CHAPTER 1 NEURAL SCIENCE; Mark Ralph Rowe; San Diego, California (Golden Hills) 92102; 11/17/2013

1.1 INTRODUCTION AND OVERVIEW JACK A. GREBB, M.D. The neurosciences are fundamentally important to the clinical specialties of psychiatry,  neurology, and neurosurgery because they explore the biology of neuronal tissues.  Two sub-specialty areas within psychiatry--neuropsychiatry and biological psychiatry--have particularly endeavored to integrate neuroscientific information neuroscientific information with clinical psychiatry.  It is unfortunate in some respects that these subspecialty concepts have evolved, since an appreciation for the basic neurosciences should infuse the clinical approaches of all professionals working with the mentally ill. MISLEADING DICHOTOMIES  There is a common tendency to divide and distinguish phenomena, even in the absence of adequate data.  This tendency has had unfortunate consequences for the mentally ill.  In recent history, people inflicted with diseases that were not understood (e.g., tuberculosis, cancer) have been ostracized from society.  Once the conditions were understood as medical diseases, these outcasts entered the relative comfort of a medical model for their afflictions.  Patients with  mental illnesses are currently caught in a transitional phase in this process.  The general  acceptance of mental illness as a disease of the brain is currently hindered by at least five misleading dichotomies. > Neurology vs. psychiatry  The clinical distinction between neurology and psychiatry is increasingly appreciated as awkward and artificial  (Chapter 2).  Neurology has traditionally focused on organic disorders with identifiable pathology, whereas psychiatry has focused on functional disorders without observable pathology.  Regardless of intentions, the implication in that neurological disorders are real diseases, whereas psychiatric disorders are not.  Functional, in this context, actually means that the pathophysiological basis has not been discovered yet--not that one does not exist.  A better term for functional might be idiopathic. The mind-brain dichotomy  The mind and the brain share the same organ.  Mind is what is called the personal experience of the brain or perhaps the experienced of change in the brain.  How can the complexity of the mind be explained by the brain?  First, the brain is undoubtedly more complex than is currently known; second perhaps minds are not as complex as generally thought. Nature vs. nurture  There is no contest: nature is nurtured, and nurture has a nature.  Nature and nurture are mutually interacting systems.  It has been shown clearly that the environment (i.e., nurture) can affect biology at very basic molecular levels (e.g. branching of dendrites, activity of enzymes).  Nurture itself can be seen as a reciprocal biological event.  Human beings affect one another, and there exist biological changes paralleled to the subjective experiences. Structure vs. function  All mental activities (behavior, thoughts, feelings) are paired with biological events in the brain.  The techniques of basic neuroscience can potentially identify the structural correlates of mental activity at the level of genes and other molecules.  The division between structure and function rest solely on which biological level is arbitrarily chosen as a cutoff point.  A more accurate approach is to accept that each biological disorder, including mental illness, has a structural pathology at some level or assortment of levels, and that this structural abnormality is reflected as a disorder of function or regulation. Biology vs. psychology  This dichotomy is both a derivative of the mind-brain issue and an unfortunate offshoot of debates within the field of psychiatry.  Biology, psychology, empirical observations.  The level and descriptive lexicon used to describe behavioral phenomena can be varied.  Ina particular situation, one model might be more enlightening or clinically appropriated than another.  OVERVIEW OF NEURAL SCIENCES The aim of this 15-section neural sciences chapter is to provide a brief introduction to the basic science principles that underlie that many biological theories, organic therapies, and research findings discussed in the chapters on specific clinical disorders.  Therefore, the sections within this chapter do not systematically review the relationships between their topics and relevant clinical disorders.  Therefore, the sections within this chapter do not systematically review the relationships between their topics and relevant clinical disorders.  Rather, this chapter can either be read as an introduction to basic biological principles or used as a reference when reading about biological material in subsequent chapters. NEUROANATOMY  Classical neuroanatomy (Section 1.2) describes regions and connections in the brain based primarily on observations from gross neuroanatomy.  Functional neuroanatomy (Section 1.3) is based more on data from studies defining the distribution of specific molecules (e.g., neurotransmitters) and from studies using advanced histochemical techniques that have defined more clearly the projection patterns of neuronal populations.  Functional neuroanatomy is possibly more relevant to psychiatric disorders than is classical neuroanatomy are slowly eclipsing some of the previous tenets of classical neuroanatomy. Neurons  The neuron, or nerve cell, is the basic functional unit of the nervous system.  Neurons vary widely in terms of size, shape, number f synapses, and chemical constituents.  The cell body, also called the some or perikaryon, typically gives rise to axons and dendrites.  The axon arises from the cell body or the base of one of the main dendrites.  The initial axon segment, the axon hillock, actually is the site of initiation for the action potential in many neurons.  Enlargements at the ends of axons are called axon terminals, or boutons, and are the sites of presynaptic neurotransmitter release.  Within the axon terminals are the synaptic vesicles, which contain neurotransmitter substances.  There are different types of synaptic vesicles, varying in sized, shape and other visual characteristics.  THese different types often contain different neurotransmitters, and conceivably these vesicles respond differentially to stimulation of the axon terminal.  There may be one or many dendrites (or none at all) emerging from the cell body.  Dendrites are usually profusely branched, and most are studded with small spikes, the dendritic spines, which along with somata and dendritic shafts, are the sites of synaptic connections. Gila  Glia, glial cells, or neuroglia are synonymous terms for a class of non-neuronal cells in the nervous system (CNS)--astrocytes, oligodendrocytes, ependyma, and microglia--and two types in the peripheral nervous system--Schwann and satellite cells.  The astrocytes provide structural support to neurons and are the major cell type in glial scar tissue in the CNS.  The oligodendrocytes are the myelin-forming cells of the CNS and also may perform a nurturing role for neurons.  Both astrocytes and oligodendrocytes are involved in phagocytosis. of the spinal cord.  The surfaces of ependymal cells have a more direct and critical role in neuronal activity than is currently believed. Blood-brain barrier  An important feature of the brain to which glial cells contribute is the blood-brain barrier, a semipermeable barrier between the blood vessels and brain that prevents many chemical compounds from passing between brain and blood.  The ability of a molecule to cross the blood-brain barrier is based on its molecular size, electric charge, solubility, and the presence of specific transport systems for the compound.  The endothelial cells of brain capillaries differ from other capillaries because they are virtually continuous with each other and lack the pinocytotic vesicles that have been implicated in transport of substances from one side of the membrane to the other.  The biogenic amine neurotransmitters (e.g., clinical trials of a new drug)l Membranes  All cells, including neurons and glia, are enclosed in cell membranes that function as a complex regulatory site.  The membrane is a sea of phospholipids, organized as a bilayer either the hydrophobic ends of the lipid molecules pointing toward the middle of the membrane.  Within this lipid bilayer are various types of protein molecules.  Some proteins are embedded in the external or internal surfaces of the membrane.  Neurotransmitter receptors (Section 1.4), for example, are proteins that are located partially on the outside surface of the membrane and transmit a message to another protein (e.g., and enzyme [Section 1.6]) that is located on the inside surface of the membrane.  Other proteins, such as ion channels (Section 1.7), extend the entire width of the membrane. Cerebrospinal fluid  The CNS ventricular system is filled with CSF, produced by the cerebral plexi in the cerebral ventricles.  CSF leaves the ventricular system via the median aperture of Magendie and the two lateral apertures of Luschka and is then absorbed into the venous system through the drainage resulting in increased CSF pressure.  THis can often be seen in computed tomographic (CT) scans by the presence of dilated ventricles.       The CSF has a volume of approximately 125 ml in the normal adult, and approximately 500 ml are made each day.  The total volume of CSP, therefore, is replaced approximately four time each day.  The use of lumbar punctures to obtain CSF is routine neurological practice.  The CSF also is a source of research information in psychiatry because it reflects neurochemical activity in the brain.  However, metabolites from the spinal cord may significantly contribute to the chemical content of CSF, and neurotransmitter metabolites from deep brain structures may not reach the CSF efficiently.  Other consideration when evaluation research data based on CSF measurements are the possibilities of a vertical gradient in the concentration of the chemical within CSF and also of rhythmic variations of production of the chemical with time (e.g., diurnal variation). NEUROTRANSMISSION  Neurotransmission can occur either through chemical or electrical synapses.  The role of electrical synapses, also called gap junctions, in the CNS is poorly understood.  IN contrast, a great deal is known about chemical synapses.  Chemical neurotransmission classically involves a presynaptic neuron that releases a neurotransmitter that diffuses across a synaptic cleft, where it binds to a specific receptor that initiates a series of molecular events in the postsynaptic neuron.  THe three major classes of chemical postsynaptic neuron.  The three major classes of chemical neuronmessengers are biogenic amines (also called monopeptides (Section 1.4), amino acids (Section 1.4), and neuronpeptides (Section 1.5).  The intraneuronal release and following receptor activation have recently been defined (Section 1.6). Synapses  The most conventional types of chemical synapses are the axo and axo-somatic synapses, in which the axon of the presynaptic neuron synapses, with a dendrite of the cell body, respectively, of the postsynaptic neuron.  Such synapses may be inhibitory, excitator, or modulatory.  IN axo-axonic synapses, the presynaptic axon synapses with the axon hillock or axon terminal of the postsynaptic neuron.  Such synapses may be inhibitory, excitatory, or modulatory.  In axon-axonic synapses, the presynaptic axon synapses with the axon hillock or axon terminal of the postsynaptic neuron.  It is thought that their synapses are usually inhibitory.  Two more recently discovered synapses are dendrodendritic and dendroaxonic.  Both of these synaptic types are and do not elicit postsynaptic action potentials.  One final complication of synapses is that nonsynaptic neurons probably exist as well.  These are neurons with axon terminals that CSF and therefore do not have synapses with specific neurons and may function in a paracrine fashion. Receptors  Receptors (Section 1.4) are proteins in the neuronal membrane that are, in part, exposed to the extracellular fluid and specifically recognized neuromessengers.  To be classified as a receptor, the binding to this protein should be saturable, specific, and reversible.  Saturable means that in experimental preparations it can be demonstrated that there is a finite number of the receptors present.  Specific means that the receptor binds, relatively speaking, only the alleged neurotransmitter fro that receptor. Binding to a functionally meaningful receptor os reversible, which means that the receptor must first bind, then release, the neurotransmitter so that the receptor subsequently can respond to another message.  The term putative receptor is often used to describe a binding site that has not yet been definitively shown to have all the properties required of a receptor.      Receptors can be either postsynaptic or presynaptic.  In an axo-dendritic synapse, for example, the receptors on the receiving dendrite are postsynaptic.  Receptors on the axon itself are presynaptic.  They are called either presynaptic autoreceptors if they bind the neurontransmitter released by their patent neuron or presynaptic heteroreceptors if they hind a neurotransmitter released by some other neuron.     The concepts of super-sensitivity and sub-sensitivity are applied to receptors.  When demonstrated appropriately, these properties signify that a specific postsynaptic neuron responds in either an augmented or attenuated fashion to a constant amount of neurotransmitter.  Such regulation of synaptic response could come from three receptor related changes.  First, the number of receptors available for neurotransmitter binding could increase or decrease.  Second, the binding affinity of the receptor for the neurotransmitter molecule could increase or decrease.  Third, the molecular mechanism by which the receptor translates its message into the neuron could be more or less efficient. Neuromessengers Neuromessenger is a generic term that includes neurotransmitters, neuromodulators, and neurohormones. The term neurotransmitters, however, is also commonly used to mean any type of chemical interneuronal message. More specifically, however, neurotransmitters are the classic neuromessengers that are rapidly released by the presynaptic neuron upon stimulation, diffuse across the synaptic cleft, and have either an excitatory or inhibitory effect on a postsynaptic neuron. Neuromodulators also bind to specific receptors, but are conceptualized as tuning or grading specific receptors, but are conceptualized as tuning or grading the response of the postsynaptic cell to the neurotransmitter. It obviously is somewhat arbitrary and artificial to decide how much tuning is merely modulation as opposed to actual transmission. Neurohormones are chemical messengers that are released by neurons into the bloodstream, rather than into the synaptic cleft or extraneuronal space. The differentiation of these three different neuromessenger types is usually less clear in actuality. Furthermore, any specific chemical may act in all three roles depending on the specific synaptic or neuronal system under consideration. Other chemical messengers In addition to biogenic amines, amino acids, and neuropeptides, there are other chemical messengers that are the subject of active research investigations. The eicosanoids include arachidonic acid and its metabolites--prostaglandins (PGs), thromboxanes, and leukotrienes. Although all of the eicosanoids are involved in neurochemical processes, the prostaglandins have been most studied in neuropsychiatric disorders. The eicosanoids differ from classical neurotransmitters in that they are not synthesized and then stored fro future release; rather, they are synthesized de novo when needed. The PGs are subtyped into several series (D, E, F, etc.) and series subtypes (e.g., PGE2). The PGEs have been hypothesized to have a role in the sedative, anticonvulsant, and analgesic effects of various medications. Lithium has been reported to decrease PGE1 stimulation of adenylate cyclase, and tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) have been hypothesized to act through down-regulation the activity of PGE2. Adenosine is a nucleoside that functions as a neuromessenger. The adenosine receptors are linked to adenylate cyclase such tat A1 receptors inhibit cyclic adenosine monophosphate (cAMP) production and A2 receptors stimulate cAMP production. Two other nucleosides, guanosine and inosine, may also function as neuromessengers Electrophysiology and clinical brain imaging THe electrophysiological properties of single neurons (Section 1.8) can largely be explained by the movements of four ions--sodium, potassium, chloride, and calcium--across the neuronal membranes. The effects of neuromessengers and sys drugs are ultimately translated into changes in the fluxes of these ions. Several clinical test--=electroencephalograms, evoked potentials, and computerized mapping of brain electrical activity )SEction 1.8)--measure the mass effects of these ionic changes. Both gross anatomy and brain function can now be imaged in living human subjects (Section 1.10). CT and magnetic resonance imaging (MRI) can image gross anatomy. Positron emission tomography (PET), regional cerebral blood flow (rCBF), magnetic spectroscopy, and single photon emission computed tomography (SPECT) measure various aspects of the brain function. Psychonoendocrinology and psychoneuroimmunology The nervous system, the endocrine system (Section 1.11), and the immune system (Section 1.12) are the three bodily systems that can communicate within themselves though complex chemical signals. It is now appreciated that each of these systems also can communicate with the other two, creating a triad of intercommunicating systems (Section 1.12). THe neuroendrocrine system may be the major mediator of of environmental stress, and soon the neuroimmune system may help explain the pathophysiology of psychosomatic disorders. Someday, the seemingly straightforward division of disorders into neurological, immunological, or endocrinological may seem archaic. Chronobiology and plasticity in the mature CNS Virtually every objective biological measure discussed in Sections 1.2 to 1.12 changes with time in a regular fashion. THe study of these biological rhythms is called chronobiology (Section 1.13). THe brain is a plastic, mutable organ that also evidences nonrhythmic changes (Section 1.14), such as changes in the neuronal shape, the number and quality of synaptic connections, and the intraneuronal molecular contents. Although, for all intents and purposes, mammalian neurons cannot divide in the adult, there remain remarkable mechanisms for moderating changes in the CNS. Genetics Molecular genetics (Section 1.15) is the study of genes and gene expression at the basic chemical level. The techniques of molecular genetics have made it conceptually possible to diagnose, prevent, and treat mental disorders at this most basic molecular level. Although molecular genetics currently is one of the most exciting areas of neuroscience, population genetics, the study of the inheritance of phenotypes is groups of individuals, provides the historical and conceptual foundation for much of biological oriented psychiatry. Research Strategies in descriptive population genetics In addition to linkage studies (Section 1.15) there are five general types of studies in descriptive population--pedigree analyses, family risk studies, twin studies, adoption studies, and high-risk studies. The validity of any of these of investigations requires both an unbiased identification and an accurate diagnosis of all subjects studied. Pedigree analysis Pedigree analysis involves the study of individual families that contain members who are affected by the disorder under investigation. Family tress can be constructed to diagram marriages, children, deaths, and affected by the disorder under investigation. Pedigree analysis can suggest hypothesis regarding whether disorders are inheritable and what the type of inheritance might be (e. g., dominant, recessive, X-linked). However, because of the small number of individuals who have been studied, as will as the biased ascertainment method and the possible role of nongenetic environmental influences, pedigree analysis is generally useful only for the generation of hypothesis that will subsequently be tested by other types of studies.