Neuronal Alterations Research Articles

Methyl jasmonate rescues structural alterations in cortico-limbic neurons produced by the unpredictable chronic mild stress model of depression

Methyl jasmonate rescues structural alterations in cortico-limbic neurons produced by the unpredictable chronic mild stress model of depression

Morphohistochemical alterations of neurons of the supraoptic nucleus of the rat hypothalamus at different durations of the photoperiod and melatonin administration.

We studied the morphologic and histochemical organization of neurons of the hypothalamic supraoptic nucleus in rats exposed to different durations of photoperiod and injection of melatonin. Morphometric and histochemical analyses of neurons were performed after staining brain histological sections for RNA. Prolonged illumination leads to more pronounced changes in the parameters of hypothalamic structures at 2 a.m. than at 2 p.m., particularly decreasing the concentration of RNA in the cell nuclei. The use of exogenous melatonin does not normalize the revealed changes in the parameters of the studied structures of the neurons of the supraoptic nucleus of the hypothalamus caused by the prolonged stay of rats under conditions of constant illumination.

Migraine attacks as a result of hypothalamic loss of control

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs’ brain activity over an entire migraine cycle.Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack.We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase.The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.

Brain stimulation by tDCS as treatment option in Autism Spectrum Disorder-A systematic literature review.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and interaction as well as stereotypical and repetitive behavior. Transcranial direct current stimulation (tDCS) has been proposed as a new intervention method in ASD with the potential to improve cognitive, motor and social communication abilities by targeting specific underlying neuronal alterations. Here, we report results of a systematic literature review on tDCS effects on EEG and behavioral outcomes, and discuss tDCS as treatment option for ASD. PsychInfo, PubMed, ScienceDirect, Web of Science, https://clinicaltrials.gov and the German Clinical Trials Register (Deutsches Register Klinischer Studien) were searched systematically for randomized, sham-controlled clinical trials of tDCS in individuals with ASD, and information regarding study designs and relevant results was extracted. Six eligible studies were identified. The dorsolateral prefrontal cortex (DLPFC) was targeted in four trials, with core ASD symptoms and working memory as outcome measures. One study targeted the primary motor cortex (M1) with motor skills as outcome, and one study targeted the temporoparietal junction (TPJ) with social communication skills as outcome measure. Comparison of the implemented study designs showed high methodological variability between studies regarding stimulation parameters, trial design and outcome measures. Study results indicate initial support for improved cognitive and social communication skills in ASD following tDCS stimulation. However, systematic and comparison studies on the best combination of stimulation intensity, duration, location as well as task related stimulation are necessary, before results can be translated into routine clinical application.

Carveol Attenuates Seizure Severity and Neuroinflammation in Pentylenetetrazole-Kindled Epileptic Rats by Regulating the Nrf2 Signaling Pathway.

Epilepsy is a neurodegenerative brain disorder characterized by recurrent seizure attacks. Numerous studies have suggested a strong correlation between oxidative stress and neuroinflammation in several neurodegenerative disorders including epilepsy. This study is aimed at investigating the neuroprotective effects of the natural compound carveol against pentylenetetrazole- (PTZ-) induced kindling and seizure model. Two different doses of carveol (10 mg/kg and 20 mg/kg) were administered to male rats to determine the effects and the effective dose of carveol and to further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in PTZ-induced kindling model. Our results demonstrated reduced levels of innate antioxidants such as superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), and glutathione (GSH), associated with elevated lipid peroxidation (LPO) and inflammatory cytokines level such as tumor necrosis factor-alpha (TNF-α), and mediators like cyclooxygenase (COX-2) and nuclear factor kappa B (NFκB). These detrimental effects exacerbated oxidative stress and provoked a marked neuronal alteration in the cortex and hippocampus of PTZ-intoxicated animals that were associated with upregulated Nrf2 gene expression. Furthermore, carveol treatment positively modulated the antioxidant gene Nrf2 and its downstream target HO-1. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated PTZ toxicity. Moreover, carveol treatment induced cholinergic system activation by mitigating acetylcholinesterase level which is further linked to attenuated neuroinflammatory cascade. The extent of blood-brain barrier disruption was evaluated based on vascular endothelial growth factor (VEGF) expression. Taken together, our findings suggest that carveol acts as an Nrf2 activator and therefore induces downstream antioxidants and mitigates inflammatory insults through multiple pathways. This eventually alleviates PTZ-induced neuroinflammation and neurodegeneration.

Ethanol exacerbates manganese-induced oxidative/nitrosative stress, pro-inflammatory cytokines, nuclear factor-κB activation, and apoptosis induction in rat cerebellar cortex.

Manganese (Mn) exposure is causing public health concerns as well as heavy alcohol consumption. This study investigates the mechanisms of neurotoxicity associated with Mn and ethanol (EtOH) exposure in the rat cerebellar cortex. Experimental animals received 30 mg/kg of Mn alone, 5 g/kg of EtOH alone, co-exposed with 30 mg/kg of Mn and 1.25or 5 g/kg EtOH, while control animals received water by oral gavage for 35 days. Subsequently, alterations in the neuronal morphology of the cerebellar cortex, oxidative/nitrosative stress, acetylcholinesterase (AChE) activity, neuro-inflammation and protein expression of p53, BAX, caspase-3, and BCL-2 were investigated. The results indicate that Mn alone and EtOH alone induce neuronal alterations in the cerebellar cortex, decrease glutathione level and antioxidant enzyme activities, along with an increase in AChE activity, lipid peroxidation, and hydrogen peroxide generation. Mn alone and EtOH alone also increased neuro-inflammatory markers, namely nitric oxide, myeloperoxidase activity, interleukin-1β, tumor necrosis factor-α,and nuclear factor-κB (NF-κB) levels in the cerebellar cortex. Immunohistochemistry analysis further revealed that exposure of Mn alone and EtOH alone increases the protein expression of cyclooxygenase-2, BAX, p53, and caspase-3 and decrease BCL-2 in the rat cerebellar cortex. Furthermore, the results indicated that Mn co-exposure with EtOH at 1.25and 5 g/kg EtOH significantly (p ≤ .05) increases the toxicity in the cerebellum when compared with the toxicity of Mn or EtOH alone. Taken together, co-exposure of Mn and EtOH exacerbates neuronal alterations, oxidative/nitrosative stress, AChE activity, pro-inflammatory cytokines, NF-κB signal transcription, and apoptosis induction in the rat cerebellar cortex.

Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient’s genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers βIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ.

Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer's Disease.

Substantial evidence in the literature demonstrates the pleiotropic effects of the administration of recombinant human erythropoietin (rhEPO) and its molecular variants in different tissues and organs, including the brain. Some of these reports suggest that the chemical properties of this molecule by itself or in combination with other agents (e.g., growth factors) could provide the necessary pharmacological characteristics to be considered a potential protective agent in neurological disorders such as Alzheimer’s disease (AD). AD is a degenerative disorder of the brain, characterized by an aberrant accumulation of amyloid β (Aβ) and hyperphosphorylated tau (tau-p) proteins in the extracellular and intracellular space, respectively, leading to inflammation, oxidative stress, excitotoxicity, and other neuronal alterations that compromise cell viability, causing neurodegeneration in the hippocampus and the cerebral cortex. Unfortunately, to date, it lacks an effective therapeutic strategy for its treatment. Therefore, in this review, we analyze the evidence regarding the effects of exogenous EPOs (rhEPO and its molecular variants) in several in vivo and in vitro Aβ and tau-p models of AD-type neurodegeneration, to be considered as an alternative protective treatment to this condition. Particularly, we focus on analyzing the differential effect of molecular variants of rhEPO when changes in doses, route of administration, duration of treatment or application times, are evaluated for the improved cellular alterations generated in this disease. This narrative review shows the evidence of the effectiveness of the exogenous EPOs as potential therapeutic molecules, focused on the mechanisms that establish cellular damage and clinical manifestation in the AD.

Toll-Like Receptor 4 Signaling and Drug Addiction.

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations.

Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.

Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content.

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.SIGNIFICANCE STATEMENT Menkes and Wilson disease affect copper homeostasis and characteristically afflict the nervous system. However, their molecular neuropathology mechanisms remain mostly unexplored. We demonstrate that copper homeostasis in neurons is maintained by two factors that localize to the Golgi apparatus, ATP7 and the conserved oligomeric Golgi (COG) complex. Disruption of these mechanisms affect mitochondrial function and localization to synapses as well as neurotransmission and synaptic plasticity. These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

Local sleep-like cortical reactivity in the awake brain after focal injury.

The functional consequences of focal brain injury are thought to be contingent on neuronal alterations extending beyond the area of structural damage. This phenomenon, also known as diaschisis, has clinical and metabolic correlates but lacks a clear electrophysiological counterpart, except for the long-standing evidence of a relative EEG slowing over the injured hemisphere. Here, we aim at testing whether this EEG slowing is linked to the pathological intrusion of sleep-like cortical dynamics within an awake brain. We used a combination of transcranial magnetic stimulation and electroencephalography (TMS/EEG) to study cortical reactivity in a cohort of 30 conscious awake patients with chronic focal and multifocal brain injuries of ischaemic, haemorrhagic and traumatic aetiology. We found that different patterns of cortical reactivity typically associated with different brain states (coma, sleep, wakefulness) can coexist within the same brain. Specifically, we detected the occurrence of prominent sleep-like TMS-evoked slow waves and off-periods-reflecting transient suppressions of neuronal activity-in the area surrounding focal cortical injuries. These perilesional sleep-like responses were associated with a local disruption of signal complexity whereas complex responses typical of the awake brain were present when stimulating the contralesional hemisphere. These results shed light on the electrophysiological properties of the tissue surrounding focal brain injuries in humans. Perilesional sleep-like off-periods can disrupt network activity but are potentially reversible, thus representing a principled read-out for the neurophysiological assessment of stroke patients, as well as an interesting target for rehabilitation.

ALS-CSF-induced structural changes in spinal motor neurons of rat pups cause deficits in motor behaviour.

Amyotrophic lateral sclerosis (ALS) is a late-onset, neurodegenerative disease associated with the loss of motor neurons in the spinal cord, brain stem and primary motor cortex. Deficit in the motor function is one of the clinical features of this disease. However, the association between adverse morphological alterations in the spinal motor neurons and motor deficit in sporadic ALS (SALS) is still debated. The present study has sought to investigate the effects of serial intrathecal injections of ALS-CSF into rat pups, at post-natal (P) days 3, 9 and 14, on the motor neuronal (MN) morphology at the cervical and lumbar levels of the spinal cord at P16 and P22. The present study used Cresyl violet and Golgi-Cox staining methods to determine the progressive changes in the morphology of spinal MNs in both cervical and lumbar extensions. The study found a loss of motor neurons in the spinal cord (36% for P16 in cervical and 41.7% in P16 lumbar and 49.57% for P22 cervical and 44.63% for P22 lumbar) and reduced choline acetyl transferase (ChAT) expression after repeated infusion of ALS-CSF. Significant increase in the soma area was also found in ALS-CSF rats (around 21% in P22 cervical and 26.4% in P22 lumbar). Soma hypertrophy was associated with increased dendritic arborization of MNs at both cervical and lumbar levels of the spinal cord. The data also showed a direct correlation between ALS-CSF induced changes in the MN number in the spinal cord and motor behavioral deficits. The loss of MNs, reduced ChAT, changes in soma and dendritic morphology with declined rotarod performance, thus, confirming the pathological phenotypes as seen in ALS patients.

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

SummaryAcute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca2+/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation, and reversed HX-induced astrogliosis. We performed for the first time high-throughput transcriptomic analysis of the piglet cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in piglet and human brain injury. Our results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

Improvement of Pursuit Eye Movement Alterations after Short Visuo-Attentional Training in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder without validated and objective diagnostic procedures. Several neurological dysfunctions in the frontal circuit, in the thalamus, and in the cerebellum have been observed in subjects with ADHD. These cortical and subcortical areas are responsible for eye movement control. Therefore, studying eye movements could be a useful tool to better understand neuronal alterations in subjects with ADHD. The aim of the present study was firstly to compare the quality of pursuit eye movements in a group of 40 children with ADHD (age 8.2 ± 1.2) and in a group of 40 sex-, IQ-, age-matched typically developing (TD) children; secondly, we aimed to examine if a short visuo-attentional training could affect pursuit performances in children with ADHD. Findings showed that children with ADHD presented a greater number of catch-up saccade and lower pursuit gain compared to TD children. Differently to TD children, in children with ADHD, the number of catch-up saccades and the pursuit gain were not significantly correlated with children’s age. Furthermore, a short visuo-attentional training period can only slightly improve pursuit performance in children with ADHD, leading to a decrease of the occurrence of catch-up saccades only, albeit the effect size was small. The absence of any improvement in pursuit performance with age could be explained by the fact that the prefrontal and fronto-cerebellar circuits responsible for pursuit triggering are still immature. Pursuit eye movements can be used as a useful tool for ADHD diagnosis. However, attentional mechanisms controlled by these cortical structures could be improved by a short visuo-attentional training period. Further studies will be necessary to explore the effects of a longer visuo-attentional training period on oculomotor tasks in order to clarify how adaptive mechanisms are able to increase the attentional capabilities in children with ADHD.

Social cognition correlation to white matter integrity alteration in mirror neurons of schizophrenic patients: DTI study

BackgroundIt is postulated that mirror neurons (MNs) abnormalities are associated with social skills. ObjectivesUsing DTI, altered structural connectivity and its association with social cognition in MNs-hub regions was investigated in schizophrenia in comparison to healthy. MethodsFifteen patients with schizophrenia in their first episode and 15 healthy controls were included in this study. They were subjected to the Structured Clinical Interview for DSM-IV Axis I Disorder (SCID-I), Scale for the Assessment of Negative Symptoms (SANS), with special consideration to “Anhedonia and Asociality” subscale, Scale for the Assessment of Positive Symptoms (SAPS) and a comprehensive cognitive assessment. DTI scans were acquired in patients and controls. FA and Trace of the regions of interest rich in mirror neurons were evaluated, i.e., anterior cingulate cortex (ACC), inferior parietal lobe (IPL) and premotor cortex (PMC). ResultsA significant difference in Trace of these 3 regions was observed in schizophrenia patients. There were no group differences in FA. There was a significant positive correlation between the Trace of the right IPL and right and left PMA, with the “Anhedonia & Associability” subscale. ConclusionsMirror neuron system in schizophrenia patients might be connected to negative symptoms, more specifically, to social deficits.

Differential alterations of insular cortex excitability after adolescent or adult chronic intermittent ethanol administration in male rats.

Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21days, relative to 2days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.

Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds

Recent studies suggest that misfolded tau molecules can be released, and taken up by adjacent neurons, propagating proteopathic seeds across neural systems. Yet critical to understanding whether tau propagation is relevant in pathophysiology of disease would be to learn if it alters neuronal properties. We utilized high resolution multi-color in situ hybridization technology, RNAScope, in a well-established tau transgenic animal, and found that a subset of neurons in the cortex do not appear to express the transgene, but do develop phospho-tau positive inclusions, consistent with having received tau seeds. Recipient neurons show decreases in their expression of synaptophysin, CAMKIIα, and mouse tau in both young and old animals. These results contrast with neurons that develop tau aggregates and also overexpress the transgene, which have few changes in expression of metabolic and synaptic markers. Taken together, these results strongly suggest that tau propagation impacts neuronal functional integrity.

Disruption of Cholinergic Circuits as an Area for Targeted Drug Treatment of Alzheimer's Disease: In Vivo Assessment of Short-Term Plasticity in Rat Brain.

The search for new therapeutics for the treatment of Alzheimer’s disease (AD) is still in progress. Aberrant pathways of synaptic transmission in basal forebrain cholinergic neural circuits are thought to be associated with the progression of AD. However, the effect of amyloid-beta (Aβ) on short-term plasticity (STP) of cholinergic circuits in the nucleus basalis magnocellularis (NBM) is largely unknown. STP assessment in rat brain cholinergic circuitry may indicate a new target for AD cholinergic therapeutics. Thus, we aimed to study in vivo electrophysiological patterns of synaptic activity in NBM-hippocampus and NBM-basolateral amygdala circuits associated with AD-like neurodegeneration. The extracellular single-unit recordings of responses from the hippocampal and basolateral amygdala neurons to high-frequency stimulation (HFS) of the NBM were performed after intracerebroventricular injection of Aβ 25–35. We found that after Aβ 25–35 exposure the number of hippocampal neurons exhibiting inhibitory responses to HFS of NBM is decreased. The reverse tendency was seen in the basolateral amygdala inhibitory neural populations, whereas the number of amygdala neurons with excitatory responses decreased. The low intensity of inhibitory and excitatory responses during HFS and post-stimulus period is probably due to the anomalous basal synaptic transmission and excitability of hippocampal and amygdala neurons. These functional changes were accompanied by structural alteration of hippocampal, amygdala, and NBM neurons. We have thus demonstrated that Aβ 25–35 induces STP disruption in NBM-hippocampus and NBM-basolateral amygdala circuits as manifested by unbalanced excitatory/inhibitory responses and their frequency. The results of this study may contribute to a better understanding of synaptic integrity. We believe that advancing our understanding of in vivo mechanisms of synaptic plasticity disruption in specific neural circuits could lead to effective drug searches for AD treatment.

Dual/double pathology in neurocysticercosis causing drug resistant epilepsy – Chance association or causal?

IntroductionNeurocysticercosis (NCC) as cause of drug resistant epilepsy (DRE) is commonly reported from India. We reviewed the neuropathological findings in patients undergoing resective surgery for DRE due to NCC, to determine the pathomechanism of epileptogenesis. MethodsClinical, demographic and neuropathological findings of histologically confirmed cases of NCC causing DRE between 2005–2019 were reviewed. NeuN, GFAP, phosphorylated neurofilament, vimentin, CD34 for glial/ neuronal alterations, and Masson trichrome, Luxol Fast blue for evidence of fibrosis/ demyelination was used to determine cause of epileptogenesis. ResultsThere were 12 cases of NCC associated with dual/ double pathology, which constituted 3.02 % (12/398) of all the operated DRE. [Age range: 17–37y, Male:Female = 1.4:1]. Seizure duration ranged from 3–32y, with seizure onset between 4–27y. On MRI, lesions were of variable signal intensity on T1 and isointense on T2 with blooming on GRE/ SWI, and CT revealed calcification.Majority (11/12) had associated hippocampal sclerosis (HS) type 1 (dual pathology), localised to the same side as cysticercal cyst, suggesting it may be involved in the pathogenesis of HS. Ten had single cysticercal lesion involving ipsilateral hippocampus in 6, parahippocampal gyrus in 2, amygdala and temporal lobe in 1 case each. One had multiple NCC located in bilateral frontal, parietal and ipsilateral hippocampus. Adjacent cortex around the NCC evaluated in 6 cases, revealed inflammation, gliosis, axonal disruption/ beading, and variable synaptic/ neuronal dystrophic changes. There was a single case of NCC with Focal cortical dysplasia (FCD) type IIb (double pathology). In 11/12 cases Engel’s post-surgery outcome was available with all having class I outcome. ConclusionHS was most common pathology associated with cysticercosis (Dual pathology), localised ipsilateral to the cysticercal cyst, suggesting that HS is a secondary/ epiphenomenon. Perilesional changes such as inflammation, gliosis, dystrophic synaptic and axonal pathology play a role in inducing or perpetuating the epileptiform activity. The association of FCD IIb with NCC in one case is likely to be a chance occurrence.