Maladaptive Changes Research Articles

Neural Plasticity in the Brain during Neuropathic Pain.

Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. Besides abnormal sensitization in the periphery and spinal cord, accumulating evidence suggests that neural plasticity in the brain is also critical for the development and maintenance of this pain. Recent technological advances in the measurement and manipulation of neuronal activity allow us to understand maladaptive plastic changes in the brain during neuropathic pain more precisely and modulate brain activity to reverse pain states at the preclinical and clinical levels. In this review paper, we discuss the current understanding of pathological neural plasticity in the four pain-related brain areas: the primary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray, and the basal ganglia. We also discuss potential treatments for neuropathic pain based on the modulation of neural plasticity in these brain areas.

Effects of a low-carbohydrate ketogenic diet on reported pain, blood biomarkers and quality of life in patients with chronic pain: A pilot randomised clinical trial rationale, study design and protocol

IntroductionA ketogenic diet has been shown to influence the nervous system and can potentially improve maladaptive changes occurring with chronic pain, specifically neuroinflammation and nervous system sensitisation. However, there is limited research on whether altering a standard western diet high in ultra-processed foods to a well-formulated ketogenic diet (WFKD) may reduce chronic pain. The aim of this clinical trial is to evaluate the effects of a WFKD on patients with chronic pain. MethodsThis is a 12-week pilot randomised clinical trial of adults with chronic musculoskeletal pain. All participants will commence with a 3-week run in whole-foods diet removing ultra-processed foods. At week 4 they will be randomised to either continue the whole food diet or start a WFKD (carbohydrate intake <50g/day). Finger prick ketone testing will evaluate the level of nutritional ketosis, and carbohydrate levels adjusted accordingly to achieve the target ketone level 0.5–3.0 mmol/L. Reported chronic pain levels, blood ketone levels, metabolic markers, inflammation and quality of life will be measured at baseline, post-intervention, and 3- months follow-up. ConclusionThis trial will evaluate the effects of a whole-food well formulated ketogenic diet on chronic pain perception. It attempts to address the commonalties between reported dietary approaches (diet quality and nutrient density) by using a comparator of equal food quality to allow the clinical evaluation of the ketogenic diet specifically on pain mechanisms. It will further the research on how a ketogenic diet may modulate physiology linked to chronic pain mechanisms such as metabolic dysregulation and inflammation.

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.

Ischemic stroke-induced polyaxonal innervation at the neuromuscular junction is attenuated by robot-assisted mechanical therapy

Ischemic stroke is a leading cause of disability world-wide. Mounting evidence supports neuromuscular pathology following stroke, yet mechanisms of dysfunction and therapeutic action remain undefined. The objectives of our study were to investigate neuromuscular pathophysiology following ischemic stroke and to evaluate the therapeutic effect of Robot-Assisted Mechanical massage Therapy (RAMT) on neuromuscular junction (NMJ) morphology. Using an ischemic stroke model in male rats, we demonstrated longitudinal losses of muscle contractility and electrophysiological estimates of motor unit number in paretic hindlimb muscles within 21 days of stroke. Histological characterization demonstrated striking pre- and postsynaptic alterations at the NMJ. Stroke prompted enlargement of motor axon terminals, acetylcholine receptor (AChR) area, and motor endplate size. Paretic muscle AChRs were also more homogenously distributed across motor endplates, exhibiting fewer clusters and less fragmentation. Most interestingly, NMJs in paretic muscle exhibited increased frequency of polyaxonal innervation. This finding of increased polyaxonal innervation in stroke-affected skeletal muscle suggests that reduction of motor unit number following stroke may be a spurious artifact due to overlapping of motor units rather than losses. Furthermore, we tested the effects of RAMT – which we recently showed to improve motor function and protect against subacute myokine disturbance – and found significant attenuation of stroke-induced NMJ alterations. RAMT not only normalized the post-stroke presentation of polyaxonal innervation but also mitigated postsynaptic expansion. These findings confirm complex neuromuscular pathophysiology after stroke, provide mechanistic direction for ongoing research, and inform development of future therapeutic strategies. SignificanceIschemic stroke is a leading contributor to chronic disability, and there is growing evidence that neuromuscular pathology may contribute to the impact of stroke on physical function. Following ischemic stroke in a rat model, there are progressive declines of motor unit number estimates and muscle contractility. These changes are paralleled by striking pre- and postsynaptic maladaptive changes at the neuromuscular junction, including polyaxonal innervation. When administered to paretic hindlimb muscle, Robot-Assisted Mechanical massage Therapy – previously shown to improve motor function and protect against subacute myokine disturbance – prevents stroke-induced neuromuscular junction alterations. These novel observations provide insight into the neuromuscular response to cerebral ischemia, identify peripheral mechanisms of functional disability, and present a therapeutic rehabilitation strategy with clinical relevance.

Downregulation of a Dorsal Root Ganglion-Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY-Triggered Ehmt2 Expression.

Nerve injury‐induced maladaptive changes of gene expression in dorsal root ganglion (DRG) neurons contribute to neuropathic pain. Long non‐coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Here, a conserved lncRNA is reported, named DRG‐specifically enriched lncRNA (DS‐lncRNA) for its high expression in DRG neurons. Peripheral nerve injury downregulates DS‐lncRNA in injured DRG due, in part, to silencing of POU domain, class 4, transcription factor 3, a transcription factor that interacts with the DS‐lncRNA gene promoter. Rescuing DS‐lncRNA downregulation blocks nerve injury‐induced increases in the transcriptional cofactor RALY‐triggered DRG Ehmt2 mRNA and its encoding G9a protein, reverses the G9a‐controlled downregulation of opioid receptors and Kcna2 in injured DRG, and attenuates nerve injury‐induced pain hypersensitivities in male mice. Conversely, DS‐lncRNA downregulation increases RALY‐triggered Ehmt2 /G9a expression and correspondingly decreases opioid receptor and Kcna2 expression in DRG, leading to neuropathic pain symptoms in male mice in the absence of nerve injury. Mechanistically, downregulated DS‐lncRNA promotes more binding of increased RALY to RNA polymerase II and the Ehmt2 gene promoter and enhances Ehmt2 transcription in injured DRG. Thus, downregulation of DS‐lncRNA likely contributes to neuropathic pain by negatively regulating the expression of RALY‐triggered Ehmt2/G9a, a key neuropathic pain player, in DRG neurons.

From secondary to tertiary mitral regurgitation: the paradigm shifts, but uncertainties remain

Secondary mitral regurgitation (MR) is the most common and undertreated form of MR, whose contribution to poor prognosis and indications to correction remains under discussion. MR has been characterized into 'proportionate' or 'disproportionate', based on left ventricle (LV) and regurgitant volumes, whereas 'tertiary' MR identifies conditions, in which regurgitation is pathologic per se and actively contributes to LV dysfunction. Echocardiographic and anatomo-pathological studies revealed that secondary MR prompts subtle leaflet maladaptive changes, actively contributing to the dynamic progression of secondary MR. We critically discuss the paradigm shift from secondary to tertiary MR and question the notion that MV leaflets play a passive role in secondary MR. We also review the role of standard transthoracic echocardiography for appraising and quantifying maladaptive MV leaflet changes and LV volumes and call for a more sophisticated and comprehensive imaging framework for classifying MR in future interventional studies.

A Brief Review on the Biology and Effects of Cellular and Circulating microRNAs on Cardiac Remodeling after Infarction.

Despite advances in diagnostic, prognostic, and treatment modalities, myocardial infarction (MI) remains a leading cause of morbidity and mortality. Impaired cellular signaling after an MI causes maladaptive changes resulting in cardiac remodeling. MicroRNAs (miRNAs/miR) along with other molecular components have been investigated for their involvement in cellular signaling in the pathogenesis of various cardiac conditions like MI. miRNAs are small non-coding RNAs that negatively regulate gene expression. They bind to complementary mRNAs and regulate the rate of protein synthesis by altering the stability of their targeted mRNAs. A single miRNA can modulate several cellular signaling pathways by targeting hundreds of mRNAs. This review focuses on the biogenesis and beneficial effects of cellular and circulating (exosomal) miRNAs on cardiac remodeling after an MI. Particularly, miR-1, -133, 135, and -29 that play an essential role in cardiac remodeling after an MI are described in detail. The limitations that will need to be addressed in the future for the further development of miRNA-based therapeutics for cardiovascular conditions will also be discussed.

Raising the Bar When Assessing Cardiovascular Disease Outcome When Studies with Patients with Type 2 Diabetes Mellitus are Constructed: Revisiting ASCEND

The emergence of Type 2 Diabetes Mellitus (T2DM) as a clinical syndrome deviating from rudimentary models including “glucose-insulin” disparities to a clinical syndrome impinged upon hyperactivation of inflammatory-mediated signaling pathways, maladaptive pathophysiological changes, and pleiotropic sequelae has not only changed the nature of discussions regarding diabetes in academic circles, but also the treatment of T2DM clinically. The new challenges faced in preventing the advancement of T2DM coupled with the management of associated chronic disease states have impelled avenues for innovative treatments for T2DM sequelae while also ensuring glycemic control. For example, Sodium-Glucose Transport 2 inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA), in addition to passing mandated Food and Drug Administration (FDA) Cardiovascular Outcome Trials (CVOT), have displayed positive outcomes with respect to cardiorenal considerations in patients with T2DM. Such performances have recently elevated these pleiotropic medications to higher tiers of recommendations by medical societies such as the American Diabetes Association and the American College of Cardiology. Moreover, the tandem of the notion that pleiotropic pharmacotherapeutic options with an expanded understanding of T2DM on the epigenetic, molecular, and cellular domains have galvanized researchers to explore pharmacologic mechanisms in the context of our ever-changing model in T2DM. In this communication, we would like to use lessons from the “Effects of aspirin for primary prevention in persons with diabetes mellitus” (ASCEND) trial to implore aspiring researchers and practitioners to explore, or at least consider external factors of the T2DM patient populous when reporting findings of cardiovascular clinical endpoints for proper context.

Interactions of hypertension, obesity, left ventricular hypertrophy, and heart failure.

Hypertension (HTN) and obesity are major risk factors for cardiac remodeling and dysfunction, leading to left ventricular hypertrophy (LVH) and heart failure (HF). In this review, we discuss the complex mechanisms and effects of HTN and obesity, and their treatments in LVH, ventricular function, and HF. Obesity and HTN impact the heart through overlapping neurohormonal pathways. However, the relationship between obesity and cardiomyopathy is more complex, and additional metabolic and hemodynamic pathways seem to contribute to cardiac dysfunction in these patients. Weight loss and blood pressure (BP) control help to prevent and reverse at least some of the damage caused by obesity and HTN even beyond what would be expected from solely the hemodynamic changes. Obesity and HTN cause maladaptive changes in the heart that can lead to LVH and HF. Weight loss and BP control help to, at least partially, reverse some of these changes and improve clinical outcomes in patients with HF.

Repetitive Transcranial Magnetic Stimulation on the Supplementary Motor Area Changes Brain Connectivity in Functional Dysphagia.

Background: Previous studies arguing that functional dysphagia could be explained by underlying neurobiological mechanisms are insufficient to explain brain regions that functionally interact in patients with functional dysphagia. Therefore, we investigated functional connectivity changes associated with functional dysphagia after applying facilitatory repetitive transcranial magnetic stimulation (rTMS) on the supplementary motor area (SMA). Materials and Methods: A patient with severe long-lasting functional dysphagia and 15 healthy controls participated in this study. A facilitatory 5 Hz rTMS protocol was applied to the patient's SMA. We performed functional magnetic resonance imaging (fMRI) using volitional swallowing tasks to investigate neural network changes before rTMS (pre-rTMS), immediately after rTMS, and 3 months later. Results: The pre-rTMS fMRI results of the patient showed extensive overactivation in the left-lateralized regions related to volitional swallowing compared with the healthy controls. Following rTMS, dysphagia symptoms partially improved. The patient showed positive connectivity with the bilateral cerebellum in the bilateral SMA seeds before rTMS treatment. Furthermore, left-lateralized overactivation was washed out immediately after completion of rTMS, and connectivity between the left SMA and left precentral gyrus recovered 3 months after rTMS treatment. Conclusion: Our findings confirm that functional dysphagia might be a neurobiological manifestation caused by maladaptive functional connectivity changes in brain structures related to swallowing. Furthermore, noninvasive brain modulation with rTMS over the SMA may facilitate functional connectivity changes between the cortical and subcortical regions. Accordingly, these changes will allow control of the movements related to swallowing and may lead to improved clinical symptoms.

Initial Weight Change and Long-Term Changes in Weight and Compensation during Supervised Exercise Training.

Our primary aim was to investigate the association between initial weight change and longer-term changes in weight and compensation (predicted weight loss-observed weight loss) during exercise. As secondary aims, we investigated if initial weight change was related to change in cardiometabolic risk markers and energy balance modulators. Two 6-month randomized controlled exercise trials conducted in individuals with overweight or obesity were analyzed (study 1, n = 312; study 2, n = 102). In both studies, participants in an exercise condition (4 kcal·kg-1·wk-1 [KKW], 8 KKW, 12 KKW, or 20 KKW) were split into tertiles based on percent weight change from baseline to week 4. Tertiles 1 and 3 exhibited the least and most initial weight loss, respectively. Changes in end points were compared between tertiles. At month 6, weight loss was lower in tertile 1 than tertile 3 (study 1: -3.6%, 95% confidence interval [CI] = -4.6 to -2.6; study 2: -1.8%, 95% CI = -3.1 to -0.4; P ≤ 0.034). Tertile 1 also showed greater compensation than tertile 3 in study 1 (3.0 kg, 95% CI = 2.2 to 3.9) and study 2 (1.5 kg, 95% CI = 0.3 to 2.6; P ≤ 0.048). Changes in triglycerides and, in study 1, HDL cholesterol were less favorable in tertile 1 versus tertile 3 (P ≤ 0.043); however, changes in other cardiometabolic markers were similar (P ≥ 0.209). In study 2, tertile 1 increased energy intake and exhibited maladaptive changes in eating behaviors relative to tertile 3 (P < 0.050). No between-tertile differences in cumulative exercise energy expenditure and physical activity were evident (P ≥ 0.321). Less initial weight loss was associated with longer-term attenuated weight loss and greater compensation during aerobic exercise training. Individuals who display less initial weight loss during exercise may require early interventions to decrease compensation and facilitate weight loss.

Sex-specific differences in left ventricular mass and myocardial energetic efficiency in non-diabetic, pre-diabetic and newly diagnosed type 2 diabetic subjects

BackgroundWomen with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than their male counterparts. However, whether the risk for CVD is higher in prediabetic women than men is still debated. We aimed to determine whether sex-related differences exist in left ventricular mass index (LVMI), and myocardial mechano-energetic efficiency (MEEi) in with normal glucose tolerant (NGT), pre-diabetic and newly diagnosed type 2 diabetic subjects.MethodsSex-related differences in LVMI and myocardial MEEi, assessed by validated echocardiography-derived measures, were examined among 1562 adults with NGT, prediabetes, and newly diagnosed T2DM, defined according to fasting glucose, 2-h post-load glucose, or HbA1c.ResultsWorsening of glucose tolerance in both men and women was associated with an increase in age-adjusted LVMI and myocardial MEEi. Women with newly diagnosed T2DM exhibited greater relative differences in LVMI and myocardial MEEi than diabetic men when compared with their NGT counterparts. Prediabetic women exhibited greater relative differences in myocardial MEEi, but not in LVMI, than prediabetic men when compared with their NGT counterparts. The statistical test for interaction between sex and glucose tolerance on both LVMI (P < 0.0001), and myocardial MEEi (P < 0.0001) was significant suggesting a sex-specific association.ConclusionsLeft ventricle is subject to maladaptive changes with worsening of glucose tolerance, especially in women with newly diagnosed T2DM. The sex-specific increase in LVM and decrease in MEEi, both being predictors of CVD, may have a role in explaining the stronger impact of T2DM on the excess risk of CVD in women than in men.

The Central Effects of Botulinum Toxin in Dystonia and Spasticity.

In dystonic and spastic movement disorders, however different in their pathophysiological mechanisms, a similar impairment of sensorimotor control with special emphasis on afferentation is assumed. Peripheral intervention on afferent inputs evokes plastic changes within the central sensorimotor system. Intramuscular application of botulinum toxin type A (BoNT-A) is a standard evidence-based treatment for both conditions. Apart from its peripheral action on muscle spindles, a growing body of evidence suggests that BoNT-A effects could also be mediated by changes at the central level including cerebral cortex. We review recent studies employing electrophysiology and neuroimaging to investigate how intramuscular application of BoNT-A influences cortical reorganization. Based on such data, BoNT-A becomes gradually accepted as a promising tool to correct the maladaptive plastic changes within the sensorimotor cortex. In summary, electrophysiology and especially neuroimaging studies with BoNT-A further our understanding of pathophysiology underlying dystonic and spastic movement disorders and may consequently help develop novel treatment strategies based on neural plasticity.

Increased Synaptic Strength and mGlu2/3 Receptor Plasticity on Mouse Prefrontal Cortex Intratelencephalic Pyramidal Cells Following Intermittent Access to Ethanol.

The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus). In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1day after 4 to 5weeks of intermittent access (IA) EtOH exposure. Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking. Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu2 and/or mGlu3 receptor function as potential treatments for AUD.

Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.

Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood

SummaryIn genetic and pharmacological models of neurodevelopmental disorders, and human data, neural activity is altered within the developing neocortical network. This commonality begs the question of whether early enhancement in excitation might be a common driver, across etiologies, of characteristic behaviors. We tested this concept by chemogenetically driving cortical pyramidal neurons during postnatal days 4–14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons, led to decreased social interaction and increased grooming activity in adult animals. In vivo optogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons and impaired recruitment of inhibitory neurons. Slice recordings in adults from prefrontal cortex layer 5 pyramidal neurons revealed decreased intrinsic excitability and increased synaptic E/I ratio. Together these results support the prediction that enhanced pyramidal firing during development, in otherwise normal cortex, can selectively drive altered adult circuit function and maladaptive changes in behavior.

Pharmacological restoration of anti-nociceptive functions in the prefrontal cortex relieves chronic pain.

Chronic pain affects one in four adults, and effective non-sedating and non-addictive treatments are urgently needed. Chronic pain causes maladaptive changes in the cerebral cortex, which can lead to impaired endogenous nociceptive processing. However, it is not yet clear if drugs that restore endogenous cortical regulation could provide an effective therapeutic strategy for chronic pain. Here, we studied the nociceptive response of neurons in the prelimbic region of the prefrontal cortex (PL-PFC) in freely behaving rats using a spared nerve injury (SNI) model of chronic pain, and the impact of AMPAkines, a class of drugs that increase central glutamate signaling, on such response. We found that neurons in the PL-PFC increase their firing rates in response to noxious stimulations; chronic neuropathic pain, however, suppressed this important cortical pain response. Meanwhile, CX546, a well-known AMPAkine, restored the anti-nociceptive response of PL-PFC neurons in the chronic pain condition. In addition, both systemic administration and direct delivery of CX546 into the PL-PFC inhibited symptoms of chronic pain, whereas optogenetic inactivation of the PFC neurons or administration of AMPA receptor antagonists in the PL-PFC blocked the anti-nociceptive effects of CX546. These results indicate that restoration of the endogenous anti-nociceptive functions in the PL-PFC by pharmacological agents such as AMPAkines constitutes a successful strategy to treat chronic neuropathic pain.

Dynamic structural neuroplasticity during and after epileptogenesis in a pilocarpine rat model of epilepsy

BackgroundThe role of neuroplasticity in epilepsy has been widely studied in experimental models and human brain samples. However, the results are contradictory and it remains unclear if neuroplasticity is more related to the cause or the consequence of epileptic seizures. Clarifying this issue can provide insights into epilepsy therapies that target the disease mechanism and etiology rather than symptoms. Therefore, this study was aimed to investigate the dynamic changes of structural plasticity in a pilocarpine rat model of epilepsy.MethodsA single acute dose of pilocarpine (380 mg/kg, i.p.) was injected into adult male Wistar rats to induce status epilepticus (SE). Animal behavior was monitored for 2 h. Immunohistochemical staining was performed to evaluate neurogenesis in the CA3 and dentate gyrus (DG) regions of hippocampus using biomarkers Ki67 and doublecortin (DCX). The Golgi-Cox method was performed to analyze dendritic length and complexity. All experiments were performed in control rats (baseline), at 24 h after SE, on day 20 after SE (latent phase), after the first and 10th spontaneous recurrent seizures (SRS; chronic phase), and in non-epileptic rats (which did not manifest SRS 36 days after pilocarpine injection).ResultsSE significantly increased the number of Ki67 and DCX-positive cells, suggesting neurogenesis during the latent phase. The dendritic complexity monitoring showed that plasticity was altered differently during epilepsy and epileptogenesis, suggesting that the two processes are completely separate at molecular and physiological levels. The numbers of spines and mushroom-type spines were increased in the latent phase. However, the dendritogenesis and spine numbers did not increase in rats that were unable to manifest spontaneous seizures after SE.ConclusionAll parameters of structural plasticity that increase during epileptogenesis, are reduced by spontaneous seizure occurrence, which suggests that the development of epilepsy involves maladaptive plastic changes. Therefore, the maladaptive plasticity biomarkers can be used to predict epilepsy before development of SRS in the cases of serious brain injury.

The Phantom Satiation Hypothesis of Bariatric Surgery.

The excitation of vagal mechanoreceptors located in the stomach wall directly contributes to satiation. Thus, a loss of gastric innervation would normally be expected to result in abrogated satiation, hyperphagia, and unwanted weight gain. While Roux-en-Y-gastric bypass (RYGB) inevitably results in gastric denervation, paradoxically, bypassed subjects continue to experience satiation. Inspired by the literature in neurology on phantom limbs, I propose a new hypothesis in which damage to the stomach innervation during RYGB, including its vagal supply, leads to large-scale maladaptive changes in viscerosensory nerves and connected brain circuits. As a result, satiation may continue to arise, sometimes at exaggerated levels, even in subjects with a denervated or truncated stomach. The same maladaptive changes may also contribute to dysautonomia, unexplained pain, and new emotional responses to eating. I further revisit the metabolic benefits of bariatric surgery, with an emphasis on RYGB, in the light of this phantom satiation hypothesis.

Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

Disrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.