**Changes in the Striatal Network Connectivity in Parkinsonian and Dyskinetic Rodent Models Parkinsonian and Dyskinetic Rodent Models**

**Changes in the Striatal Network Connectivity in** 

DOI: 10.5772/intechopen.70601

Jesús Pérez-Ortega and José Bargas Jesús Pérez-Ortega and José Bargas Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70601

#### **Abstract**

[32] Zehr JP, McReynolds LA. The use of degenerate oligonucleotides for amplification of the nifH gene from the marine cyanobacterium *Trichodesmium thiebautii*. Applied and

[33] Shimada S, Marsh DJ. Oscillations in mean arterial pressure in conscious dogs.

[34] Touitou, Haus E. Biological Rhythms in Clinical and Laboratory Medicine. Heidelberg:

[35] Rohan S. Chronotherapeutical approach: Circadian rhythm in human and its role in occurrence and severity of disease. International Journal of Pharmaceutical Technology

Environmental Microbiology. 1989;**55**:2522-2526

Circulation Research. 1979;**44**:692-700

and Research. 2012;**4**(2):765-777

Springer-Verlag; 1992

34 Pathophysiology - Altered Physiological States

In Parkinson's disease, there is a loss of dopaminergic innervation in the basal ganglia. The lack of dopamine produces substantial changes in neural plasticity and generates pathological activity patterns between basal ganglia nuclei. The treatment to relieve Parkinsonism is the administration of levodopa. However, the treatment produces dyskinesia. The question to answer is how the interactions between neurons change in the brain microcircuits under these pathological conditions. Calcium imaging is a way to record the activity of dozens of neurons simultaneously with single-cell resolution in brain slices from rodents. We studied these interactions in the striatum, since it is the nucleus of the basal ganglia that receives the major dopaminergic innervation. We used network analysis, where each active neuron is taken as a node and its coactivity with other neurons is taken as its functional connections. The network obtained represents the functional connectome of the striatal microcircuit, which can be characterized with a small set of parameters taken from graph theory. We then quantify the pathological changes at the functional histological scale and the differences between normal and pathological conditions.

**Keywords:** Parkinson's disease, L-DOPA induced dyskinesia, striatal microcircuit, functional connectome, network properties

#### **1. Introduction**

Idiopathic Parkinson's disease (PD) was first described by James Parkinson in 1817 and it is the second most common neurodegenerative disease after Alzheimer's disease. PD prevalence is lower in African, Asian, and Arabic countries than in North America, Europe, and South America [1, 2]. In the USA, the incidence of PD by ethnicity is highest among Hispanic people, followed by non-Hispanic white people, Asian people and black people [1, 2]. Gender

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

is another risk factor with a male to female incidence ratio around 3:2 [1, 2]. However, age is the greatest risk factor to develop PD: the incidence is low before the age of 50 years but increases quickly peaking around 80 years [1, 2]. In addition, there are several environmental risk factors for PD: pesticide exposure, head injury, rural living, etc.; but also there are some factors that help to decrease the risk: tobacco smoking, coffee drinking, alcohol consumption, etc. [1, 2].

interneurons. The SPNs are the 95% of the striatal neural population and they have collateral synapses between them at distances less than 100 μm [16–18]. The SPNs are divided in two populations: direct pathway SPNs (dSPNs) that connect monosynaptically to the BG output nuclei, GPi and SNr, and the indirect pathway SPNs (iSPNs) that send synaptic terminals to the GPe. Normally, SPNs have little spontaneous activity until they are activated by an excitatory drive, defined as afferents, neurotransmitter agonists, or modulators that induce the microcircuit to produce alternant neural activity [19]. When SPNs are activated, they show particular temporal patterns with oscillations between two distinct states: one with a hyperpolarized membrane potential or downstate at around −80mV, and the second with membrane potential depolarizations that last hundreds of milliseconds or seconds, the upstate, at around −50 mV [20]. It is during the upstate that SPNs fire action potentials, better respond to synaptic inputs and concert their firing with other SPNs conforming active neuronal ensembles.

Changes in the Striatal Network Connectivity in Parkinsonian and Dyskinetic Rodent Models

http://dx.doi.org/10.5772/intechopen.70601

37

On the other hand, the interneurons conform the remaining 5% of the population [15]. One class of interneuron expresses choline acetyltransferase (ChAT) with axons extending more than 1 mm. Other classes of interneurons are GABAergic and they are divided in numerous types: the fast spiking interneurons, which express parvalbumin (PV) and/or serotonin receptors (5-HT3); the low threshold spike interneurons (LTS), which could be further subdivided and may express or coexpress neuropeptide Y (NPY), somatostatin (SOM), nitric oxide synthase (NOS), or else, serotonin receptors (5-HT3), or calretinin, there are also neurogliaform interneurons (NGF), and other types still being studied [21–23]. The axonal arborizations of most interneurons may reach up to 1 mm. The exact combination of connections between these neuronal classes is still under study using electrophysiological recordings and optogenetics. There may be several valid combinations depending on function or context and further

The traditional model of the two pathways [24–25] propose that in control conditions there is an equilibrium between the activity of the direct pathway (dSPNs), which promotes movement, and the indirect pathway (iSPNs) which inhibits movement. Therefore, the balanced activation of both pathways produce coordinated movements. It is posited that in PD there is an imbalanced activity between these pathways: the activity of iSPNs becoming more important producing greater inhibition of movements. In contrast, during LID there is more activity in the direct pathway producing more involuntary movements. Unfortunately, these explanations are not supported by some experiments in monkeys, where these differences in activity were not observed [4]. Therefore, instead of staying at cellular level descriptions, in this work, we describe the interactions or functional connections between neuronal ensembles of the striatal microcircuit at the functional histological level in living brain tissue. This approach may help to identify what changes characterize control and pathological microcircuits to then

In the history of neuroscience, ideas about how neural activity is organized, one of them stands out: the cell assembly hypothesis. This hypothesis was formally proposed in its modern form

research is necessary to find out each of them.

**3. Striatal cell assemblies**

ask, in future experiments, what cellular elements produce them.

The main characteristics of PD are the motor symptoms: resting tremor, rigidity, postural instability, bradykinesia, among others [3]. The motor symptoms of PD are the result of dopaminergic denervation of the basal ganglia (BG). This loss of dopamine is due to the death of dopaminergic neurons in the *substantia nigra pars compacta* (SNc). Dopamine is essential for the proper functioning of the BG [4]. The causes of PD are still unknown. Some neurotoxic animal models have been developed to mimic and study its pathophysiology. In rodents, the most used is the hemiparkinsonian model: the unilateral lesion of the SNc with the 6-hidroxidopamine toxin (6-OHDA). It is commonly evaluated by turning behavior induced by dopaminergic agonists [5–7]. In this chapter, recent results to study pathophysiology at the microcircuit level will be disclosed together with their theoretical framework [8, 9]. The best treatment to relieve some signs and symptoms of PD is the administration of dopaminergic agonists, mainly L-DOPA. However, the long-term administration of L-DOPA produces other movement disorders: L-DOPA-induced dyskinesias (LIDs). There are three well-characterized types of LID [10]. (1) Peak dose dyskinesia, which is the most common, occurs in 80% of patients at peak of dopamine concentrations derived from L-DOPA ("on" time). (2) Diphasic dyskinesia, that occurs at the rising and falling of L-DOPA's clinical useful concentrations. (3) Early morning dystonia, that occurs when dopamine levels are very low, commonly after patients spent nighttime without L-DOPA.

LID is characterized by abnormal and involuntary movements which seem to appear randomly. It is often extremely disabling. 50% of the patients present it between 4 and 5 years after starting treatment and 75% after 10 years of treatment [11, 12]. To study this kind of dyskinesia, the 6-OHDA rodent model is treated with high doses of L-DOPA during several days and it is evaluated by counting abnormal involuntary movements (AIMs): locomotive, limb, axial, and orolingual [13]. Here, this model was used to study the dyskinetic pathophysiology at the microcircuit level [9]. We propose the study of the BG at the microcircuit level in order to better understand the detailed pathophysiology of these movement disorders.
