Historical review: The golden age of the Golgi method in human neuropathology.

Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied these methods, their impact was crucial by increasing knowledge about: (1) the morphology, orientation, and localization of neurons in human cerebral and cerebellar malformations and ganglionic tumors, and (2) the presence of abnormal structures including large and thin spines (spine dysgenesis) in several disorders linked to mental retardation, focal enlargements of the axon hillock and dendrites (meganeurites) in neuronal storage diseases, growth cone-like appendages in Alzheimer disease, as well as abnormal structures in other dementias. Although there were initial concerns about their reliability, reduced dendritic branches and dendritic spines were identified as common alterations in mental retardation, dementia, and other pathological conditions. Similar observations in appropriate experimental models have supported many abnormalities that were first identified using Golgi methods in human material. Moreover, electron microscopy, immunohistochemistry, fluorescent tracers, and combined methods have proven the accuracy of pioneering observations uniquely visualized as 3D images of fully stained individual neurons. Although Golgi methods had their golden age many years ago, these methods may still be useful complementary tools in human neuropathology.

Cajal and the discovery of a new artistic world: the neuronal forest.

The introduction of the staining method of Camillo Golgi in 1873 represented a giant step for neuroscience. Prior to this development, the visualization of neurons with the available histological techniques had been incomplete; it was only feasible to observe the cell body and the proximal portions of the dendrites and axon. However, with the Golgi method it was possible to observe neurons and glia with all their parts (cell body, dendrites, and axon in the case of neurons; cell body and processes in the case of glia). Due to the advantages of this method, all of a sudden it was possible to begin studying one of the great mysteries and critical issues of the organization of the nervous system-the tracing of the connections between neurons. Nevertheless, this method was not fully exploited until Santiago Ramón y Cajal arrived on the scene in 1888. It should be noted that, in Cajal's day, drawing was the most common method of describing microscopic images in the absence of the highly developed microphotography and other imaging techniques commonly available in today's laboratories. As a consequence, most scientific figures presented by the early neuroanatomists were their own drawings, providing an outlet for these scientists to express and develop their artistic talent. In the hands of Cajal, the Golgi method represented not only the principal tool that was to change the course of the history of neuroscience but also the discovery of a new artistic world, the neuronal forest.

Zones in the cerebellar cortex: the adventures of one participant in the unfolding story.

Prior to the late 1960s, a variety of studies suggested that a general zonal pattern existed within the cerebellar cortex. The hypothesis proposed by Voogd, based on the organization of the subcortical white matter, indicated that this pattern may be very detailed, and he noted that "a further analysis of the corticonuclear projection is still necessary." This brief paper chronicles the approach used by the author to formulate a plan, initiate a large series of experiments (over 250), and follow the sometimes confusing results to finally arrive at an understanding of the details of cerebellar corticonuclear projections. It was discovered that a series of mediolateral cortical zones were present that were topographically related to the underlying cerebellar nuclei, and within each zone, the cortex projected in a rostrocaudal sequence to a specific cerebellar nucleus. The hypothesis proposed by Voogd was fundamentally proven.

The diffuse nervous network of Camillo Golgi: facts and fiction.

The name of Camillo Golgi is inextricably associated, in the mind of most neuroscientists, with the theory that nerve cells communicate with one another by means of an intricate network of anastomosing axonal branches contained in the neuropil intervening between cell bodies in the gray matter of the brain and spinal cord. Examination, however, of Golgi's drawings in the papers published in the decade intervening between publication of his method (1873) and the beginning of his studies on malaria (1885) shows that axonal arborization in the cerebellar cortex and olfactory bulb are depicted as independent of one other. This is in striking contrast with the drawings included by Golgi in his 1906 Nobel lecture where the entire granular layer of the cerebellar cortex is occupied by a network of branching and anastomosing nerve processes. Thus, Golgi in his original papers on the cerebellum represents nerve cells as discrete units and only later in life merges axonal arborizations in the context of a lecture in defense of the reticular theory.

Golgi in retrospect: a historiographic examination of contextual influence in tracing the constructs of neuronal organization.

The concepts underlying the connectivity of neurons and the dynamics of interaction required to explain information processing have undergone significant change over the past century. A re-examination of the evolution of the modern view in historical context reveals that rules for connectivity have changed in a manner that might be expected from critical analysis enabled by technical advance. A retrospective examination of some germane issues that moved Camillo Golgi to question the widely held dogma of his era reveals network principles that could not have been recognized a century ago. The currently evolving rules of cellular discontinuity and interaction have proven sufficiently complex to justify the arguments of critical skepticism that sustain scientific progress.

The rise and fall of Golgi's school.

The Camillo Golgi's school of Histology and General Pathology in Pavia played an important role in the development of medical-biological studies in Italy in the period after Unification of the state. Founded around 1880 when Golgi (1843-1926) began to wield power at the University of Pavia, the school soon became famous for the distinctive morphological basis of its studies. Many of its staff members made important discoveries and won international acclaim. The school however went into decline after 1910 because of its rigid adherence to the morphological approach that had characterized its golden years at a time when the international scientific world was developing other fundamental methodological criteria for medical-biological studies.

The first images of nerve cells: Golgi on the olfactory bulb 1875.

The third paper by Camillo Golgi on his new method was on the olfactory bulb. This paper has never been translated into English, but is of special interest both for its pioneering description of olfactory bulb cells and for containing the first illustration by Golgi of cells stained with his new method. A translation into English is provided in this paper, together with commentaries on the significant points in his descriptions. These results are placed in the perspective of Cajal's subsequent first publication on the olfactory bulb and brief mention of the work of other early histologists. This perspective allows one to see more clearly Golgi's fundamental contributions to the olfactory bulb in particular and to the description of the neuronal architecture of the brain in general.

The growth cone as seen through Cajal's original histological preparations and publications.

During the development of the nervous system, each neuron must contact its appropriate target cell in order to establish its specific connections. More than a century ago, Ramon y Cajal discovered an amoeboid-like structure at the end of the axon of developing nerve cells. He called this structure the growth cone [cono de crecimiento] and he proposed that this structure was guided towards its target tissue by chemical substances secreted by the different cells that line its course. We have reviewed the discovery of the growth cone by Cajal using his original publications, his original scientific drawings, and by studying his histological preparations conserved at the "Instituto Cajal" (Madrid, Spain).(1) We found a very good correlation between the structure of the growth cone in the Golgi-impregnated and reduced silver-nitrate-stained material used by Cajal, and that which is revealed with present-day methods. Finally, Cajal's view of the function of the growth cone and his chemotactic hypothesis will also be considered in the light of present-day knowledge.

Lennart Heimer: concepts of the ventral striatum and extended amygdala.

Dr. Lennart Heimer, the famous neuroanatomist of Swedish descent, died last year but left a legacy that will impact the neurosciences and potentially psychosurgery for years to come. He developed an anatomical technique for demonstrating the terminal boutons that helped to delineate basal forebrain anatomy. During these studies, he realized the relationship of basal forebrain structures to the limbic system, thus initiating the concept of the ventral striatum and parallel basal ganglia circuitry. Heimer excelled as a teacher as well and honed his brain dissection technique to one of the most effective tools for understanding neuroanatomy. His legendary sessions with neurosurgical residents resulted in his recognition as one of the world's leading fiber tract dissectors. His gentle, engaging manner has been documented in several media formats.

Neuroanatomy: Cajal and after Cajal.

This essay commences with a consideration of the relative contributions of Cajal and Golgi to the study of the anatomy of the nervous system. It demonstrates the extent to which Cajal depended upon Golgi's work and how his modifications of the Golgi technique permitted a remarkable series of investigations in which the foundations of the neuron doctrine were laid and in which the intrinsic connectivity of virtually every part of the central nervous system was charted. Cajal's readiness to seize on and develop new techniques was one of the many keys to his success. After him, neuroanatomical studies tended to be focused more on long tract connectivity, using techniques such as those of Nissl and Marchi that had been in place before Cajal commenced his studies. Development of degeneration-based techniques of tracing connections in the late 1950s spearheaded a revolution in neuroanatomy while introduction of mixed aldehyde fixation made possible similarly intensive studies of the fine structure of the nervous system. At this time, the Golgi technique experienced a brief resurgence as neuroanatomists made efforts to bridge the gap between light and electron microscopy. Later developments in techniques for tracing connections included anterograde tracing by autoradiography and retrograde tracing by horseradish peroxidase. These were soon superseded by tracing techniques of increasing sensitivity and specificity that rely upon the cellular and molecular biology of neurons. Although neuroanatomy in its traditional form is perhaps no longer fashionable as a discipline, the techniques of neuroanatomy remain preeminent in many, perhaps all areas of neuroscience.

The contribution of Camillo Golgi to our understanding of the structure of the nervous system.

A hundred years ago Camillo Golgi and Santiago Ramón y Cajal were awarded the Nobel Prize for Physiology or Medicine for their investigations on the structure of the nervous system. The work of Cajal is universally acknowledged, whereas Golgi's contribution is less well known. This article reviews the main achievements of Golgi in that field. In addition to Golgi's most important results, the errors he made in interpreting his own findings are examined. These errors contributed notably to a widespread neglect and underestimation of his important contributions to our understanding of the structure of the nervous system.