Alcohol abuse is not only responsible for 5.3% of the total deaths in the world, but also has a substantial impact on neurological and memory disabilities throughout the population. One extensively studied brain area involved in cognitive functions is the hippocampus. Evidence in several rodent models has shown that ethanol produces cognitive impairment in hippocampal-dependent tasks and that the damage is varied according to the stage of development at which the rodent was exposed to ethanol and the dose. To the authors’ knowledge, there is a biomarker for cognitive processes in the hippocampus that has not been evaluated in association with memory impairment by alcohol administration. This biomarker is called Sharp Wave Ripples which are synchronous neuronal population events that are well known to be involved in memory consolidation. Methodologies for facilitation or automatic identification of ripples and their analysis have been reported for a wider bandwidth than Sharp Wave Ripples. This review is focused on communicating the state-of-the art about the relationship between alcohol, memory consolidation and ripple activity as well as the use of the main methodologies to identify SWRs automatically.

It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signaling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. The cognitive ability was assessed by novel object recognition task (NORT) and Morris water maze (MWM) test. Immunofluorescence, Golgi-cox staining were used to observe dendritic synaptic. Gamma oscillation in hippocampus CA1 was performed by Tetrode in-vivo recording. Prostaglandins were measured by HPLC/mass spectrometry. We observed the expressions of cyclic adenosine monophosphate (cAMP)/ brain-derived neurotrophic factor (BDNF) pathway proteins in hippocampus and N2a cells by Elisa and western blot. We found COX-2 gene knockout (KO) could significantly impact the learning and memory ability; reduce the expression of postsynaptic density protein 95 (PSD95) in the neuron; cause synaptic disorder; influence gamma oscillation and reduce the expression prostaglandin (PG) E2, cAMP, phosphorylated protein kinase A (p-PKA), phosphorylated cAMP response element binding protein (p-CREB) and BDNF in the hippocampus. It suggested COX-2 might play a critical role in learning, regulating synaptic plasticity and gamma oscillation in the hippocampus CA1 by regulating COX-2/BDNF signaling pathway.

Sepsis is a life-threatening organ dysfunction that results from dysregulated host response to infection. Multiple organ system dysfunction syndromes are prevalent among septic patients and are essential hallmarks of sepsis diagnosis. These syndromes involve failure of the pulmonary, hepatic, circulatory, renal, gastrointestinal and central nervous systems. Neurological dysfunction is part of this syndrome and has gained research attention recently [1]. Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioral deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioral impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+-dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO) which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.

Multimodal studies evaluating associations between specific for Parkinson’s disease (PD) neuroimaging and neurophysiological biomarkers in revealing executive dysfunction mechanisms are scarce and needed to be validated. Hence, our study aimed to evaluate associations between electroencephalographic power spectral density (PSD-EEG), striatal [18F]Fluorodopa uptake and neuropsychological testing parameters in PD. Additional aim was to estimate PD diagnostic accuracy of the PSD-EEG parameters. We compared resting PSD-EEG, striatal [18F]Fluorodopa uptake ratio with positron emission computed tomography ([18F]FDOPA PET/CT), and neuropsychological test outcomes between PD patients and healthy controls, and then calculated correlations among these outcomes. Additionally we estimated PD diagnostic sensitivity and specificity (with the receiver operating characteristic curves) of the PSD-EEG parameters in reference to the gold diagnostic standard of the striatal [18F]FDOPA PET/CT uptake ratio.PD patients exhibited (i) increased power of the EEG theta and lower-alpha bands in the frontal lobe areas, (ii) decreased putaminal and caudate nuclei [18F]FDOPA PET/CT uptake ratios and (iii) longer performance times of part A and B of the Trail Making Test (TMT-A and TMT-B). Most of the PSD-EEG parameters negatively correlated with striatal [18F]FDOPA PET/CT uptake ratios and positively correlated with TMT-A and TMT-B. Furthermore, [18F]FDOPA PET/CT uptake ratios positively correlated with TMT-A and TMT-B. Theta and lower-alpha bands PSD-EEG were found to have high diagnostic accuracy. Our findings showed that slowing of EEG waves in the frontal lobe was correlated with striatal dopaminergic deficiency and executive dysfunction in mild PD patients, and appears to be a promising biomarker of PD-related executive dysfunction.

Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic, and optogenetic approaches now provide causal evidence for dopamine's role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction, and convey the signal via activation of D1-4 receptor sites particularly in the amygdala, prefrontal cortex, and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval, and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.

Parkinson’s disease is a neurodegenerative disorder characterized by the progressive dysfunction and loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in DA neuron death, such as apoptosis, necrosis, pyroptosis, ferroptosis as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying DA neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 (RIP1) and its kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 (RIP3) and its kinase (RIP3 kinase, RIPK3), and mixed lineage kinase domain like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analyzing the biomarkers for necroptosis, such as the levels and oligomerization of pRIPK3 and pMLKL, in several PD preclinical models and in PD human tissue. While there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Thus drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD.

Many clinical and research efforts aim to develop antidepressant drugs for those suffering from major depressive disorder (MDD). Yet even today, the available treatments are suboptimal and unpredictable, with a significant proportion of patients enduring multiple drug attempts and adverse side effects before a successful response; and for many patients, no response at all. Thus, a clearer understanding of the mechanisms underlying MDD is necessary. In the “Brain Development and Disease” class of our Master’s program in Cognitive Sciences, we ask students to collect data about the expression of a gene whose altered expression and/or function is related to a brain disorder. The students’ final exam assignment consists of writing a research article in which the collected data are discussed in relation to the relevant disorder. In the course of one of these assignments, we identified the FKBP5 gene as a key player uniting two major hypotheses of MDD pathogenesis and treatment response. FKBP5 controls biological processes including immunoregulation and glucocorticoid function, both of which are separately implicated in the development and prognosis of MDD. Gene expression analyses from the human, non-human primate, and mouse Allen Brain Atlases revealed that FKBP5 is expressed in brain regions involved in MDD, particularly at ages susceptible to early-life stressors. Data re-analysis from published studies confirmed that FKBP5 expression is upregulated in relevant brain regions in human MDD and preclinical mouse models of MDD. Our experience shows that classes engaging students in data collection and analysis projects may effectively result in novel data-driven hypotheses.

Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase), and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded four weeks after nerve transection and repair and two weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 hours with CP11, neurites were nearly 50% longer than in vehicle-treated controls, and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signaling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.

As we speak, corollary discharge mechanisms suppress the auditory conscious perception of the self-generated voice in healthy subjects. This suppression has been associated with the attenuation of the auditory N1 component. To analyze this corollary discharge phenomenon (agency and ownership), we registered the Event-Related Potentials of forty-two healthy subjects. The N1 and P2 components were elicited by spoken vowels (talk condition; agency), by played-back vowels recorded with their own voice (listen-self condition; ownership), and by played-back vowels recorded with an external voice (listen-other condition). The N1 amplitude elicited by the talk condition was smaller compared to the listen-self and listen-other conditions. There were no amplitude differences in N1 between listen-self and listen-other conditions. The P2 component did not show differences between conditions. Additionally, a peak latency analysis of N1 and P2 components between the three conditions showed no differences. These findings corroborate previous results showing that the corollary discharge mechanisms dampen sensory responses to self-generated speech (agency experience), and provide new neurophysiological evidence about the similarities in the processing of played-back vowels with our own voice (ownership experience) and with an external voice.

Combining magnetic resonance imaging (MRI) data from multi-site studies is a popular approach for constructing larger datasets to greatly enhance the reliability and reproducibility of neuroscience research. However, the scanner/site variability is a significant confound that complicates the interpretation of the results, so effective and complete removal of the scanner/site variability is necessary to realize the full advantages of pooling multi-site datasets. Independent component analysis (ICA) and general linear model (GLM) based harmonization methods are the two primary methods used to eliminate scanner/site-related effects. Unfortunately, there are challenges with both ICA-based and GLM-based harmonization methods to remove site effects completely when the signals of interest and scanner/site-related variables are correlated, which may occur in neuroscience studies. In this study, we propose an effective and powerful harmonization strategy that implements dual-projection (DP) theory based on ICA to remove the scanner/site-related effects more completely. This method can separate the signal effects correlated with site variables from the identified site-related effects for removal without losing signals of interest. Both simulations and vivo structural MRI datasets, including a dataset from Autism Brain Imaging Data Exchange II and a traveling subject dataset from the Strategic Research Program for Brain Sciences, were used to test the performance of DP-based ICA harmonization method. Results show that DP-based ICA harmonization has superior performance for removing site effects and enhancing the sensitivity to detect signal of interest as compared with GLM-based and conventional ICA harmonization methods.

Functional connectivity (FC) indicates the interdependencies between brain signals recorded from spatially distinct locations in different frequency bands, which is modulated by cognitive tasks and is known to change with aging and cognitive disorders. Recently, the power of narrow-band gamma oscillations induced by visual gratings has been shown to reduce with both healthy aging and in subjects with mild cognitive impairment (MCI). However, the impact of aging/MCI on stimulus-induced gamma FC has not been well studied. We recorded electroencephalogram (EEG) from a large cohort (N=229) of elderly subjects (>49 years) while they viewed large cartesian gratings to induce gamma oscillations and studied changes in alpha and gamma FC with healthy aging (N=218) and MCI (N=11). Surprisingly, we found that aging and disease changed power and FC in different ways. With healthy aging, alpha power did not change but FC decreased significantly. MCI reduced gamma but not alpha FC significantly compared with age and gender matched controls, even when power was matched between the two groups. Overall, our results show distinct effects of aging and disease on EEG power and FC, suggesting different mechanisms underlying aging and cognitive disorders.

A document by Michael Willis. Click on the document to view its contents.

The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in-vivo and in-vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol, and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal CGRP release in-vitro hemiskull preparations. Mechanical allodynia was tested by von-Frey filaments. CGRP concentrations in trigeminovascular structures and in-vitro superfusates, and c-Fos levels in brainstem were determined by ELISA. Meningeal-mast cells were evaluated with toluidine-blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations, and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in-vitro, while the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated migraine pain by further enchancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migrane like conditions.

A document by Jinfeng Huang. Click on the document to view its contents.

Parkinson’s Disease (PD) and vitamin D share a unique link as Vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of Vitamin D biology in PD might be crucial for therapeutic strategies emphasizing Vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (Vitamin D Receptor) or GC (Vitamin D Binding Protein), may aid the process along with polymorphisms of Vitamin D metabolizing genes (e.g., CYP2R1, CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to Vitamin D levels [GC (GC1-rs7041, GC2-rs4588), CYP2R1, CYP24A1, CYP27B1] and Vitamin D function [VDR (FokI - rs2228570, ApaI - rs7976091, BsmI-rs1544410, TaqI-rs731236)] was conducted to explore their relationship with PD severity globally. Furthermore, the DisGeNET database was utilized to explore the gene-disease associations in PD, and STRING alongside Cytoscape was utilized to identify critical genes associated with PD. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese, and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected Vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, and thereby influencing PD pathophysiology. Knowledge of the polymorphisms associated with vitamin D appears promising for developing new therapeutic strategies against PD.

It is well known that the nervous system adjusts itself to its environment during development. Although a great deal of effort has been directed toward understanding the developmental processes of the individual sensory systems (e.g., vision, hearing, etc.), only one major study has examined the maturation of multisensory processing of cortical neurons. Therefore, the present investigation sought to evaluate multisensory development in a different cortical region and species. Using multiple single-unit recordings in anesthetized ferrets (n=18) of different ages (from postnatal day 80 through 300), we studied the responses of neurons from the rostral posterior parietal area (PPr) to presentations of visual, tactile and combined visual-tactile stimulation. The results showed that multisensory neurons were infrequent at the youngest ages (pre-pubertal) and progressively increased through the later ages. Significant response changes that result from multisensory stimulation (defined as multisensory integration, MSI) were observed in post-pubertal adolescent animals and the magnitude of these integrated responses also increased across this age group. Furthermore, non-significant multisensory response changes were progressively increased in adolescent animals. Collectively, at the population level, MSI was observed to shift from primarily suppressive levels in infants to increasingly higher levels in later stages. These data indicate that, like the unisensory systems from which it is derived, multisensory processing shows developmental changes the specific time course of which may be regionally and species dependent.

Post-stroke depression (PSD), a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, PSD treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to PSD; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases, and neurotransmitters influence depressive behavior by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in PSD by summarizing recent research and analyzing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and PSD helps to better understand the pathological process of PSD and improve its treatment.

Background: Cross-education, a phenomenon where unilateral strength (or skill) training enhances strength (or skill) in the contralateral untrained limb, has been well studied in able-bodied individuals. However, whether non-paretic leg movements can modulate corticomotor excitability (CME) and improve motor control of the paretic leg in stroke remains unclear. Objective: To determine the effects of non-paretic leg movements on corticomotor responses and motor control of the paretic leg in persons with severe stroke. Methods: Seventeen post stroke individuals with severe leg motor impairment performed three 20-min motor trainings using their non-paretic ankle: skill (targeted dynamic movements), strength (isometric resistance), and sham (sub-threshold electrical nerve stimulation). Transcranial magnetic stimulation measured CME of the contralateral pathways from the non-lesioned motor cortex (M1) to the non-paretic tibialis anterior (TA) muscle, ipsilateral pathways to the paretic TA, and transcallosal inhibition (TCI) from the non-lesioned to lesioned M1. Paretic ankle motor control was measured using a reaction time paradigm. Results: CME of the non-paretic TA increased after skill (23%) and strength (19%) training (p<0.01). Ipsilateral CME of the paretic TA (23%) and TCI (36%) increased after skill (p<0.05) but not strength training. Reaction time of the paretic ankle improved after skill and strength training (~12%; p<0.05) and was sustained at 60 minutes. No changes were observed during the sham condition. Conclusion: Our findings may inform future studies for using non-paretic leg movements as a priming modality, especially for those who are contraindicated to other priming paradigms (e.g., brain stimulation) or unable to perform paretic leg movements.