated during learning to identify the form of plasticity that underlies memory, (2) the many distinct forms of plasticity important for memories that naturally decay both within and between organisms, and (3) unifying principles underlying the formation and maintenance of long-term memories. Overall, the diversity of molecular mechanisms underlying memories that naturally decay contrasts with more unified molecular mechanisms implicated in long-lasting changes. Despite many advances, important questions remain as to which mechanisms of neuronal plasticity underlie memory.

Applying the Properties of Neurons in Machine Learning: A Brain-like Neural Model with Interactive Stimulation for Data Classification

Some neural models achieve outstanding results in image recognition, semantic segmentation and natural language processing. However, their classification performance on structured and small-scale datasets that do not involve feature extraction is worse than that of traditional algorithms, although they require more time to train. In this paper, we propose a brain-like neural model with interactive stimulation (NMIS) that focuses on data classification. It consists of a primary neural field and a senior neural field that play different cognitive roles. The former is used to correspond to real instances in the feature space, and the latter stores the category pattern. Neurons in the primary field exchange information through interactive stimulation and their activation is transmitted to the senior field via inter-field interaction, simulating the mechanisms of neuronal interaction and synaptic plasticity, respectively. The proposed NMIS is biologically plausible and does not involve complex optimization processes. Therefore, it exhibits better learning ability on small-scale and structured datasets than traditional BP neural networks. For large-scale data classification, a nearest neighbor NMIS (NN_NMIS), an optimized version of NMIS, is proposed to improve computational efficiency. Numerical experiments performed on some UCI datasets show that the proposed NMIS and NN_NMIS are significantly superior to some classification algorithms that are widely used in machine learning.

The effectiveness of the occupational therapy technologies in restoring sensitivity of the paretic upper limb in the early recovery stage of ischemic stroke

Aim. To restore the sensory functions of the paretic upper limb in patients with post-stroke hemiparesis by applying the occupational therapy in order to improve the ability to daily activities and independence.Material and methods. Under observation there were 63 patients with post-stroke hemiparesis. The level of sensory functions of the upper limb was determined using the tests recommended by the European Stroke Organization for stroke control in clinical practice.Results. While developing the program of the occupational therapy intervention a correctional and developmental strategy was chosen. Patients were randomized into 2 groups. In the main group the “mirror” therapy was used, it was combined with the art therapy. At the beginning, the “mirror” therapy was used for 1 month, followed by the functional tasks and the art therapy. As a result of the program applied, the sensory functions of the upper limb were completely restored or significantly improved in the vast majority of patients, which led to recovery and improvement of its dexterity.
 Conclusions. Sensory insufficiency of the paretic upper limb, which is formed during ischemic stroke, is a limiting factor in restoring its motor activity in the vast majority of patients, and it hinders independence in their domestic and professional activities.The use of the “mirror” therapy as a key trigger, a starting factor to stimulate the mechanisms of neuronal plasticity with further addition of the art therapy, with the purposeful application of tasks for training of proprioceptive and perceptual qualities, made it possible to restore or significantly improve the sensory functions of the paretic upper limb and its dexterity.Key words: ischemic stroke; occupational therapy; recovery of sensitivity.

A Progressive Build-up of Perineuronal Nets in the Somatosensory Cortex Is Associated with the Development of Chronic Pain in Mice.

Chronic pain is sustained by a maladaptive form of neuronal plasticity occurring in all stations of the pain neuraxis, including cortical regions of the pain matrix. We report that chronic inflammatory pain induced by unilateral injection of complete Freund's adjuvant (CFA) in the hindpaw of male mice was associated with a progressive build-up of perineuronal nets (PNNs) in the contralateral somatosensory cortex (SSC), medial prefrontal cortex (mPFC), and reticular thalamic nucleus. In the SSC, the density of PNNs labeled by Wisteria floribunda agglutinin (WFA) was increased at both 3 and 7 d following CFA injection, but only after 7 d in the mPFC. The number of parvalbumin (PV)-positive interneurons enwrapped by WFA+/PNNs was also increased in all three brain regions of mice injected with CFA. Remarkably, PNN degradation induced by intracortical infusion of chondroitinase-ABC significantly reduced mechanical and thermal pain, and also reversed the increased frequency of IPSCs recorded in layer 5 pyramidal neurons of the contralateral SSC in CFA-injected mice. These findings suggest a possible relationship between cortical PNNs and nociceptive sensitization, and support the hypothesis that PNNs maintain their plasticity in the adult life and regulate cortical responses to sensory inputs.SIGNIFICANCE STATEMENT The brain extracellular matrix not only provides structural support, but also regulates synapse formation and function, and modulates neuronal excitability. We found that chronic inflammatory pain in mice enhances the density of perineuronal nets (PNNs) in the somatosensory cortex and medial prefrontal cortex. Remarkably, enzymatic degradation of PNNs in the somatosensory cortex caused analgesia and reversed alterations of inhibitory synaptic transmission associated with chronic pain. These findings disclose a novel mechanism of nociceptive sensitization and support a role for PNNs in mechanisms of neuronal plasticity in the adult brain.

Thrombospondin-1 (TSP-1) and Neuronal Plasticity: Implications in Down Syndrome

Down syndrome is the most common genetic cause of intellectual disability. Nevertheless, under certain stimulation processes, Down syndrome people can develop certain intellectual skills, suggesting an active mechanism of neuronal plasticity. Defects in both dendritic arborization and dendritic spines could affect neuronal plasticity and contribute to the degree of intellectual disability in people with Down syndrome. However, the cellular mechanisms involved in this process are unknown. Thrombospondin-1 (TSP-1) is an astrocyte-secreted protein involved in the development and maintenance of dendritic spines and synapses, which is altered in Down syndrome. Nonetheless, the role of TSP-1 in neuronal plasticity is not well characterized. In this study, we analyze whether TSP-1 is involved in neuronal microstructure changes induced by environmental enrichment, a model of experience-dependent neuronal plasticity. We found that the increase in dendritic spine density induced by environmental enrichment is associated with an increase in TSP-1 levels in the hippocampus of wild-type mice. The lack of TSP-1 in TSP-1-/- mice produce changes in the number and length of dendritic branches and a decrease in both, the number of intersections and density of dendritic spines. Exposure of TSP-1-/- mice to environmental enrichment did not affect the dendritic length and branching and number of intersections, but increased the density of dendritic spines significantly. These results suggest a role of TSP-1 as an important factor regulating brain microstructural plasticity, whose activity is reduced in Down syndrome.

HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction.

Simple SummaryGene expression controls all aspects of life, including that of humans. Genes are expressed by copying the information stored in the DNA into RNA molecules, and this process is regulated in part by multiple RNA-binding proteins (RBPs). One such protein, HuD, plays a critical role in the development of neurons and has been implicated in childhood brain tumors, neurodegenerative disorders (Parkinson’s, Alzheimer’s, and ALS), and drug abuse. In addition, HuD participates in neuronal remodeling mechanisms in the mature brain and promotes regeneration of peripheral nerves. HuD primarily binds to transcribed messenger RNAs, which are then stabilized for translation into proteins. However, recent studies demonstrate that HuD also regulates the expression of non-coding RNAs, such as circular RNAs (circRNAs) and microRNAs (miRNAs). In this study, we examined the role of HuD in the control of non-coding RNA expression in the mouse striatum, a brain region associated both with normal behaviors and pathological conditions such as drug abuse. Our results show that HuD regulates mRNA-circRNA-miRNA networks involved in the expression of genes associated with brain development and remodeling of neuronal connections. These findings suggest the possibility of new mechanisms controlling brain development, neurodegenerative diseases, and substance use disorders.The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology.

Effect of Anti-inflammatory Treatment with AMD3100 and CX3CR1 Deficiency on GABAA Receptor Subunit and Expression of Glutamate Decarboxylase Isoforms After Stroke

Following stroke, attenuation of detrimental inflammatory pathways might be a promising strategy to improve long-term outcome. In particular, cascades driven by pro-inflammatory chemokines interact with neurotransmitter systems such as the GABAergic system. This crosstalk might be of relevance for mechanisms of neuronal plasticity, however, detailed studies are lacking. The purpose of this study was to determine if treatment with 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and partial allosteric agonist to CXCR7 (AMD3100) alone or in combination with C-X3-C chemokine receptor type 1 (CX3CR1) deficiency, affect the expression of GABAA subunits and glutamate decarboxylase (GAD) isoforms. Heterozygous, CX3CR1-deficient mice and wild-type littermates were subjected to photothrombosis (PT). Treatment with AMD3100 (0.5 mg/kg twice daily i.p.) was administered starting from day 2 after induction of PT until day 14 after the insult. At this time point, GABAA receptor subunits (α3, β3, δ), GAD65 and GAD67, and CXCR4 were analyzed from the peri-infarct tissue and homotypic brain regions of the contralateral hemisphere by quantitative real-time PCR and Western Blot. Fourteen days after PT, CX3CR1 deficiency resulted in a significant decrease of the three GABAA receptor subunits in both the lesioned and the contralateral hemisphere compared to sham-operated mice. Treatment with AMD3100 promoted the down-regulation of GABAA subunits and GAD67 in the ipsilateral peri-infarct area, while the β3 subunit and the GAD isoforms were up-regulated in homotypic regions of the contralateral cortex. Changes in GABAA receptor subunits and GABA synthesis suggest that the CXCR4/7 and CX3CR1 signaling pathways are involved in the regulation of GABAergic neurotransmission in the post-ischemic brain.

Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse

The neuroimmune system is required for normal cognitive functions such as learning and memory in addition to its critical role in detecting and responding to invading pathogens and injury. Understanding the functional convergence of neurons, astrocytes, and microglia at the synapse, particularly in the hippocampus, is key to understanding the nuances of such diverse roles. In the healthy brain, communication between all three cells is important for regulating neuronal activation and synaptic plasticity mechanisms, and during neuroinflammation, the activity and functions of all three cells can produce and be modulated by inflammatory cytokines. An important remaining component to this system is the conclusive evidence of sex differences in hippocampal plasticity mechanisms, hormone modulation of synaptic plasticity, functional properties of hippocampal neurons, and in neuroimmune activation. Sex as a biological variable here is necessary to consider given sex differences in the prevalence of memory-related disorders such as Alzheimer's disease and Post-Traumatic Stress disorder, both of which present with neuroimmune dysregulation. To make meaningful progress towards a deeper understanding of sex biases in memory-related disease prevalence, I propose that the next chapter of psychoneuroimmune research must focus on the signal integration and transduction at the synapse between experience-dependent plasticity mechanisms, neuroimmune activation, and the influence of biological sex.

Frontotemporal Transcranial Direct Current Stimulation Decreases Serum Mature Brain-Derived Neurotrophic Factor in Schizophrenia.

Although transcranial direct current stimulation (tDCS) shows promise as a treatment for auditory verbal hallucinations in patients with schizophrenia, mechanisms through which tDCS may induce beneficial effects remain unclear. Evidence points to the involvement of neuronal plasticity mechanisms that are underpinned, amongst others, by brain-derived neurotrophic factor (BDNF) in its two main forms: pro and mature peptides. Here, we aimed to investigate whether tDCS modulates neural plasticity by measuring the acute effects of tDCS on peripheral mature BDNF levels in patients with schizophrenia. Blood samples were collected in 24 patients with schizophrenia before and after they received a single session of either active (20 min, 2 mA, n = 13) or sham (n = 11) frontotemporal tDCS with the anode over the left prefrontal cortex and the cathode over the left temporoparietal junction. We compared the tDCS-induced changes in serum mature BDNF (mBDNF) levels adjusted for baseline values between the two groups. The results showed that active tDCS was associated with a significantly larger decrease in mBDNF levels (mean −20% ± standard deviation 14) than sham tDCS (−8% ± 21) (F = 5.387; p = 0.030; η2 = 0.205). Thus, mature BDNF may be involved in the beneficial effects of frontotemporal tDCS observed in patients with schizophrenia.

Quantification of Dendritic Spines Remodeling under Physiological Stimuli and in Pathological Conditions.

Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.

Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome

Dysregulation of brain insulin signaling with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer disease (AD). This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1. Since Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration in DS and whether they contribute to early onset AD in DS.We evaluated levels and activation of proteins belonging to the insulin signaling pathway (IR, IRS1, BVR-A, MAPK, PTEN, Akt, GSK3β, PKCζ, AS160, GLUT4) in the frontal cortex of Ts65dn (DS model) (n = 5–6/group) and euploid mice (n = 6/group) at different ages (1, 3, 9 and 18 months). Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) markers (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin-1 and BDNF).Ts65dn mice showed an overall impairment of the above-mentioned pathways, mainly characterized by defects of proteins activation state. Such alterations start early in life (at 1 month, during brain maturation). In particular, accumulation of inhibited IRS1, together with the uncoupling among the proteins downstream from IRS1 (brain insulin resistance), characterize Ts65dn mice. Furthermore, reduced levels of mitochondrial complexes and Sirt1, as well as increased indices of OS also were observed. These alterations precede the accumulation of APP-C99 in Ts65dn mice. Tellingly, oxidative stress levels were negatively associated with IR, IRS1 and AS160 activation as well as mitochondrial complexes levels in Ts65dn mice, suggesting a role for oxidative stress in the observed alterations.We propose that a close link exists among brain insulin resistance, mitochondrial defects and OS that contributes to brain dysfunctions observed in DS, likely favoring the development of AD in DS.

Connectivity changes in major depressive disorder after rTMS: a review of functional and structural connectivity data

Abstract Aims In the search for effective therapeutic strategies for depression, repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive, promising treatment. This is because the antidepressant effect of rTMS might be related to neuronal plasticity mechanisms possibly reverting connectivity alterations often observed in depression. Therefore, in this review, we aimed at providing an overview of the findings reported by studies investigating functional and structural connectivity changes after rTMS in depression. Methods A bibliographic search was conducted on PubMed, including studies that used unilateral, excitatory (⩾10 Hz) rTMS treatment targeted on the left dorsolateral prefrontal cortex (DLPFC) in unipolar depressed patients. Results The majority of the results showed significant TMS-induced changes in functional connectivity (FC) between areas important for emotion regulation, including the DLPFC and the subgenual anterior cingulate cortex, and among regions that are part of the major resting-state networks, such as the Default Mode Network, the Salience Networks and the Central Executive Network. Finally, in diffusion tensor imaging studies, it has been reported that rTMS appeared to increase fractional anisotropy in the frontal lobe. Limitations The small sample size, the heterogeneity of the rTMS stimulation parameters, the concomitant use of psychotropic drugs might have limited the generalisability of the results. Conclusions Overall, rTMS treatment induces structural and FC changes in brain regions and networks implicated in the pathogenesis of unipolar depression. However, whether these changes underlie the antidepressant effect of rTMS still needs to be clarified.