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Exploration of Variability of Arkypallidal and Prototypical Projections to Dopamine 1 and Dopamine 2 Populations of the Putamen

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Exploration of Variability of Arkypallidal and Prototypical Projections to Dopamine 1 and Dopamine 2 Populations of the Putamen Exploration of Variability of Arkypallidal and Prototypical Projections to Dopamine 1 and Dopamine 2 Populations of the Putamen Moa Karmefors Idvall [email protected] under the direction of Assoc. Prof. Konstantinos Meletis Department of Neuroscience Karolinska Institute Research Academy for Young Scientists July 13, 2016 Abstract The human brain is one of the world’s greatest mysteries, the process of mapping its inter- actions have only just begun. The basal ganglia, which is the medial section of the human brain, is believed to have a crucial role in our ability to voluntarily move. This study investigates the internal connections of the basal ganglia; more specifically the monosy- naptic connections between the putamen and the external segment of globus pallidus. The connections of prototypic and arkypallidal neurons (located in the external segment of globus pallidus) to both dopamine 1 and dopamine 2 receptor neurons of the putamen are explored by using retrograding viral tracing and immunofluorescence staining. The results of this study show the location of neurons in the external segment of globus pal- lidus projecting to the either dopamine 1 or dopamine 2 receptor neurons. The results also show the preferential target neurons of both arkypallidal and prototypic neurons. Contents 1 Introduction 2 1.1 The Basal Ganglia . 2 1.1.1 Anatomy of the Basal Ganglia . 2 1.1.2 The Motor Circuit . 4 1.1.3 The External Segment of Globus Pallidus . 5 1.2 Background to Method . 6 1.2.1 Retrograding Viral Neural Tracing with Deactivated Rabies Virus and Cre-expressing Mice Lines . 6 1.2.2 Antibodies and Immunofluorescence Staining . 8 1.3 Aim of Study . 9 2 Method 9 2.1 Stereotactic Viral Injection . 9 2.2 Fragmentation of Mice Brain Using Vibratome . 10 2.3 Immunofluorescence Staining . 11 2.4 Sample Mounting . 12 2.5 Epifluorescence Microscope . 13 3 Results 13 3.1 Retrograde Labeling of Starter Neurons in Putamen . 13 3.2 Topography of the Putamen-projecting Neurons in the External Segment of Globus Pallidus . 14 3.3 Immunofluorescences Staining to Identify Prototypic and Arkypallidal Neu- rons in the External Segment of Globus Pallidus . 15 4 Discussion 18 4.1 Source of Errors . 19 4.2 Conclusion . 19 1 4.3 Future Research . 20 References 21 List of Abbreviations CPu Putamen Cre Cre recombinase Cy Cyanine D1 Dopamine 1 D2 Dopamine 2 G Rabies Glycoprotein GFP Green Fluorescent Protein GP Globus Pallidus GPe External segment of Globus Pallidus GPi Internal segment of Globus Pallidus PBS Phosphate-buffered saline RVdG Rabies-glycoprotein-deleted rabies virus STN Subthalamic Nucleus TBS-T Triss-buffered saline containing 0,03% Trikon 1 1 Introduction Patients suffering from neuropsychiatric disorders, such as depression, schizophrenia, autism, Parkinson’s disease and bipolar disorders, are today treated with psychother- apeutic drugs developed from findings brought to light before 1960 in conjunction with clinical observation. Researchers are currently working on mapping the neural pathways for future use in medical purposes. If the human brain were successfully mapped, many side effects of current treatments could be avoided. Since there are both ethical and prac- tical difficulties with examining the human brain, animal models are frequently used, most commonly used are transgenic mice. [1] 1.1 The Basal Ganglia The human brain contains neurons, glial cells and blood vessels and is divided into several sections [2]. The basal ganglia, part of the cerebrum and located under the cerebral cortex, has a central role in the voluntary movement and, contradictory to other parts of the motor system, does not directly interact with the spinal cord [2]. Research has lead to an overall knowledge about the basal ganglia circuits and due to its relevance for future treatments of movement disorders, the motor circuit is the most recently studied, a work we will continue [3]. 1.1.1 Anatomy of the Basal Ganglia The basal ganglia consists of numerous linked subcortical nuclei that receive input from the cerebral cortex and thalamus. The nuclei send the output through the thalamus back to the cortex and directly to the brain stem. The four functionally distinct groups important for the motor circuit are: the striatum, the globus pallidus (GP), the substantia nigra and the subthalamic nucleus, see (Figure 1a). [2] 2 The striatum is divided into two regions: the caudate nucleus and the putamen (CPu), see Figure 1b. The striatum is thought to be the primary input station for information from the cerebral cortex, thalamus and the brain stem. Further on, the signals arriving in the striatum proceed to reach the globus pallidus and the substantia nigra. These two sections of the basal ganglia are considered to be the output nuclei and inhibit their target area in the thalamus and brain stem. The inhibitory outputs are thought to be controlled by two different neural pathways: the direct and the indirect pathway. [2] (a) (b) Figure 1: Structure of the basal ganglia. (a) The four bigger sections of the basal ganglia; the striatum, the globus pallidus, the subthalamic nucleus and the substantia nigra.1(b) Cross-section of the human brain showing; the caudate nucleus and the putamen (stria- tum), globus pallidus (internal and external segment), substantia nigra and subthalamic nucleus. The figure also illustrates the cortex, thalamus and the hypothalamus. 2 1Nostalgos. Neural Circuits of Fear and Anxiety towards the Extinction of Anxiety, Phobias and Psychological Traumas [Online]. [cited 2016-07-09] Available from: http://www.nostalgos.com/8.html 2We All Have Unique Brains. Basal Ganglia [Online] [cited 2016-07-12] Available from: http://www. weallhaveuniquebrains.com/brain_anatomy/basal_ganglia/ 3 1.1.2 The Motor Circuit The striatum receives input from the cortex and the substantia nigra [4]. The output neu- rons of the striatum have either dopamine 1 (D1) or dopamine 2 (D2) receptors which bind to dopamine, a common neurotransmitter [2]. These receptors generate the direct and indirect pathway [2], found in Figure 2. D2 receptors activate the indirect pathway whereas the direct pathway is activated by binding to D1 receptors [2]. The direct pathway proceeds from the striatum, more specifically from the caudate nu- cleus and the putamen, when inhibitory projections reach the inhibitory neurons in the internal section of the globus pallidus (GPi). The GPi then projects to the thalamus. In the indirect pathway inhibitory neurons in the external section of globus pallidus (GPe) are activated by signals proceeding from inhibitory neurons in the striatum (caudate and putamen). The neurons of the GPe project to the subthalamic nucleus. The subthalamic nucleus also receives strong excitatory signals from the cortex. All signals picked up in the subthalamic nucleus then proceed to the GPi. The activating drive of the subtha- lamic nucleus then works to resist the disinhibitory response of the direct pathway. In corresponding ways the indirect pathway regulates the direct pathway effect. [4] The motor circuit (the circuit between the basal ganglia and the thalamus) is provided with both positive and negative feedback. The positive feedback comes from the direct pathway whereas the negative feedback is received from the indirect pathway. By stimu- lation of the direct pathway, the thalamus is disinhibited and increases its activity. The indirect pathway works the other way around and decreases the thalamocortical activity. This results in an activation of the direct pathway which promotes movement, whereas an inhibition of movement is accomplished by stimulation of the indirect pathway. [2] 4 Figure 2: The direct and indirect pathway of the basal ganglia. The direct pathway (activated by dopamine binding to D1 receptors) proceeds from the striatum to the thalamus via the GPi. The indirect pathway is activated when dopamine binds to the D2 receptors and proceeds from the striatum to the GPi via the GPe and the subthalamic nucleus before reaching the thalamus. The striatum receives input from the cortex and the substantia nigra. The amount of dopamine released determines the balance between the direct and indirect pathway signals. A release of dopamine in the striatum increases the motion of signals along the direct pathway which is initially activated by the binding of dopamine and D1 receptors. Dopamine released in the striatum also acts on D2 receptors, connected to the indirect pathway, and decreases efficiency along the indirect pathway. In case of a lower dopamine concentration in striatum, the indirect pathway works more efficiently than the direct pathway. [3] 1.1.3 The External Segment of Globus Pallidus Although the direct and indirect pathway model hypothesizes that the GPe receives input from the striatum and sends downstream signals to the subthalamic nucleus, some re- 5 searchers believe that the pathway communication through the GPe is even more complex [5]. It has also been predicted that a deeper understanding of the GPe neurons heterogen- ity would be crucial to comprehend both the basal ganglias function and dysfunction [5]. Research has indicated that the GPe consists of two types of neurons; arkypallidal and prototypic neurons [6]. The arkypallidal neurons are thought to only project input to the striatum whereas the prototypic neurons are believed to sporadically innervates the stria- tum but also consistently send downstream signals in the basal ganglia circuit [5]. The prototypic neurons express, among others, the transcription factor Nkx2-1 while arky- pallidal neurons express the FoxP2 transcription factor [6]. This genetic difference could be important when differentiating the two GPe neurons. The majority of the prototypic neurons also express the protein parvalbumin (PV) [5]. 1.2 Background to Method 1.2.1 Retrograding Viral Neural Tracing with Deactivated Rabies Virus and Cre-expressing Mice Lines Around 2007 a method using a rabies virus where rabies glycoprotein (G) has been deleted (RVdG) was introduced and has been widely used since.
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