**8. Primitive process in the striatal microcircuit**

a key role in the connectivity: they provide the physical substrate to have mutual innervation and connect different ensembles. Since Sherrington description, this property is necessary to alternate activity between ensembles. Even if a network is scale-free, it does not mean that has a modular organization as hypothesized for brain microcircuits [55–57]. Thus, a next question to answer was whether the connectome is constituted hierarchically, in a modular way. This was shown to be the case because the distribution of clustering coefficients C(k) of the nodes were also well fitted to a power law function [58]. Thus, a modular architecture has been seen in the striatal microcircuit [9], as well as in the somatosensory and auditory cortices microcircuits [51]. In summary, the striatal microcircuit connectome is a complex network, with "small-world" and scale-free properties forming hierarchical modules. In addition, network analysis allowed to describe with single neuron resolution some particular neurons identified

Since some neurons can be identified by their particular connectivity as hub neurons, the next step is to know what class of neurons they are. There are evidences that some hub neurons are interneurons (unpublished). The functional connectome in the striatum was observed in

500 μm, while synapses between projection neurons can only be found at a distances less than 100 μm [16–18]. Indeed, only interneurons can extend their axons to connect neurons at distances up to 1 mm. This inference was confirmed by whole cell patch clamp recordings of some hub neurons identifying fast-spiking (PV), low-threshold spiking (LTS) and cholinergic interneurons (ACh) [9, 36]. Transgenic mice in which optogenetic stimulation activates a particular neural population [59] shows that hub neurons connect with different groups of neurons perhaps inducing the coactivity that underlies network states, and therefore, are responsible for their alternation. However, further experiments using transgenic animals and optogenetics are needed to identify the classes of neurons that form striatal modular circuits

To know the role of cortical afferents in the striatal microcircuit, we used decorticated striatal slices. The decorticated striatal microcircuit preserves some active network states conforming temporal sequences, albeit alternation between ensembles is greatly reduced. In fact, network analysis revealed a loss of active hub neurons [9]. This result suggested that cortical afferents maintain privileged connections with striatal hub neurons, probably interneurons, to orga-

Similarly, in the rodent model of Parkinson's disease, there is a significant loss of hub active neurons. Not strangely, the Parkinsonian striatal microcircuit shows less transitions between network states, confirming that one larger neuronal ensemble becomes dominant [8, 38],

**7. Pathological changes in the functional connectome**

with hub neurons connecting many neurons at distances larger than

by their connectivity as "hub neurons."

**6. Key role of hub neurons**

40 Pathophysiology - Altered Physiological States

an area of about 1 mm<sup>2</sup>

and under what conditions.

nize striatal activity.

It is well known that pyramidal neurons connect preferentially to interneuron pools and not to the projections neurons or motoneurons in the spinal cord [66]. Thus, the present findings suggest a principle of general organization, which can explain how the same cell assemblies could be used in different behaviors depending on the activation of certain hub neurons by the cortical commands. According to Huyck [31, 67], any neural model at the microcircuit level should fulfill a primitive process: to have an input that selects the operators, apply operators on the operands, store results, and generate an output. In the striatum, the working hypothesis would be that input coming from the cortex selects the interneurons—operators and apply their operations on the projections neurons—operands—the information is stored and striatal output is generated, the result of the whole operation: activation and inhibition of agonist and antagonist muscles in sequence (**Figure 1**). This hypothesis implies that cortical afferents organize groups of interneurons to induce the activity in a similar way as in the processes described by the cognitive theory of Allen Newel [31, 67]. Being the hub neurons the operators and the projections neurons the operands, the process of alternating network states, the sequences and the reverberations could underlie the actions of minimal motor routines [29]. Each microcircuit could be associated with others to produce different actions, depending on the group of operators activated by the cortex. This would explain the changes in the dynamics of the microcircuit and the functional relations between their neurons [68]. Now, there is technology to record several simultaneous neurons *in vivo* at the microcircuit level to study the functional connectome under different behaviors. Thus, the multiple combinations of connections being described at the cellular level may make sense.

groups. These groups underlie the neural states that alternate and reverberate. The structure of the striatal connectome has "small-world" properties, is scale-free and has a hierarchical modular organization, as other complex networks seen in nature. The cortical commands use the hub neurons to organize the dynamics of the circuit and given the distances between the neurons that conform a neuronal ensemble, it can be inferred that hub neurons should be long axon neurons, that is, interneurons. After striatal decortication or during the 6-OHDA model of Parkinson's disease hub neurons decrease significantly and as a consequence, the transitions between ensembles and circuit dynamics decrease, reflecting metaphorically hypokinesia and rigidity, and supporting previous studies that show a breakdown of corticostriatal communication in Parkinsonian subjects. In L-DOPA-induced dyskinesia, the opposite happens: the number of hub neurons and the transitions between ensembles increase. However, this occurs together with a loss of the hierarchical architecture. This also is reminiscent of the signs seen in dyskinetic subjects: uncoordinated involuntary movements. Finally, we conclude that the pathophysiology and pharmacology of the nervous system can be studied in living tissue at histological scale by using simultaneous recording and network analysis.

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

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

43

División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma

[2] Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: Risk factors

[3] Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson's disease.

[4] Jenner P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nature Reviews

[5] Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neu-

[6] Schwarting R, Huston J. The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Progress in

**Author details**

**References**

Jesús Pérez-Ortega and José Bargas\*

de México, Mexico City, Mexico

\*Address all correspondence to: jbargas@ifc.unam.mx

Trends in Neurosciences. 2000;**23**:S2-S7

Neuroscience. 2008;**9**(9):665-677

Neurobiology. 1996;**50**(2-3):275-331

[1] Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;**386**:896-912

and prevention. The Lancet Neurology. 2016;**15**:1257-1272

rons. European Journal of Pharmacology. 1968;**5**(1):107-110

**Figure 1.** New model of cell assemblies activation in the striatal microcircuit.
