r r r Cell Signalling Biology Michael J. Berridge Module 10 Neuronal Signalling 10 1 Module 10 Neuronal Signalling Synopsis The brain contains approximately one trillion (1012) neurons that are located in different brain regions. Within each region, neurons are connected to each other to form neural circuits of bewildering complexity. To function in such circuits, each neuron must receive and process information entering from one set of neurons and then relay signals to other neurons in the circuit. The neuronal processes of signal reception and transmission are key elements of neuronal function and are located at opposite ends of the neuron. Specific attention will be focused on the operation of neural circuits in regions such as the hippocampus, cortex, cerebellum and the respiratory centre in the brainstem. Neural circuits are established during development and remain relatively constant throughout adult life. The only exception in humans is the hippocampus, where the neuronal elements of the circuit are constantly being replaced by a process of neurogenesis. In addition to the large number of neurons, the nervous system contains an equally large number of glial cells,suchasastrocytes and the microglia, insinuate themselves between the neurons to provide a functional scaffold. This is not a passive scaffold, because the glial cells and neurons carry on a constant two-way dialogue that is essential for the computational operation of the neuronal circuits. Neuronal morphology reveals that information is received at one end (the dendritic tree) and is transmitted at the synaptic endings at the opposite end. The key event is the process of synaptic transmission, during which presynaptic events release neurotransmitters from one neuron to induce localized excitatory or inhibitory postsynaptic events in the target neuron. The localized excitatory events are integrated to generate more global neural signals that trigger action potentials that initiate from the axon hillock. These action potentials then spread in two directions. They can flow in the forward direction down the axons to the synaptic endings. In addition, they can also flow backwards, and these back-propagating action potentials invade the dendritic tree to create global Ca2 + signals. A very important aspect of neuronal signalling concerns the action potential frequency, which can vary over a wide range. At one extreme, there is the circadian clock, where the output of the suprachiasmatic clock neurons changes over 24 h. At the other end of the scale, we have the very rapid transfer of information that occurs between neurons in the 0.5--200 Hz frequency range that characterizes the brain rhythms detected by electroencephalograms (EEGs). Any consideration of synaptic transmission must take into account the fact that the rate of synaptic transmission is often extremely high. Another example of the significance of timing concerns neuronal coincident detection, during which a neuron integrates information coming in from more than one input, as occurs during the processes of learning and memory. Modulation of neuronal activity can occur at many levels. Presynaptic events display a process of facilitation, whereby transmitter release is enhanced. Varying the permeability of K + channels can modulate membrane excitability, which determines whether or not a neuron will transmit information by firing an action potential. Information transfer across the synapse can also vary, and the mechanism of synaptic plasticity can persist for variable times. Enhancement of transmitter release through the process of facilitation is very brief, whereas the processes of long-term potentiation (LTP) and long-term depression (LTD), which are thought to be responsible for some memory processes, can last for hours. A process of memory consolidation functions to make these short-term changes more permanent through mechanisms that depend upon neuronal gene transcription and neuronal protein synthesis. Ca2 + plays a key role in this modulation of neuronal activity in that it can act locally to influence excitability and synaptic strength, or it can have global effects on gene transcription, neuronal survival and axonal outgrowth. The neuron is not a static unit, but is highly plastic, and this underlies the process of learning and memory. The remarkable aspect of neuronal plasticity responsible for learning is that memory acquisition can occur within seconds, and can then be retained for a very Green text indicates links to content within this module; blue text indicates links to content in other modules. Please cite as Berridge, M.J. (2012) Cell Signalling Biology; doi:10.1042/csb0001010 C 2012 Portland Press Limited www.cellsignallingbiology.org Licensed copy. Copying is not permitted, except with prior permission and as allowed by law. r r r Cell Signalling Biology Michael J. Berridge Module 10 Neuronal Signalling 10 2 long time in long-term memory (months to years) through a process of memory consolidation.In considering neuronal signalling, we therefore have to understand how individual neurons carry out their day-by-day computational functions while retaining the ability to form memories by suddenly modifying this capacity to process information. The section on hypothalamic pituitary regulation describes the interaction between the nervous and endocrine systems. The hypothalamus contains neurons that release a variety of hormones that regulate the endocrine cells located in the anterior pituitary. Some hypothalamic neurons, which send axons to the posterior pituitary, release hormones such as vasopressin and oxytocin. Neurons in the respiratory centre located in the brainstem have the respiratory pacemaker mechanisms that control breathing. Specialized neurons that function in the sensory systems are responsible for detecting information from both the internal and external environment. Photoreceptors in the eye are responsible for photoreception. Sensory neurons spread throughout the body function in nociception, temperature sensing and touch. Olfactory receptor cells in the nasal epithelium function in olfaction and taste receptors on the tongue function in taste. Hair cells in the ear are mechanoreceptors that function in hearing. Specialized cells and neurons function in the hypoxia-sensing mechanisms. Brain regions • Parietal lobe, which functions in perception, orienta- The brain is a highly complex organ that is divided into tion, recognition and movement. different functional regions. Each region has a specific • Occipital lobe, which functions in visual processing compliment of neurons that are connected together into • Temporal lobe, which functions in recognition of aud- local circuits to generate characteristic output signals that itory stimuli, speech and memory. are then sent either to other regions or to the periphery Both hemispheres of the cortex contain motor areas that as is the case for the motor neurons. The high degree control voluntary movements. The premotor cortex selects of connectivity between neurons is responsible for the out which movements to perform and these are then car- multiple computational processes carried out in these ried out by the primary motor cortex. The dorsolateral different brain regions. In the following description of prefrontal cortex also plays a role in the decision-making neural cell signalling mechanisms, the primary emphasis process that controls voluntary movements. will be on the way individual neurons interact with The cortex consists of an extensive sheet of neural tissue each other to form neural circuits. The organization and that can be divided into six horizontal layers that con- function of these integrated local circuits are described in tains different neuronal cell types and is often referred to the following brain regions: as grey matter (Module 10: Figure dorsolateral prefrontal • Cortex cortex). The white matter located beneath this region of • Limbic system grey matter contains the myelinated axons that provide the connections to other regions of the cortex and the brain. Amygdala The typical organization of the cortical grey matter is il- Hippocampus lustrated by the dorsolateral prefrontal cortex, which is of Hypothalamus particular interest, because changes in the operation of the Thalamus local circuits in this area have been linked to schizophrenia. • Cerebellum • Respiratory centre Dorsolateral prefrontal cortex (DLPFC) Cortex The dorsolateral prefrontal cortex (DLPFC) plays an im- The cortex, which is also known as the cerebrum, is the portant role in the executive control of the brain by par- largest part of the brain. The surface area of this outer ticipating in the process of working memory, which is cortical layer is highly wrinkled and the numerous indent- responsible for carrying out thought processes and vari- ations serve to enhance the surface area and the number of ous behavioural sequences. During working memory, an neurons. The cortex carries out many of the ‘higher’ brain initial input through either a sensory or thought process functions that one associates with consciousness, such as is maintained through a sustained and co-ordinated firing perceptual awareness, thought, memory, spatial reasoning, of groups of DLPFC pyramidal neurons that then enables language and the generation of motor commands. It is di- the brain to decide upon the subsequent initiation of a vided into two: the left and right hemispheres that are con- behavioural response. This firing pattern is an emergent nected to each other