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«DISSERTATION Effects of deep brain stimulation (DBS) on microglia phenotype in rodent model of psychiatric disorder zur Erlangung des akademischen ...»

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Aus dem Max Delbrück Centrum für Molekulare Medizin

DISSERTATION

Effects of deep brain stimulation (DBS) on microglia

phenotype in rodent model of psychiatric disorder

zur Erlangung des akademischen Grades

Doctor medicinae (Dr.med.)

vorgelegt der Medizinischen Fakultät

Charité – Universitätsmedizin Berlin

von

Le Dong

aus Beijing, China

Datum der Promotion: 05.06.2016

1

To my beloved family

2

Content

List of abbreviations

1a.

Abstract

(English)

1b. Abstrakt (German)

2 Introduction

2.1 Depression and schizophrenia

2.1.1 Definition and epidemiological features

2.1.2 Clinical diagnosis and treatment

2.1.3 Etiology

2.2 CNS inflammation and psychiatric disorders

2.2.1 Immune system and CNS function

2.2.2 Inflammation evidence link to depressive disorder

2.2.3 Inflammation evidence link to schizophrenia

2.3 Microglia

2.3.1 Origin and properties of microglia

2.3.3 Microglial dysregulation in schizophrenia.

2.3.4 Microglial dysregulation in depressive disorder.

2.4 Deep brain stimulation (DBS)

2.4.1 Background of DBS

2.4.2 The application of DBS in depression

2.4.3 The application of DBS in schizophrenia

2.5 Aim of the dissertation

3 Materials and methods

3.1 Materials

3.1.1 Devices and equipment

3.1.2 Reagents and chemicals

3.1.3 Antibodies for immunohistochemistry

3.1.4 Buffers

3.1.5 DBS system

3.1.6 Software

3.2 Methods

3.2.1 Animals

3.2.2 Poly(I:C) injections

3.2.3 Surgery and deep brain stimulation treatment

3 3.2.4 Isolation of microglia

3.2.5 Total RNA isolation, cDNA synthesis and quantitative PCR detection..................34 3.2.6 Brain section preparation

3.2.7 Immunofluorescence staining of microglia

3.2.8 Confocal microscope scanning and image analysis

3.2.9 Statistical analysis

4 Results

4.1 Microglia dysregulation in the animal model of schizophrenia

4.1.1 Microglia density and soma size is increased in hippocampus and nucleus accumbens (Nacc) in the Poly(I:C) group

4.1.2 The density of microglia is decreased in caudate putamen in the Poly(I:C) group.37

4.2 Effects of DBS on microglia in the schizophrenia model

4.2.1 Electrode implantation per se can lead to an increase in the density and soma size of microglia in local brain region, which were normalized by DBS

4.2.2 mPFC DBS can effectively attenuate microglial changes in the projection area (hippocampus and Nacc)

4.2.3 Nacc DBS attenuates microglial density and soma size in the hippocampus in the Poly(I:C) group

4.2.4 Nacc DBS treatment increases the density of microglia in the mPFC and CPu in the Poly(I:C) group.

4.2.5 The levels of cytokine expression in microglia in the hippocampus

4.3 The density changes of microglia in the depression model

4.4 Effects of DBS on microglia in a depression model

4.4.1 Electrode implantation and DBS current did not significantly change the density of microglia in the targeted brain region

4.4.2 mPFC-DBS treatment did not change the density of microglia in projection area (Nacc) in FSL/FRL rats

5 Discussion

5.1 Microglial dysregulation in a schizophrenia model

5.2 Cytokine changes in the schizophrenia model

5.3 Microglia dysregulation in a depression model

5.4 Treatment effects of DBS in schizophrenia and depression.

5.4.1 Effects of DBS on microglia in targeted area

5.4.2 Effects of DBS on microglia in the projection area

–  –  –

Major depressive disorder (MDD) Dopamine (DA) N-methyl-D-aspartic acid (NMDA) Phencyclidine (PCR) Interleukin (IL) Tumor necrosis factor (TNF) Central nervous system (CNS) C-Reactive protein (CRP) Corticotrophin cortisol hormone (CRH) Adreno-corticotrophin hormone (ACTH) Indoleamine 2,3 Dioxygenase (IDO) Positron emission tomography (PET) Cerebro-spinal fluid (CSF) Colony-stimulating factor (CSF) Transforming growth factor (TGF) Nitric oxide (NO) Embryonic day (E) Human leukocyte antigen (HLA) Polyriboinosinic-polyribocytidylic acid (Poly I:C) Quinolinic acid (QA) Inducible nitric oxide synthase (iNOS) Lipopolysaccharide (LPS) Deep brain stimulation (DBS) Food and Drug Administration (FDA) Treatment-resistant depression (TRD)

–  –  –

Nucleus accumbens (Nacc) Ventromedial prefrontal cortex (vmPFC) Forced swim test (FST) Sprague Dawley (SD) Pre-pulse inhibition (PPI) Acoustic startle reflex (ASR) Dorsomedial thalamus (DM) Flinders Sensitive Line (FSL) Flinders Resistant Line (FRL) Gestation day (G) Postnatal day (P) Anterior to bregma (AP) Lateral to the midline (ML) Ventral to dura (DV) Phosphate Buffered Saline (PBS) Caudate putamen (CPu) Polymerase chain reaction (PCR) Blood-brain barrier (BBB) Long-term potentiation (LTP) Long-term depression (LTD) Indoleamine 2,3-dioxygenase (IDO) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)

–  –  –





Background Since inflammation was closely linked to the onset and development of mental disorders, recent studies focus more and more on the contribution of the resident immune cells of the brain the microglia. Evidence from clinical and animal studies has demonstrated a change in the microglial phenotype in both schizophrenia and depressive disorder. Deep brain stimulation (DBS) is a novel treatment for neurological disorders. It has been proved that DBS can effectively ameliorate the symptoms of psychiatric disorders, but the effects of DBS on microglia in schizophrenia and depression are not clear yet.

Methods We were using immunohistochemistry and PCR techniques to investigate the changes of microglia with and without DBS treatment in a rat model of schizophrenia and depressive disorder.

Results In the rat model of schizophrenia, microglial density and soma size in the hippocampus and nucleus accumbens (Nacc) were significantly increased. Deep brain stimulation (DBS) treatment in the medial prefrontal cortex (mPFC) and Nacc effectively attenuated these changes of microglia in both regions. More than that, Nacc-DBS treatment also raised the density of microglia in the mPFC and caudate putamen (CPu) in the schizophrenic rats. In the depressive rat model, the density of microglia in the mPFC was deregulated compared to the control group. However, there was no significant DBS effect detected in the depression model. Furthermore, we confirmed that implantation of electrode can cause an activation of microglia in the targeted region and DBS current reduced microglia activity.

Conclusion The results thus show that there is microglial dysregulation in a rat model of schizophrenia and depression. DBS treatment can normalize microglia density and soma size in both targeted area as well as projection area in schizophrenic rats, but no valuable effect of DBS on microglia can be detected in the rat model of depression.

71b. Abstrakt (German)

Hintergrund Neue Erkenntnisse zeigen das Entzündungsreaktionen im Gehirn einen großen Einfluss auf die Entstehung und die Entwicklung von psychischen Erkrankungen haben. Im speziellen zeigen eine steigende Anzahl von Studien den Einfluss von Mikroglia, als Gehirn spezifische Immunzellen, auf diese Erkrankungen.

Sowohl klinische als auch Tier basierte Studien zeigen eine phänotypische Veränderung von Mikroglia in der Schizophrenie als auch depressiven Erkrankungen.

Weitere Studien zeigen, dass eine Tiefenhirnstimulation (eng. Deep Brain Stimulation = DBS) die Symptome von psychischen Erkrankungen lindern kann. Jedoch ist der Effekt einer Tiefenhirnstimulation auf Mikroglia noch nicht aufgeklärt.

Methoden Um die phänotypischen Veränderungen in Mikroglia aufzuklären wurden immunhistochemische Färbungen und qualitative RT-PCR von wahlweise eines Rattenmodels für Schizophrenie oder depressive Erkrankungen mit und ohne Tiefenhirnstimulationsbehandlung durchgeführt.

Ergebnisse Im Schizophrenierattenmodel ist sowohl die Dichte als auch die Größe des Zytosomas der Mikrolgia im Hippocampus und Nucleus accumbens (Nacc) gegenüber einer gesunden Ratte signifikant reduziert. Diese Reduktion konnte durch eine Tiefenhirnstimulation im Cortex praefrontalis medialis (eng. medial prefrontal cortex = mPFC) oder im Nacc aufgehoben werden. Darüber hinaus führt eine Tiefenhirnstimulation im Nacc im Schizophrenierattenmodel zu einer Erhöhung der Mikrogliadichte im mPFC und im Caudate Putamen (Cpu). Im Rattenmodel für depressive Erkrankungen reduziert sich die Dichte der Mikroglia nur im mPFC. In diesem Fall konnte die Tiefenhirnstimulationsbehandlung keine signifikante Änderung herbeiführen. Des Weiteren konnten wir zeigen, dass die Implantation der Elektrode für die Tiefenhirnstimulation an sich Mikroglia in der jeweiligen Region inflammatorisch aktiviert. Diese Aktivierung kann durch eine Aktivierung der Tiefenhirnstimulation jedoch wieder reduziert werden.

Fazit Die Ergebnisse zeigen eine Dysregulation der Mikroglia im Rettenmodel der Schizophrenie und der depressiven Erkrankungen. Im Falle des

–  –  –

2.1 Depression and schizophrenia 2.1.1 Definition and epidemiological features The most common psychiatric disorder is depression (including major depressive disorder, MDD). Nearly one in five people experience an episode of major depression in their lifetime worldwide. It was the fourth leading cause of disability across all countries in 2001 and will be perhaps the second most disabling disease of all forms of illness in 2020 (World Health Organization 2001). Biology, psychology, and social factors have an effect on the incidence of this disease. The time of onset is normally between the ages of 20 and 30 years, with a peak between 30 and 40 years (Hamilton et al. 2011). Depressive patients lose their interest and the ability to feel pleasure (anhedonia), suffer from anxiety, sadness, irritability or restless feelings.

These patients are often unable to communicate, experience serious sleep disturbances, hopelessness and even end their lives by committing suicide.

Depression causes not only a tremendous negative impact for the patients themselves, but also for the whole family (Crown et al. 2002). Another serious mental disorder with unclear causes is schizophrenia. Schizophrenia is often characterized by a failure to recognize what is real and attended by abnormal social behavior.

"Splitting of mental functions" is also used to describe this kind of disease. Unlike depression, the onset of schizophrenia is mostly sub-acute in young adulthood, peaking around 25 to 27 years and is much rarer in childhood. Males are affected earlier than females (Cascio et al. 2012). According to the World Health Organization statistics, approximately 1% of the world’s population suffers from schizophrenia and the disorder resulted in 20,000 deaths in 2010 (R. Lozano et al. 2012). In 2011, there were more than 24 million patients worldwide (Mas-Expósito et al. 2011). Clinical symptoms of schizophrenia are diverse and complex. They are related to various aspects such as perception, feeling, emotion, and behavior, therefore it is generally described in terms of positive and negative (or deficit) symptoms. The positive symptoms are: unclear or confused thinking, auditory, or visual hallucinations and false beliefs. Positive symptoms generally respond well to medication (American Psychiatric Association and Association 2000). The negative symptoms of schizophrenia are: inability to experience pleasure, deficits of emotion and motivation,

–  –  –

2.1.2 Clinical diagnosis and treatment The diagnosis of psychiatric disorders is based on the patient’s behavior reported by relatives and friends, patient's self-reported experiences and a mental status examination. Physicians may request tests for physical conditions that can cause similar symptoms, but there is no specific laboratory test for major depression or schizophrenia. The most common treatment for psychiatric patients is pharmacotherapy. Serotonin uptake inhibitors like Zoloft (sertraline) is primarily used to treat major depression in outpatients, and antipsychotic medication balancing dopamine, glutamate and serotonin, like risperidone, olanzapine, amisulpride and clozapine, are considered to be the first-line treatment for schizophrenia (NICE 2009). Other treatment options also include psychosocial therapy or electroconvulsive therapy. However, although a broad range of treatments has been developed, a significant portion of psychiatric patients remain refractory to multiple modes of therapies (Cleary et al. 2015). Apart from this, the use of antipsychotics can lead to various adverse side effects, which commonly include headaches, weight gain, and extrapyramidal side effects, such as tardive dyskinesia, etc. Therefore, new treatments are urgently needed for those patients.

2.1.3 Etiology

Although physicians and scientists have made great efforts in dealing with this issue, the pathogenesis of schizophrenia and depressive disorder is still uncertain. In recent decades, various hypotheses of the etiology of schizophrenia and depression have been proposed.



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