Prenatal Exposure to High Cortisol Induces ADHD-like Behaviors with Delay in Spatial Cognitive Functions during the Post-weaning Period in Rats

Sang-Chan Jeon,Hye-Ji Kim,Eun-A Ko,Sung-Cherl Jung 한국뇌신경과학회 2021 Experimental Neurobiology Vol.30 No.1

High levels of cortisol in blood are frequently observed in patients with major depressive disorders and increased cortisol level induces depressivelike symptoms in animal models. However, it is still unclear whether maternal cortisol level during pregnancy is a critical factor resulting in neuropsychiatric disorders in offspring. In this study, we increased cortisol level in rats by repetitively injecting corticosterone subcutaneously (Corti. Mom, 20 mg/kg/day) during pregnancy and evaluated the behavioral patterns of their pups (Corti.Pups) via forced swimming (FS), open field (OF), elevated plus maze (EPM) and Morris water maze (MWM) tests during the immediate post-weaning period (postnatal day 21 to 25). In results, corticosterone significantly increased plasma cortisol levels in both Corti.Moms and Corti.Pups. Unlike depressive animal models, Corti.Pups showed higher hyperactive behaviors in the FS and OF tests than normal pups (Nor.Pups) born from rats (Nor.Moms) treated with saline. Furthermore, Corti.Pups spent more time and traveled longer distance in the open arms of EPM test, exhibiting higher extremity. These patterns were consistent with behavioral symptoms observed in animal models of attention deficit hyperactivity disorder (ADHD), which is characterized by hyperactivity, impulsivity, and inattention. Additionally, Corti.Pups swam longer and farther to escape in MWM test, showing cognitive declines associated with attention deficit. Our findings provide evidence that maternal cortisol level during pregnancy may affect the neuroendocrine regulation and the brain development of offspring, resulting in heterogeneous developmental brain disorders such as ADHD.

Quantitative Proteomic Analysis Reveals Impaired Axonal Guidance Signaling in Human Postmortem Brain Tissues of Chronic Traumatic Encephalopathy

Baibin Bi,최한필,현승재,Shengnan Sun,Ning Su,Yuguang Liu,이정희,Neil W Kowall,Ann C McKee,Jing-Hua Yang,류훈 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.3

Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that associated with repetitive head trauma. CTE is neuropathologically defined by the perivascular accumulation of abnormally phosphorylated tau protein in the depths of the sulci in the cerebral cortices. In advanced CTE, hyperphosphorylated tau protein deposits are found in widespread regions of brain, however the mechanisms of the progressive neurodegeneration in CTE are not fully understood. In order to identify which proteomic signatures are associated with CTE, we prepared RIPA-soluble fractions and performed quantitative proteomic analysis of postmortem brain tissue from individuals neuropathologically diagnosed with CTE. We found that axonal guidance signaling pathwayrelated proteins were most significantly decreased in CTE. Immunohistochemistry and Western blot analysis showed that axonal signaling pathway-related proteins were down regulated in neurons and oligodendrocytes and neuron-specific cytoskeletal proteins such as TUBB3 and CFL1 were reduced in the neuropils and cell body in CTE. Moreover, oligodendrocyte-specific proteins such as MAG and TUBB4 were decreased in the neuropils in both gray matter and white matter in CTE, which correlated with the degree of axonal injury and degeneration. Our findings indicate that deregulation of axonal guidance proteins in neurons and oligodendrocytes is associated with the neuropathology in CTE. Together, altered axonal guidance proteins may be potential pathological markers for CTE.

Memantine Improves Cognitive Function and Alters Hippocampal and Cortical Proteome in Triple Transgenic Mouse Model of Alzheimer’s Disease

Xinhua Zhou,Liang Wang,Wei Xiao,Zhiyang Su,Chengyou Zheng,Zaijun Zhang,Yu Qiang Wang,Benhong Xu,Xifei Yang,Maggie Pui Man Hoi 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.3

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer’s disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.

FxClear, A Free-hydrogel Electrophoretic Tissue Clearing Method for Rapid De-lipidation of Tissues with High Preservation of Immunoreactivity

Jungyoon Choi,이은수,June Hoan Kim,선웅 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.3

Over the last two decades, several tissue clearing methodologies have been established that render tissues optically transparent and allow imaging of unsectioned tissues of significant volumes, thus improving the capacity to study the relationships between cell and 3D tissue architecture. Despite these technical advances, the important unsolved challenges that these methods face include complexity, time, consistency of tissue size before and after clearing, and ability to immunolabel various antibodies in cleared tissue. Here, we established very simple and fast tissue clearing protocol, FxClear, which involves acrylamide-free electrophoretic tissue clearing (ETC). By removal of the acrylamide infusion step, we were able to achieve fast reaction time, smaller tissue expansion, and higher immunoreactivity. Especially, immunoreactivity and fluorescence intensity were increased in FxClear-processed tissues compared to un-cleared tissues. Our protocol may be suitable for small-sized biopsy samples for 3D pathological examinations.

A Computational Modeling Reveals That Strength of Inhibitory Input, E/I Balance, and Distance of Excitatory Input Modulate Thalamocortical Bursting Properties

박상건,손정우,조재원,허여울 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.5

The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.

Mental Disorders Linked to Crosstalk between The Gut Microbiome and The Brain

최태용,최영표,구자욱 한국뇌신경과학회 2020 Experimental Neurobiology Vol.29 No.6

Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.

Diffusion MRI Connections in the Octopus Brain

Russell E. Jacobs 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.1

Using high angle resolution diffusion magnetic resonance imaging (HARDI) with fiber tractography analysis we map out a meso-scale con- nectome of the Octopus bimaculoides brain. The brain of this cephalopod has a qualitatively different organization than that of vertebrates, yet it exhibits complex behavior, an elaborate sensory system and high cognitive abilities. Over the last 60 years wide ranging and detailed studies of octopus brain anatomy have been undertaken, including classical histological sectioning/staining, electron microscopy and neuronal tract tracing with injected dyes. These studies have elucidated many neuronal connections within and among anatomical structures. Diffusion MRI based trac- tography utilizes a qualitatively different method of tracing connections within the brain and offers facile three-dimensional images of anatomy and connections that can be quantitatively analyzed. Twenty-five separate lobes of the brain were segmented in the 3D MR images of each of three samples, including all five sub-structures in the vertical lobe. These parcellations were used to assay fiber tracings between lobes. The connectivity matrix constructed from diffusion MRI data was largely in agreement with that assembled from earlier studies. The one major difference was that connections between the vertical lobe and more basal supra-esophageal structures present in the literature were not found by MRI. In all, 92 con- nections between the 25 different lobes were noted by diffusion MRI: 53 between supra-esophageal lobes and 26 between the optic lobes and other structures. These represent the beginnings of a mesoscale connectome of the octopus brain.

Neonatal Mice Spinal Cord Interneurons Send Axons through the Dorsal Roots

Osuna-Carrasco Laura Paulina,Dueñas-Jiménez Sergio Horacio,Toro-Castillo Carmen,De la Torre Braniff,Aguilar-García Irene,Alpirez Jonatan,Castillo Luis,Dueñas-Jiménez Judith Marcela 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.2

Spontaneous interneuron activity plays a critical role in developing neuronal networks. Discharges conducted antidromically along the dorsal root (DR) precede those from the ventral root’s (VR) motoneurons. This work studied whether spinal interneurons project axons into the neonate’s dorsal roots. Experiments were carried out in postnatal Swiss-Webster mice. We utilized a staining technique and found that interneurons in the spinal cord’s dorsal horn send axons through the dorsal roots. In vitro electrophysiological recordings showed antidromic action potentials (dorsal root reflex; DRR) produced by depolarizing the primary afferent terminals. These reflexes appeared by stimulating the adjacent dorsal roots. We found that bicuculline reduced the DRR evoked by L5 dorsal root stimulation when recording from the L4 dorsal root. Simultaneously, the monosynaptic reflex (MR) in the L5 ventral root was not affected; nevertheless, a long-lasting after-discharge appeared. The addition of 2-amino-5 phosphonovaleric acid (AP5), an NMDA receptor antagonist, abolished the MR without changing the after-discharge. The absence of DRR and MR facilitated single action potentials in the dorsal and ventral roots that persisted even in low Ca2+ concentrations. The results suggest that firing interneurons could send their axons through the dorsal roots. These interneurons could activate motoneurons producing individual spikes recorded in the ventral roots. Identifying these interneurons and the persistence of their neuronal connectivity in adulthood remains to be established.

Astrocyte-targeted Overproduction of IL-10 Reduces Neurodegeneration after TBI

Shanaki-Barvasad Mahsa,Almolda Beatriz,González Berta,Castellano Bernardo 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.3

Traumatic brain injury is the greatest cause of disability and death in young adults in the developed world. The outcome for a TBI patient is determined by the severity of the injury, not only from the initial insult but, especially, as a product of the secondary injury. It is proposed that this secondary injury is directly linked to neuro-inflammation, with the production of pro-inflammatory mediators, activation of resident glial cells and infiltration of peripheral immune cells. In this context, anti-inflammatory treatments are one of the most promising therapies to dampen the inflammatory response associated with TBI and to reduce secondary injury. In this sense, the main objective of the present study is to elucidate the effect of local production of IL-10 in the neurological outcome after TBI. For this purpose, a cryogenic lesion was caused in transgenic animals overproducing IL-10 under the GFAP promoter on astrocytes (GFAP-IL10Tg mice) and the neuro-protection, microglial activation and leukocyte recruitment were evaluated. Our results showed a protective effect of IL-10 on neurons at early time-points after TBI, in correlation with a shift in the microglial activation profile towards a down-regulating phenotype and lower production of pro-inflammatory cytokines. Concomitantly, we observed a reduction in the BBB leakage together with modifications in leukocyte infiltration into the affected area. In conclusion, local IL-10 production modifies the neuro-inflammatory response after TBI, shifting it to anti-inflammatory and neuro-protective conditions. These results point to IL-10 as a promising candidate to improve neuro-inflammation associated with TBI.

Blood-brain Barrier Damage is Pivotal for SARS-CoV-2 Infection to the Central Nervous System

Rodríguez-Morales Jahir,Guartazaca-Guerrero Sebastián,Rizo-Téllez Salma A.,Viurcos-Sanabria Rebeca,Barrón Eira Valeria,Hernández-Valencia Aldo F.,Nava Porfirio,Escobedo Galileo,Carrillo-Ruiz José Dami 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.4

Transsynaptic transport is the most accepted proposal to explain the SARS-CoV-2 infection of the CNS. Nevertheless, emerging evidence shows that neurons do not express the SARS-CoV-2 receptor ACE2, which highlights the importance of the blood-brain barrier (BBB) in preventing virus entry to the brain. In this study, we examine the presence of SARS-CoV-2 messenger ribonucleic acid (mRNA) and the cytokine profile in cerebrospinal fluids (CSF) from two patients with a brain tumor and COVID-19. To determine the BBB damage, we evaluate the Q- albumin index, which is an indirect parameter to assess the permeability of this structure. The Q-albumin index of the patient with an intraventricular brain tumor suggests that the BBB is undamaged, preventing the passage of SARS-CoV-2 and pro-inflammatory molecules. The development of brain tumors that disrupt the BBB (measured by the Q-albumin index), in this case, a petroclival meningioma (Case 1), allows the free passage of the SARS-CoV-2 virus and probably lets the free transit of pro-inflammatory molecules to the CNS, which leads to a possible activation of the microglia (astrogliosis) and an exacerbated immune response represented by IL-13, IFN-γ, and IL-2 trying to inhibit both the infection and the carcinogenic process.