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The "basal ganglia" refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions. Proposed more than two decades ago, the classical basal ganglia model shows how information flows through the basal ganglia back to the cortex through two pathways with opposing effects for the proper execution of movement. Although much of the model has remained, the model has been modified and amplified with the emergence of new data. Furthermore, parallel circuits subserve the other functions of the basal ganglia engaging associative and limbic territories. Disruption of the basal ganglia network forms the basis for several movement disorders. This article provides a comprehensive account of basal ganglia functional anatomy and chemistry and the major pathophysiological changes underlying disorders of movement. We try to answer three key questions related to the basal ganglia, as follows: What are the basal ganglia? What are they made of? How do they work? Some insight on the canonical basal ganglia model is provided, together with a selection of paradoxes and some views over the horizon in the field.T he basal ganglia and related nuclei consist of a variety of subcortical cell groups engaged primarily in motor control, together with a wider variety of roles such as motor learning, executive functions and behavior, and emotions. The term basal ganglia in the strictest sense refers to nuclei embedded deep in the brain hemispheres (striatum or caudate-putamen and globus pallidus), whereas related nuclei consist of structures located in the diencephalon (subthalamic nucleus), mesencephalon (substantia nigra), and pons ( pedunculopontine nucleus). Ideas and concepts regarding the functions of the basal ganglia were strongly influenced by clinical observations during the 20th century, which showed that lesions of the lenticular nucleus ( putamen and globus pallidus) and the subthalamic nucleus (STN) were associated with parkinsonian signs, dystonia, and hemiballismus (Wilson 1925;Purdon-Martin 1927). Thus, the terms extra-pyramidal system and extra-pyramidal syndrome were frequently used in the past to refer to the pathological basis of movement disorders in an attempt to make a clear distinction from the pyramidal system (corticofugal neurons that give rise to corticospinal projections). At present, these terms and distinctions are considered obsolete and misleading and, therefore, will not be used in

The development of new axonal tract tracing and cell labelling methods has revolutionised neurobiology in the last 30 years. The aim of this review is to consider some of the key methods of neuroanatomical tracing that are currently in use and have proved invaluable in charting the complex interconnections of the central nervous system. The review begins with a short overview of the most frequently used tracers, including enzymes, peptides, biocytin, latex beads, plant lectins and the everincreasing number of¯uorescent dyes. This is followed by a more detailed consideration of both well established and more recently introduced neuroanatomical tracing methods. Technical aspects of the application, uptake mechanisms, intracellular transport of tracers, and the problems of subsequent signal detection, are also discussed. The methods that are presented and discussed in detail include: (1) anterograde and retrograde neuroanatomical labelling with¯uorescent dyes in vivo, (2) labelling of post mortem tissue, (3) developmental studies, (4) transcellular tracing (phagocytosis-dependent staining of glial cells), (5) electrophysiological mapping combined with neuronal tract tracing, and (6) simultaneous detection of more than one axonal tracer. (7) Versatile protocols for three-colour labelling have been developed to study complex patterns of connections. It is envisaged that this review will be used to guide the readers in their selection of the most appropriate techniques to apply to their own particular area of interest. 7

Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

Most of our current understanding of brain function and dysfunction has its firm base in what is so elegantly called the 'anatomical substrate', i.e. the anatomical, histological, and histochemical domains within the large knowledge envelope called 'neuroscience' that further includes physiological, pharmacological, neurochemical, behavioral, genetical and clinical domains. This review focuses mainly on the anatomical domain in neuroscience. To a large degree neuroanatomical tract-tracing methods have paved the way in this domain. Over the past few decades, a great number of neuroanatomical tracers have been added to the technical arsenal to fulfill almost any experimental demand. Despite this sophisticated arsenal, the decision which tracer is best suited for a given tracing experiment still represents a difficult choice. Although this review is obviously not intended to provide the last word in the tract-tracing field, we provide a survey of the available tracing methods including some of their roots. We further summarize our experience with neuroanatomical tracers, in an attempt to provide the novice user with some advice to help this person to select the most appropriate criteria to choose a tracer that best applies to a given experimental design.