Alan G Watts. Learning and Memory. Editor: John H Byrne. 2nd edition, Macmillan Reference USA, 2004.
The adult human brain weights about 1,400 grams, the heaviest of any species relative to total body weight. This perhaps most impressive human organ appears to be responsible for our intellectual superiority over other species—although, paradoxically, human intelligence is not strongly correlated to brain size.
The modern discipline of neuroanatomy has developed over the past 400 years through the descriptive studies of workers such as Vesalius, Willis, Retzius, Purkinje, Brodmann, Campbell, Ramón y Cajal, and Golgi. Rather than answering a pedestrian question—What does it look like?—the main objective of studying anatomy of the brain is to create physiologically and psychologically meaningful structural inferences. The capacity and the choice of visualization methods define the level of differentiation of the brain structure from gross features to a single neuron.
In actuality, the anatomy of the brain proceeds on four levels, depending on the aim of the description. At the most superficial level, based on the evolutionary and embryonic development, the brain can be divided into the forebrain, the midbrain, and the hind-brain. In development, neurons, which consitute these subdivisions, multiply, develop distinct appearance and aggregate into groups forming nuclei, layers, or areas of the brain. This cellular level of brain anatomy, called cytoarchitectonic, differentiates cell types and their location. Further differentiating brain structures are the biochemical properties of neurons, which permit classification of different cell groups into chemically coded systems. At the most sophisticated level of resolution development are cytoarchitecture and chemoarchitecture, along with information about cellular connections and aspects of neuronal functioning. These eclectic criteria of structural classification provide the most meaningful structural references within the general scope of brain and bodily function.
In early embryonic development the brain has rather simple gross features and is composed of just three vesicles, the hindbrain, the midbrain, and the forebrain. These soon subdivide to give place to more complicated arrangement of four vesicles: rhombencephalon (parallelogram-brain), mesencephalon (middle-brain), diencephalon (between-brain) and telencephalon (end-brain) (many neuroanatomists still use Greek to name newly discovered structures). Progressive development gives the brain a sophisticated form, which is traditionally segmented into numerous smaller structures on the basis of gross anatomical features. For example, the frontally positioned forebrain gives rise to two voluminous hemispheres of the cerebral cortex (brain “bark”) separated from each other by the longitudinal fissure. The surface of the cortex is convoluted into folds known as gyri, which are separated by groves known as sulci. The cortex enfolds numerous subcortical neuronal structures, such as thalamus (the main relay for neural input to the cortex), hypothalamus (the neuro-hormonal regulatory center that keeps the rest of the body alive), hippocampus, and amygdala (structures implicated in emotional behavior, learning, and memory), caudate, putamen, and globus pallidus (major parts of the so-called basal ganglia, which seem to play a role in learning and control of movement). Other obvious gross features of the forebrain include cerebral ventricles (a network of fluid-filled cavities) and prominent fiber tracts such as the external capsule, which interconnects the cortex with sub-cortical structures and spinal cord, and the corpus collosum, which connects two cortical hemispheres.
The midbrain in mammals is a much smaller structure than the forebrain. Topographically the midbrain is a caudal continuation of the thalamus and the hypothalamus. Two major gross features of the midbrain are the upper tectum (the roof) and the lower tegmentum (the covering). (Latin terminology is still prominent in neuronatomy alongside the Greek.) The tectum also features two swellings on each side of the midline: the superior and the inferior colliculi, which harbor major visual and auditory pathways, respectively. Another prominent feature of the midbrain is the cerebral aqueduct, a canal connecting ventricular systems of the forebrain and the hindbrain.
The most caudal part of the brain, the hindbrain, is composed of three major parts: the pons (bridges), the cerebellum (small brain) and the medulla oblongata (long brain). In neuroanatomy the medulla, pons, and midbrain are often collectively refered to as the brain stem. The pons are positioned immediately caudally to the midbrain and appear as a large protuberance (a bridge) on the ventral surface of the brain. Dorsally the pons are covered by the tegmentum pontis, which is a caudal continuation of the mesencephalic tegmentum. The cerebellum is positioned on the posterior surface of the brain and connected to it by three pars of cerebellar peduncules (pillars). In gross terms the cerebellum features two lateral hemispheres abutting the middle structure called the vermis (worm). Finally, the medulla is the most posterior part of the brain, immediately succeeded by the spinal cord. Superficially, it resembles the spinal cord with the major exception of the presence of bilateral inferior olives on its ventro-lateral surface and the floor of the fourth ventricular cavity on its dorsal surface.
The brain of humans and the head ganglion of mosquitoes are both made up of two general types of cells: neurons and glial cells. Although glial cells are the most numerous cells in the brain—they outnumber neurons by about twenty-five to one—it is neuronal activity that is associated with brain function. Neurons show greater diversity in shape and size than any other type of cell in the body. In contrast to other cells in the body, neurons can generate and relay electrical impulses—”action potentials.” In order to transmit action potentials over great distances, neurons have extended processes—axons that, for some spinal motor neurons of large mammals, may have lengths on the order of meters.
Since neurons usually do not communicate by direct contact—each neuron operates as an independent unit—they have evolved highly specialized points of interaction: synapses. Synapses are essentially clefts between neurons. They are asymmetrically flanked by structures that release specialized chemicals neurotransmitters from one presynaptic neuron in response to the presence of action potentials. The response of the recipient—the postsynaptic neuron—is determined by highly specific detectors: receptors. The structure of the synapse allows information to flow in one direction only. Throughout the nervous system different neurons utilize a multiplicity of both neurotransmitters.
Staining cellular ribosomes with a Nissl substance stain allows light microscopic visualization of the cellular morphology of the brain. This process reveals that neurons within the various parts of the brain look different and are not evenly distributed—they are, rather, grouped into structures, which make up the cytoarchitectonic plan of the brain. The form, size, and position of neurons in the cerebral cortex reveal the layered organization of this structure. Studies have demonstrated differences in cytoarchitectonic organization of neuronal layers in different parts of the cortical mantle. These differences lead to the differentiation of fifty-two cortical areas in the frequently used cortical map of Brodmann.
Subcortical structures demonstrate even greater cytoarchitectonic diversity. In small areas of the thalamus and hypothalamus, neurons are grouped into numerous nuclei, areas, and zones with distinct morphological characteristics and topographical positions. The hypothalamus, for example, contains over forty nuclei and areas on either side of the third ventricle with distinct cytoarchitectonic characteristics. Cytoarchitectonic differentiation can go even further: The paraventricular nucleus of the hypothalamus is composed of ten subnuclei of specific neuronal types and topographical positions. These subnuclei also differ in function. Reflecting back onto brain areas identified by their gross anatomical features, most of them show complicated cytoarchitectonic organization. Several cytoarchitectonically distinct nuclei have been identified in the amygdala, whereas the layered organization of neurons in the hippocampus shows only four distinct areas. Cytoarchitecture has revealed an internal and an external component of the globus pallidus and has shown that neurons in the putamen are organized in patch-matrix compartments.
There are several neuronal groups in the mid-brain, the best known of which is the substantia nigra (black substance), a complex, compartmentalized structure whose cells die in Parkinson’s disease. Neurons of the superior and inferior colliculi are organized in layers, while the tegmentum contains nuclei of the oculomotor and trochlear cranial nerves responsible for eye movement and pupil constriction. The periaqueductal gray, another distinct cellular structure of the midbrain, is composed of neurons surrounding the cerebral aqueduct and appears to play a role in the regulation of blood pressure.
The cytoarchitecture of the pons also features several cranial nerve nuclei, raphe nuclei, and a dispersed area called the reticular formation, which is, however, not confined to pons but is spread throughout the entire brain stem. The cytoarchitecture of the cerebellum resembles the citoarchitecture of the fore-brain in also having a cortex with a layered arrangement of cells and several subcortical nuclei.
In contrast to the diverse cytoarchitecture of the cerebral cortex, that of the cerebellar cortex is very homogeneous. Although topographically the medulla can be viewed as a dorsal extension of the spinal cord, the cytoarchitecture of the medulla differs radically from that of the spinal cord and embodies a tightly packed amalgam of dispersed areas, compact nuclei, and fiber tracts. The medulla contains nuclei of several cranial nerves, including the nucleus of the hypoglossal nerve and a complex of nuclei of the vagus nerve. In fact, many medullary nuclei boast complex compartmental cytoarchitecture; the nucleus of the solitary tract, for example, is composed of nine cytoarchitectonically distinct sunuclei.
Glial cells are the most numerous cells in the central nervous system. They are less complex than neurons, and they show less structural diversity. Unlike neurons, they retain the ability to divide, a facility they use in their participation in the reaction of nervous tissue to injury. There are two types of glial cells in the CNS: oligodendrocytes and astrocytes. The peripheral nervous system contains a related cell type, the Schwann cell, which is crucial to the formation and maintenance of the myelin sheaths of peripheral nerves. Within the brain, glial cells are involved with structural and metabolic maintenance of neuronal function and the blood-brain barrier. During the fetal and postnatal development, glial cells play a role in axon guidance and the correct arrangement of neural patterns.
An overview of the cellular anatomy of the brain would be incomplete without reference to the ependymal cells lining the cerebral ventricles, the meningeal membranes surrounding and physically supporting the brain, and the network of blood vessels that form the vascular supply to the brain. Unlike neurons and glial cells, these elements are not exclusive to the nervous system. They share many common structural and functional features with other support cells found throughout the body.
For most of the twentieth century, the understanding of human neuroanatomy was gleaned mainly from cytoarchitectonic observations. The most widely used maps of the human cortex were produced by Brodmann in 1909 on the basis of Nissl substance and myelin staining, while the most detailed neuroanatomical description of the human hypothalamus was published by Brockhaus in 1942 and was also based on early cytoarchitectonic techniques. The main shortcoming of early neuroanatomical techniques was their distance from the mechanisms underlying human brain function. One of the most exciting developments in neuroanatomy 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. Chemoarchitecture establishes a bridge between structural and functional characteristics of neuronal populations in the brain. 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 useful in identifying chemically specified connections in animals. Finally, it has helped to derive hypotheses on the function of brain pathways and nuclei. Chemical neuroanatomy has developed as a branch of the structural brain mapping methodology that was previously based largely on cytoarchitectonic 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.
Studies using chemical neuroanatomy were first carried out in rats to facilitate logistical and technical applications. It was not until the 1980s that the chemoarchitectonic techniques of histochemistry and immunohistochemistry became sensitive enough to allow their full application to human brain tissue. Thus, it became increasingly possible to reveal the distribution of some of the important neurotransmitters, receptors, and enzymes of in the human brain and then make cross-species comparisons. An advantage of chemoarchitecture is that each chemical substance offers a different window on the organization of the central nervous system, with successive stains revealing more of the areas of interest. There are, of course, significant species differences, and any given substance may have inconsistent distributions in otherwise homologous nuclei and areas. Nevertheless, in terms of overall value, chemoarchitectonic delineations have become a preferred method in comparative neuroscience. 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 γ-aminobutyric acid (GABA) are neuroactive chemical compounds that can characterize neuronal subgroups. However, the term chemoarchitecture implies the use of chemical compounds for differentiation between neuronal populations. These compounds are not only neurotransmitters but can also be enzymes, receptors, peptides, and molecules related to neuronal metabolism—calcium-binding proteins, for example.
Catecholamines are a family of functionally important neurotransmitters. The application of the tyrosine hydroxylase enzyme immunohistochemistry allowed the identification of fifteen groups of catecholaminergic neurons in the mammalian brain. These cell groups were not confined to traditional cytoarchitectonic boundaries and sequentially were termed A1 to A16 (there is no A3 cell group), extending throughout the mammalian brain from the medulla to olfactory bulbs. In the human, as in the rat, the majority (A1-A2 and A4-A10) of catecholaminegic neuronal groups were found in the brain stem, where, for example, tyrosine hydroxylase immunostaining has been used to delineate the intermediate reticular zone. Four prominent tyrosine hydroxylase positive catecholaminergic cell groups (A11-A15) are located in the hypothalamus and one (A16) in the substantia innominata of the ventral forebrain. The later cell group is thought to be homologous to the rat’s catecholaminergic cell group in the olfactory bulb. Subsequent work has shown that cell groups such as the A1 and C1 catecholaminergic neurons are critical for autonomic control in experimental animals and also that these cell groups are strikingly similar in rats and humans. A number of studies used multiple markers to confirm a high degree of conservation in the chemical identity of brain-stem neurons among rats, monkeys, and humans.
Neuropeptides are largely neuron-specific chemical compounds that, depending on the neuropeptide, are characteristic of specific neuronal subgroups. For example, vasopressin is characteristic of large cells in the lateral magnocellular subnucleus of the paraventricular hypothalamic nucleus. The corticotropin-releasing factor (or hormone CRF) is a neuroendocrine peptide in the cortex, basal telencephalon, brain stem, and hypothalamus. The distribution of CRF is very specific. In neuroanatomy CRF distribution has been used in the human brain to distinguish the subcompartmental organization of specific nuclei in the medulla and hypothalamus. In the paraventricular hypothalamic nucleus, for example, CRF neurons are confined to the parvicellular compartment, whereas the neurons that contain oxytocin are found primarily in the dorsal compartment. Applying these two markers to the same brain allowed researchers to distinguish between these subcompartments, which otherwise appear to be amalgamated, and also allowed the establishment of subcompart-mental homologies between the paraventricular nucleus in rats and humans.
As an example of a distinct receptor distribution, the NK3 receptor (a component of Neuromedin K peptide circuitry) in the human hypothalamus was found in neurons of the paraventricular nucleus, specifically in the parvicellular and posterior subnuclei, thus distinguishing these structural subcompartments. Another prominent population of NK3-containing cells in the human hypothalamus was found in the perifornical nucleus, distinguishing it from the rest of the lateral hypothalamic area. The neuromedin K circuitry in experimental animals seems to play an important role in blood-pressure regulation; in cross-species comparison there were marked similarities in the distribution of NK3 in the human and rat hypothalamus.
The anatomy of functional systems reflects, first of all, the neural basis of specific neural functions. At the systems level we can introduce a functional aspect to structural neuroanatomy. By this means we can begin to address which regions are involved with which function and determine those aspects of cellular and regional anatomy that contribute to specialized functions. For example, in the visual system the sensory part is made up of a sensory transducer (the retina) and a sensory nerve (the optic nerve). After some initial processing, these components transmit visual information into two structures in the thalamus and midbrain (the lateral geniculate nucleus and then the superior colliculus) for further processing. Visual information is then projected to the visual regions of the neocortex (in the occipital lobes) for final assessment. Cellular and regional neuroanatomy can tell us the detailed structure of each component, but at the systems level we want to know how the components interact: which neurotransmitters are used in which connections, which cells receive which type of information, and what routes are used between the various structures.
It is important to study the connections between neuronal groups. There are various techniques that reveal neuronal connections, including axonal degeneration, anterograde and retrograde tracing, various dyes, and even virus tracing, which enables researchers to trace not just one affiliation but an entire functional pathway. Techniques such as the tensor MRI (magnetic resonance imaging) allow the identification of projection and their direction in the living brain. Combined with cytoarchitecture tracing techniques, such advances have enabled researchers to make meaningful conclusions about the neural circuitry underlying specific functions.
Many of the pioneer neurophysiologists (e.g., David Ferrier, Charles Sherrington) who provided the seminal experimental observations of the functions of the nervous system appreciated the contributions that neuroanatomy made to the interpretation of their findings. Since the same strategy is still a prerequisite for the neuroscience of today, a great deal of current research concentrates on describing the direction and the biochemical and molecular composition of the neurons connecting different neural systems.
The complicated array of cell groups and fiber pathways in the brain form an incestuous web rather than a hierarchy; however, the connecting threads can be teased apart thanks to advances in neuroanatomical methods that allow a cellular level of resolution.