FKN/CX3CR1 Axis Facilitated Migraine-like Behaviors via Activating Thalamic-cortical Network Microglia in SE Rat Models

Abstract Background: The incidence of migraines is higher among people with epilepsy than healthy people, and these two common diseases are proposed to have some shared pathophysiological mechanisms. Excitation/inhibition imbalance plays an essential role in the comorbidity of epilepsy and migraine. Microglia activation is crucial for abnormal neuronal signal transmission. However, whether and how microglia are activated, and their role in comorbidities after activation remains unclear. This study aimed to explore the characteristics and mechanism of microglia activation after seizures and its effect on migraine.Methods: Status epilepticus (SE) rat models induced by lithium chloride (LiCl)-pilocarpine intraperitoneal injection and migraine rat models induced by repeated inflammatory soup (IS) dural injections were generated and assessed for molecular and histopathologic evidence of microglial activation target of fractalkine (FKN) signaling. HT22-BV2 transwell coculture was used to explore the interaction between neurons and microglia. LPS (a microglia agonist) and FKN stimulation of BV2 microglia cells were used to evaluate changes in BDNF content after microglia activation.Results: Microglia were specifically hyperplasia and activation in the cortical-thalamus-sp5c neural circuit, which were pain-related brain regions, accompanied by the upregulation of FKN and CX3CR1 four days after seizures. Meanwhile, SE-induced increased nociceptive behavior and the FKN/CX3CR1 axis in migraine rat models. AZD8797 (a CX3CR1 inhibitor) prevented the worsening of hyperalgesia and microglia activation in migraine rat models after seizures, while FKN infusion in migraine rat models exacerbated hyperalgesia and microglia activation associated with BDNF-Trkb signaling. Furthermore, in neuron-BV2 coculture, microglial activation and FKN/CX3CR1/BDNF/iba1 expression were increased. Activating microglia with LPS and FKN stimulation increased BDNF synthesis in BV2 microglia.Conclusions: Our results indicated that epilepsy facilitated migraine through the cortical-thalamus-sp5c microglia activated and interactions with neurons by the FKN/CX3CR1 axis, resulting in BDNF release. Blocking the FKN/CX3CR1 axis and microglia activation are potential therapeutic targets for preventing and treating migraine in patients with epilepsy.

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Inflammational Animal Models for Schizophrenia

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000216 ◽

2015 ◽

Vol 223 (3) ◽

pp. 157-164 ◽

Cited By ~ 1

Author(s):

Georg Juckel

Keyword(s):

Animal Model ◽

Animal Models ◽

Immune Activation ◽

Microglial Activation ◽

Treatment Options ◽

Early Adulthood ◽

Brain Regions ◽

Synaptic Connections ◽

Preventive Interventions ◽

Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

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Synergistic Effect of Several Neurotransmitters in PFC-NAc-VTA Neural Circuit for the Anti-Depression Effect of Shuganheweitang in a Chronic Unpredictable Mild Stress Model

Natural Product Communications ◽

10.1177/1934578x211002415 ◽

2021 ◽

Vol 16 (3) ◽

pp. 1934578X2110024

Author(s):

Xin Chen ◽

Yuanchun Ma ◽

Xiongjun Mou ◽

Hao Liu ◽

Hao Ming ◽

...

Keyword(s):

Animal Behavior ◽

Neural Circuit ◽

Concentration Level ◽

Brain Regions ◽

Mild Stress ◽

Depression Effect ◽

Monoamine Neurotransmitters ◽

Reward Circuitry ◽

High Doses ◽

The Brain

Depression, a major worldwide mental disorder, leads to massive disability and can result in death. The PFC-NAc-VTA neuro circuit is related to emotional, neurovegetative, and cognitive functions, which emerge as a circuit-level framework for understanding reward deficits in depression. Neurotransmitters, which are widely distributed in different brain regions, are important detected targets for the evaluation of depression. Shuganheweitang (SGHWT) is a popular prescription in clinical therapy for depression. In order to investigate its possible pharmacodynamics and anti-depressive mechanism, the complex plant material was separated into different fractions. These in low and high doses, along with low and high doses of SGHWT were tested in animal behavior tests. The low and high doses of SGHWT were more effective than the various fractions, which indicate the importance of synergistic function in traditional Chinese medicine. Furthermore, amino acid (GABA, Glu) and monoamine neurotransmitters (DA, 5-HT, NA, 5-HIAA) in the PFC-NAc-VTA neuro circuit were investigated by UPLC-MS/MS. The level trend of DA and 5-HT were consistent in the PFC-NAc-VTA neuro circuit, whereas 5-HIAA was decreased in the PFC, Glu was decreased in the PFC and VTA, and NA and GABA were decreased in the NAc. The results indicate that the pathogenesis of depression is associated with dysfunction of the PFC-NAc-VTA neural circuit, mainly through the neural projection effects of neurotransmitters associated with various brain regions in the neural circuit. PCA and OPLS-DA score plots demonstrated the similarities of individuals within each group and the differences among the groups. In this study, SGHWT could regulate the concentration level of different neurotransmitters in the PFC-NAc-VTA neuro circuit to improve the depression, which benefitted from the recognition of the brain reward circuitry in mood disorders.

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Forced Normalization Revisited: New Concepts About a Paradoxical Phenomenon

Frontiers in Integrative Neuroscience ◽

10.3389/fnint.2021.736248 ◽

2021 ◽

Vol 15 ◽

Author(s):

José Augusto Bragatti

Keyword(s):

Imaging Techniques ◽

Brain Regions ◽

Experimental Models ◽

Psychotic Symptoms ◽

Resting State Networks ◽

Epileptiform Discharges ◽

New Concepts ◽

Forced Normalization ◽

Electrical Stimuli ◽

Patients With Epilepsy

The phenomenon of Forced Normalization (FN) was first described by Landolt in 1953, who described the disappearance of epileptiform discharges in the EEG of patients with epilepsy, concomitant with the development of psychotic symptoms. Later, Tellenbach coined the term “alternative psychosis” referring specifically to the alternation between clinical phenomena. Finally, in 1991, Wolf observed a degenerative process involved in the phenomenon, which he called “paradoxical normalization.” Initially, FN was explained through experimental models in animals and the demonstration of the kindling phenomenon, in its electrical and pharmacological subdivisions. At this stage of research on the epileptic phenomenon, repetitive electrical stimuli applied to susceptible regions of the brain (hippocampus and amygdala) were considered to explain the pathophysiological basis of temporal lobe epileptogenesis. Likewise, through pharmacological manipulation, especially of dopaminergic circuits, psychiatric comorbidities began to find their basic mechanisms. With the development of new imaging techniques (EEG/fMRI), studies in the area started to focus on the functional connectivity (FC) of different brain regions with specific neuronal networks, which govern emotions. Thus, a series of evidence was produced relating the occurrence of epileptic discharges in the limbic system and their consequent coactivation and deactivation of these resting-state networks. However, there are still many controversies regarding the basic mechanisms of network alterations related to emotional control, which will need to be studied with a more homogeneous methodology, in order to try to explain this interesting neuropsychiatric phenomenon with greater accuracy.

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Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1911097117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6708-6716 ◽

Cited By ~ 6

Author(s):

Maryann P. Platt ◽

Kevin A. Bolding ◽

Charlotte R. Wayne ◽

Sarah Chaudhry ◽

Tyler Cutforth ◽

...

Keyword(s):

Microglial Activation ◽

Neural Circuit ◽

Psychiatric Symptoms ◽

Neuropsychiatric Symptoms ◽

Autoimmune Encephalitis ◽

Abrupt Onset ◽

Synaptic Proteins ◽

Excitatory Synapses ◽

Odor Processing ◽

Th17 Lymphocytes

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group AStreptococcus(GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood–brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.

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The Role of Corticotropin-Releasing Hormone at Peripheral Nociceptors: Implications for Pain Modulation

Biomedicines ◽

10.3390/biomedicines8120623 ◽

2020 ◽

Vol 8 (12) ◽

pp. 623

Author(s):

Haiyan Zheng ◽

Ji Yeon Lim ◽

Jae Young Seong ◽

Sun Wook Hwang

Keyword(s):

Signal Transmission ◽

Brain Regions ◽

Pain Modulation ◽

Corticotropin Releasing Hormone ◽

Releasing Hormone ◽

Inhibitory Function ◽

Peripheral Pain ◽

Functional Profiles ◽

Pituitary Adrenal Axis

Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation.

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Topography of microglial activation in sensory- and affect-related brain regions in chronic pain

Journal of Neuroscience Research ◽

10.1002/jnr.23883 ◽

2016 ◽

Vol 95 (6) ◽

pp. 1330-1335 ◽

Cited By ~ 33

Author(s):

Anna M.W. Taylor ◽

Sadaf Mehrabani ◽

Steve Liu ◽

Alison J. Taylor ◽

Catherine M. Cahill

Keyword(s):

Chronic Pain ◽

Microglial Activation ◽

Brain Regions

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Synaptic plasticity in the mesolimbic dopamine system

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2002.1236 ◽

2003 ◽

Vol 358 (1432) ◽

pp. 815-819 ◽

Cited By ~ 78

Author(s):

Mark J. Thomas ◽

Robert C. Malenka

Keyword(s):

Synaptic Plasticity ◽

Drugs Of Abuse ◽

Neural Circuit ◽

Long Term Potentiation ◽

Brain Regions ◽

Mesolimbic Dopamine ◽

Dopamine System ◽

Mesolimbic Dopamine System

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

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