Chemoarchitecture

Chemical neuroanatomy has been used to establish the organizational plan of brain regions in experimental animals and to infer their human homologies. It has also been used to identify chemically specified connections in animals. Finally, it has been used to derive an hypothesis on the function of brain pathways and nuclei. Chemical neuroanatomy has developed as a branch of the structural brain mapping methodology that previously was almost entirely based on cytoarch-itectonic consideration of cell shape, size, and density. The insubordination of chemically specified neurons to classic cytoarchitectonic boundaries required a more meaningful delineation of the brain—one that incorporates the information about the distribution of neuroactive substances, connectivity, and function. In this respect, chemical neuroanatomy opened a new dimension in neuroscience and allowed greater precision, resolution, and reliability in differentiating cell groups and brain areas.

Scientists have made use of chemical neuroanatomy in studying affiliations of neurons in experimental animals. Knowing the neurotransmitter carried by a neuronal projection precisely characterizes the pathway. This approach has not been extensively followed in the human; consequently, we only mention it in passing. Once the cells of origin and the terminal fields of a pathway have been chemically specified in experimental animals, then scientist can search for homologous cells and terminals in the human.

Chemical neuroanatomy is used to identify and correlate functional networks across species, particularly when focused on a specific neuroactive circuit

Encyclopedia of the Human Brain Volume 1

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within the brain. Thus, chemical characteristics of brain structure reflect numerous important qualities of the neuronal cell groups, including neurotransmitter or neuromodulator content, receptor arsenal, structural proteins, intrinsic metabolic characteristics as reflected by enzyme activity profiles, and genotype.

In the human brain, chemical neuroanatomy is an essential method of investigation because conventional functional studies as well as neuroanatomical tracing techniques, as routinely performed on laboratory animals, are virtually impossible in humans. Noninvasive imaging techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are useful clinical tools, but their resolution is often disappointingly low for testing modern hypotheses. At the same time, pathological investigations base their conclusions largely on detailed structural and cytoarchitectonic comparisons with normal human neuroanatomy. Importantly, existing presumptions about the organization of the normal human brain are largely made by extrapolating findings from laboratory animals to humans on the basis of structural homology.

For most of the 20th century the understanding of human neuroanatomy was obtained mainly from cytoarchitectonic observations. Thus, the most widely used maps of the human cortex were produced by Brodmann in 1909 on the basis of Nissl substance and myelin staining, whereas the most detailed neuroana-tomical description of the human hypothalamus was published by Brockhaus in 1942 and was also based on early cytoarchitectonic techniques. Without detracting from the historical significance of these fundamental studies, it is easy to see the main shortcoming of early neuroanatomical techniques, namely, their distance from mechanisms underlying human brain function. One of the most exciting developments in neuroanat-omy was the identification of chemical coding for individual neural pathways and the proliferation of chemoarchitectonic techniques, which allow almost unlimited scope in the classification of neuronal groups. Importantly, chemical neuroanatomy establishes a bridge between structural and functional characteristics of neuronal populations in the brain.

Studies using chemical neuroanatomy were first carried out in rats, in which it was logistically and technically easier to apply. It was not until the 1980s that the chemoarchitectonic techniques of histo- and immunohistochemistry reached sufficient sensitivity that allowed them to be applied in full capacity to human brain tissue. Thus, it became increasingly possible to reveal the distribution of some of the neurotransmitters, receptors, and enzymes of importance in the human brain and then make cross-species comparisons. An advantage of chemoarchitecture is that each chemical substance offers a different view of the organization of the central nervous system, with successive stains revealing more of the areas of interest. Of course, there are significant species differences and any given substance may have inconsistent distributions in otherwise homologous nuclei and areas. Nevertheless, in terms of overall value, chemoarchi-tectonic delineations have become a preferred method in comparative neuroscience.

Chemoarchitectonic studies are also very important for the understanding, diagnosis, and treatment of neurological and psychiatric disorders, such as obesity, Alzheimer's, disease, Parkinson's disease, Huntington's disease, depression, and schizophrenia. In the past 50 years, researchers have compared the distribution and content of neuroactive chemical compounds of brains from individuals affected with various diseases with those of the brains of control subjects. This has led to development of pathological models of neurochemical imbalance in animals and to extrapolation of these models into the human using chemical neuroanatomy.

In chemical neuroanatomy, the first and most obvious question for the investigator is the choice of the chemical marker. Naturally, the neuroactive profile of neurons offers grounds for determining the organization of neuronal groups within a species and for comparing them across species. For example, dopamine, norepinephrine, epinephrine, and g-amino-butyric acid (GABA) are neuroactive chemical compounds that can characterize neuronal subgroups. The term chemoarchitecture implies the use of chemical compounds for differentiation between neuronal populations. These compounds are not only neurotrans-mitters but also can be enzymes, receptors, peptides, and molecules related to neuronal metabolism, such as calcium-binding proteins. Cross-referencing patterns of distribution of many chemicals from different brains or, better yet, studying distribution patterns of different chemicals on the adjacent sections of one brain provide high resolution and reliability in identifying neuronal cell groups.

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