PHSI3001 PHSI3901

University of Sydney
COURSE BOOK
Department of Anatomy & Histology Department of Physiology
and

2004

COURSE COORDINATORS Dr John Mitrofanis (Anatomy) Dr Dario Protti (Physiology)

Dr John MITROFANIS Course Coordinator Anatomy Room: S419 Ext/Email: 12838; zorba@anatomy.usyd.edu.au Research: Parkinson Disease

Dr Dario PROTTI Course Coordinator Physiology Room:visionlab Ext/Email: 13928 dprotti@physiol.usyd.edu.au Research: Vision

Dr Kevin KEAY Room: S502 Ext/Email: 14132; keay@anatomy.usyd.edu.au Research: Organisation and integration of pain pathways; sexual brain

Dr Bill PHILLIPS Room: N348 Ext/Email: 14598; billp@physiol.usyd.edu.au Research: Development and plasticity of synapses

Dr Vladimir BALCAR Room: E465 Ext/Email: 15664 vibar@anatomy.usyd.edu.au Research: Glutamate

Prof Max BENNETT Room: Neurobiology Laboratory, Ground Floor Ext/Email: 12034; max@physiol.usyd.edu.au Research: Formation and function of synapses

A/Prof Simon CARLILE Room: Auditory lab Ext/Email: 16876; simonc@physiol.usyd.edu.au Research: Auditory Neuroscience Dr Karen CULLEN Room: S464 Ext/Email:17064 kcullen@anatomy.usyd.edu.au Research: Alzheimer Disease

Dr Catherine LEAMEY Room: developmentlab Ext/Email: 13928 cathy@physiol.usyd.edu. au Research: Brain Development

This course is evaluated by students through the ITL questionaire at the end of semester. All feedback is considered. When there is feedback on a large scale, the course will be modified accordingly in the year that follows. All lecturers are subject to feedback questionaire by students at end of semester. If students have any issues with a lecturer or their lectures, they should see either the lecturer concerned, the course coordinator or the Head of Department (Anatomy).

http://www.anatomy.usyd.edu.au/teaching/courses/index.html

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COURSE OUTLINE
This course is run by the Department of Anatomy & Histology and Department of Physiology. There are 4 major components to this course - each are compulsory.

1. LECTURES (start Week 1)

Day Monday Wednesday Thursday Friday Time 12pm 8am 9am 2pm Place Eastern Avenue Main Quad N205 Main Quad N205 Eastern Avenue

Exam: Lecture series will assessed by 2 exams at the end of the semester, each of 2 hours. The 1st exam will consist of multichoice (singe best answer) covering all the topics treated in lectures. The 2nd exam will be essay style questions. There will be 1 or 2 questions for each topic, so you will answer a total of 4 questions (each 1/2 Hour) from at least 3 different topics. This means you can study and prepare in more depth those topics which are of most interest to you.

2. NEUROANATOMY TUTORIALS (start Week 4)

Day Weds or Weds Time 10-12 11-1 Place Anatomy Tutorial Rooms

There will be 2 sessions, one starts at 10, the other at 11. First hour of each will be a lecture style presentation in W413. In the second hour, students will adjourn to tutorial rooms to examine specimens (self directed learning). (student lists displayed in week 3) Spot test: You will be presented with 10 specimens. You will have to identify 4 structures on each, and you will be asked a short question which will be related (directly or indirectly) to one of the identified structures.

3. PHYSIOLOGY PRACTICALS (start week 6)

Date Time Place Mon 2-6 Anderson Stuart Teaching rooms OR Wed 2-6 Anderson Stuart Teaching rooms You will be assigned one of these time slots - if you want to change, see the Physiology Liaison Officer. The practical "Axovacs" involves group design and execution of 1 or more mini-experiments using computer simulation. Each group should hand in one report (max 10 pages) including the experimental background, results and graphs, and interpretation of the results, and everyone in the group gets the same mark. Assessment for "Eye movements" and Vision practical classes will be by a 2 page report on one aspect of the demonstration or prac. Practical reports: are due on the Friday of the week following the Eye movements and Axovacs classes.

4. PAPER SESSIONS / MAJOR ESSAY (start week 3)

Paper discussion sessions In 3-5 pm time slot on Fridays (or whenever organised by your supervisor/tutor) you will meet with your supervisor and he/she will inform you what is required in that his/her paper session series (eg, mode or presentation and general assessment every group has a slightly different method). Most paper sessions in Carslaw tutorial rooms. Major Essay An essay (~3500wds) is due on Friday week 13. All essays are to be handed in to Debbi Douglass (Anatomy Office). For late essays please refer to the departments policy, posted in the notice board. Papers included for the essay reading lists are also the basis for the paper discussion sessions. A form sheet to sign up for your essay topic will be handed out to you and you should provide 3 preferences. Hand these in to Debbie Douglass by the end of week 1. Final essay lists (with no changes subsequently) will be posted at the Anatomy Notice Board office on Monday week 2. Every effort will be made to ensure that you get your 1st preference.

ASSESSMENT

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Exam - multichoice (singe best answer): 20% Exam - essay: 25% Major Essay: 20% Paper presentation: 10% Neuroanatomy spot test: 15% Axovacs report: 6%; Eye movements/vision report: 4%

Successful completion of the course requires that all essays and assignments are submitted. ADVANCED NEUROSCIENCE Students undertaking the Advanced stream of the course will carry out lab work and generate a report on that work by the end of term. Students will chose projects that are offered by different labs (supervised by Lecturers in this course). The report should be in the form and style of a Neuroscience Letters publication. Students should see Dr Mitrofanis for further details. This lab report will replace the essay, but not the paper discussion sessions and presentation, assessment of the course. COURSE AIMS To give you a broad insight into the marvels of brain structure and function. You will explore the organisation of synapses and receptors, together with the ways by which neural cells communicate through their functional interconnections. You will also be led into the mysteries of the sick brain and mechanisms that manifest neural dysfunction and abnormality. Some of the symptoms of neural degeneration, disease or insult will be explored. The lecture course addresses aspects of neural organisation and function, in health and disease. The practical component of the course consists of small group tutorials in neuroanatomy, experimental and computer based sessions on physiological methods, and small group sessions in which you will discuss current research papers related to the lecture topics. RECOMMENDED TEXTS The following textbooks are all available in multiple copies in Burkitt-Ford library. They are more than adequate for the core material in the course. Students that intend to study Neuroscience in second semester should consider purchasing Kandel et al instead of Bear et al. Individual lecturers may give reading lists for in depth study. Core texts 1) Neuroscience: Exploring the brain. Bear, Connors, Paradiso. Baltimore: Williams & Wilkins, 1996 OR Principals Of Neural Science. Kandel, Schwartz, Jessel. 4th Ed, Elsevier, NY, 1998. 2) The Human Brain. Nolte. 4th Ed, C.V. Mosby Co., St Louis, Washington D.C., Toronto, 1999 3) Neuroanatomist's Colouring Book. Stone, Dreher, Trk. 3rd Ed, Maitland Pub. Sydney 1990 Reference texts Principals Of Neural Science. Kandel, Schwartz, Jessel. 4th Ed, Elsevier, NY, 1998. Core text of Neuroanatomy. Carpenter. 4th Ed, Williams & Wilkins, 1991 An Introduction to Molecular Neurobiology. Hall. Sinauer Associates, Inc Pub Massachusetts, 1992

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Time WEEK 1 M 8/3 W 10/3 T 11/3 F 12/3 WEEK 2 M 15/3 W 17/3 T 18/3 F 19/3 WEEK 3 M 22/3 W 24/3 T 25/3 F 26/3 WEEK 4 M 29/3 W 31/3 T 1/4 F 2/4 WEEK 5 M 5/4 W 7/4 T 8/4 F 9/4 WEEK 6 M 19/4 W 21/4 T 22/4 F 23/4 WEEK 7 M 26/4 W 28/4 T 29/4 F 30/4 WEEK 8 M 3/5 W 5/5 T 6/5 F 7/5 WEEK 9 M 10/5 W 12/5 T 13/5 F 14/5 WEEK 10 M 17/5 W 19/5 T 20/5 F 21/5 WEEK 11 M 24/5 W 26/5 T 27/5 F 28/5 WEEK 12 M 31/5 W 2/6 T 3/6 F 4/6 WEEK 13 M 7/6 W 9/6 T 10/6 F 11/6

Lecture

1. LECTURES

Lecturer Dr J Mitrofanis Dr J Mitrofanis Dr W Phillips Dr W Phillips Dr K Keay Dr V Balcar Dr V Balcar Dr W Phillips Dr W Phillips Dr W Phillips Dr W Phillips Dr W Phillips Dr W Phillips Dr V Balcar Dr V Balcar Dr V Balcar Dr V Balcar Dr V Balcar Dr V Balcar Dr C Leamey Dr C Leamey Dr K Cullen Dr K Keay Dr K Keay Dr K Keay Dr K Keay Dr K Keay A/Prof S Carlile A/Prof S Carlile A/Prof S Carlile A/Prof S Carlile Dr D Protti Dr D Protti Dr D Protti Dr D Protti Dr D Protti Dr D Protti Dr K Keay Dr K Keay Dr K Keay Prof M Bennett Prof M Bennett Dr J Mitrofanis Dr J Mitrofanis Dr K Keay Dr J Mitrofanis Dr K Cullen Dr J Mitrofanis

Introduction Methods 1: Anatomical techniques Methods 2: Physiological techniques Methods 3: Molecular Biological techniques Methods 4: Behavioural techniques Neurochemistry Chemoarchitecture Neuronal reflex circuits Pattern generators, descending influences and locomotion Modulation of neurone excitability Development of neuronal connections I Development of neuronal connections II Neuromuscular Disorders Spinal Cord 1: General organisation Spinal Cord 2: The tracts Brainstem Diencephalon Cerebral cortex 1: General organisation Cerebral cortex 2: Functional areas Good Friday Brain Development 1 Brain Development II No Lecture Glial cells Anzac Day Somatosensory 1: Pathways Somatosensory 2: Sensation Somatosensory 3: Pain Somatosensory 4: Pain 2 Somatosensory 5: Analgesia Audition 1 Audition 2 Audition 3 Audition 4 No Lecture Vision 1: Eye Vision Vision Vision Vision 2: Retina 3: Retinal Circuits 4: Colour 5: Higher Centres: subcortex and cortex

Vision 6: Visual processing: plasticity in the visual system Chemical Sensory Pathways 1: Olfaction Chemical Sensory Pathways 2: Gustation Feeding/Thirst/Sex Memory 1 Memory 2 Motor 1: Basal ganglia Motor 2: Cerebellum Motor 3: Emotional systems Motor 4: Motor Disorders Brain Aging Overview and feedback

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LECTURE OBJECTIVES
DR VLADIMIR BALCAR Neurochemistry Lecture synopsis: Synthesis and storage of transmitter Structure of chemical synapses Objectives: (1) -To discuss briefly the functional components of the chemical synapse: - synthesis & storage of synaptic transmitters 2+ - Ca -dependent release mechanism - synaptic receptors (post-, pre- or extrasynaptic/ion-channel linked versus metabotropic) - inactivating mechanisms (enzymes, "high affinity uptake", diffusion) (2) -To describe the main characteristics of the chemical synapse and the possible links to the synaptic function: - synaptic vesicles (synthesis, storage, release) - adjacent glial elements (inactivation, transport, metabolic support) - synaptic densities - round v. flat vesicles, symmetric (type II) v. asymmetric (type I) synapses and excitatory v. inhibitory nature of synapses - "free" nerve endings, direct synaptic v. paracrine action of transmitters (3) -To mention "unusual" structures related to synaptic transmission: - tight junctions - "ribbon" synapses - dendritic (or dendro-dendritic) synapses - synaptic triads (4) - To explain the concept of a "synaptic marker" in neuroanatomical studies. Chemoarchitecture Objectives: (1)To present an overview of transmitter-specific pathways: - amino acids - acetylcholine - monoamines - neuropeptides (2)To discuss the characteristics of monoaminergic pathways: - main features of MA neurones - their distribution (perikarya, axons and nerve endings of dopaminergic, noradrenergic and serotinergic neurones) (3) -To discuss the characteristics of cholinergic pathways: - typical cholinergic neuron/synapse - distribution of cholinergic neurones/nerve endings/synapses (4)To describe the main characteristics of amino-acidergic neurones/synapses: - glutamatergic/aspartergic (excitatory - GABAergic (inhibitory) (5)To stress the unusual features of peptidegic neurones/synapses (synthesis of neuropeptides in perikarya, distinct localisation of some of the peptidergic neurones, co-localisation of neuropeptides with other transmitters, uncertainties about the actual role of neuropeptides, endocrine and paracrine actions). Spinal Cord 1: General organisation Functions of the spinal cord; what does it do and why do we have one? A general look at grey and white matter and the inputs and outputs of the spinal cord. Different types of peripheral receptors and their associated fibre classes. Introduction to reflexes; flexor, stretch and _ loop. The ascending and descending pathways of the spinal cord; which are the more important ones? Start with ascending tracts - the pain and temperature (spino-thalamic tract) and tactile (dorsal column) pathways. Follow these through, from a start in the periphery to a finish in the neocortex. Spinal Cord 2: The tracts Exploring more spinal cord ascending tracts: proprioceptive (spino-cerebellar tract and dorsal column), a division into conscious and unconscious pathways. Again, follow these through, from a start in the periphery to a finish in the neocortex or cerebellum. Introduction to descending tracts, the ones coming down from above. Two sets medial (vestibulospinal, reticulospinal) and lateral (rubrospinal, corticospinal). Where do they start and finish? What is their function? Brainstem Understand the three major divisions of the brainstem; midbrain, pons and medulla. What do they look in section? What sorts of structures are found in the brainstem, cell types and fibre pathways? Explore the concept of the brainstem reticular formation (diffuse vs specific) and the cell groups (eg, raphe, locus coeruleus, substantia nigra) associated with different neurotransmitter systems, serotonin, acetylcholine, dopamine and noradrenaline. What are the ascribed functions and projections of each of these systems? Understand what cranial nuclei and nerves are. The different types of nuclei and the different types of functional fibres that one can find in a given cranial nerve. Explore the differences between functional and topographical classifications of the cranial system. Familiarise the broad areas of distribution and function of each cranial nerve. In terms of functions, get to know the different functional columns that each cranial nucleus forms part of. Thalamus

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What is the thalamus, what are its connections and where is it located? Detail the currently ascribed functions to this Jewel of neuronal machinery. Understand the concept of a thalamic nucleus, the cell types that make-up a given nucleus and the sorts of inputs that an individual thalamic cell may receive. Familiarise the many different thalamic nuclei, from the lateral geniculate nucleus to the pulvinar. What functional class does each thalamic nucleus belong first-order, higher-order or intralaminar/midline? What are some differences between a dorsal thalamic and a ventral thalamic nucleus? Know which nuclei are dorsal thalamic and which are ventral thalamic. Cerebral cortex 1: General organisation Introduction to the three basic types of cortex (neo, paleo, archi). Focus on neocortex. There are two types of neocortical cells (pyramidal, non-pyramidal); what are their major attributes? Familiarise the three types of pyramidal cells (projection, commissural, higher-order). Explore the basic neocortical organisation; concept of the laminae. The means of cortical packaging and Brodmans areas. Cerebral cortex 2: Functional areas Introduction to the three types of neocortical areas: primary, secondary, higher-order. What are the major differences between each of these neocortical types and what are their general functions? Know where each type of neocortex is located. Familiarise specific examples of each type of neocortex, from primary somatosensory to prefrontal, and understand their particular functions. A look at some special neocortical areas: speech and language. PROF MAX BENNETT Memory 1 declarative and non-declarative forms of memory the cerebellum and non-declarative forms of memory the hippocampus and declarative forms of memory the structure of the hippocampus, memory and epilepsy Memory 2 the synaptic relations of CA3 region of hippocampus long - term potentiation of synaptic transmission and memory molecular mechanisms in potentiation gene knock - out experiments that effect potentiation and memory the relation between memory and consciousness A/PROF SIMON CARLILE Audition 1 Primary Ascending auditory pathways The auditory cortical areas Descending auditory system A Polysensory interface: the superior colliculus Audition 2 The nature of the stimulus The peripheral apparatus Filtering and transduction When it all goes wrong Cochlear prosthesis Tactile coders of sound Auditory aids for the blind Audition 3 Describe the nature of sound and the phenomena of resonance. Describe how sound is encoded by the ear. Filtering by the outer ear Impedance matching by the middle ear Sensory transduction by the inner ear Describe the most common types of middle and inner ear dysfunction. Audition 4 Describe how complex sounds are represented in the auditory nerve. Describe the evidence for parallel processing in the auditory system by relating the cytoarchitecture of the Cochlear Nucleus to the segregation and streaming of auditory information into the brainstem. Describe the topographic representation of complex stimulus parameters within the subcortical auditory nuclei and primary auditory cortex. Describe how the location of a sound source is encoded and represented by the auditory system. DR KAREN CULLEN Glial cells Objectives: * To understand the multiple roles of neuroglia mechanical and neurochemical support, immunological support, facilitation of neurotransmission Brain Ageing Objectives:

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* To understand the major hypotheses of cellular ageing, * To identify which of these hypotheses are applicable to neuronal ageing, * To identify the (minor) brain changes in ageing, to briefly identify the major brain changes associated with the most common cause of dementia (Alzheimers disease). DR KEVIN KEAY Methods 4: Behavioural techniques General principles of behavioural studies (subject, task, analysis, interpretation). Naturalistic vs laboratory observations. The homecage and the open field. Conditioning paradigms. Approach and avoidance. Testing memory and cognition in rats and primates. Brain lesions and stimulation. Drug administration. Intracranial self stimulation. Anxiogenesis and anxiolysis. Depression and despair. Somatosensory 1: Sensation How do we know when something is rough? smooth?, hot?, slippery? or vibrating? Theories of somatosensation. Coding sensory signals. The skin and its receptors. Deeper structures and their receptors. Somatosensory 2: Pathways An overview of the representation of somatosensation in the spinal cord and brainstem. Somatotopy. The dorsal column nuclei. Brainstem trigeminal complex. Somatosensation in midbrain. Thalamus and touch. Somatosensation in the cortex. Somatosensory 3: Pain- Peripheral Mechanisms & Spinal Pathways What is pain ? The nociceptor: does it exist ? how does it work? Injury and inflammation. Nociceptors in skin, muscle and viscera are they the same or different ? Are there specific "pain fibres" what and where are they ? How does information about pain get in to the brain? First pain and second pain. Is pain just about the dorsal horn ? Somatosensory 4: Pain- Sensation, Perception & Emotion What is sensation? What is emotion? Nociception, pain behaviour and suffering. The spinoreticular pathways and somatosympathetic reflexes. The spinomesencephalic pathways, pain-behaviour and emotional expression. The spinothalamic pathway: ventroposterior nuclei vs midline nuclei is it really a case of emotional expression vs sensory/discriminative processing ? Is cortex really involved in pain processing ? The cortex and suffering. What would it be like to feel no pain? Somatosensory 5: Antinociception and Analgesia What are antinociception, analgesia and anaesthesia. How can the brain regulate its own sensory inputs? Which areas of the brain can do this? How do they do this? What are the spinal and descending inhibitory mechanisms that affect spinal nociceptive processing ? Which brain regions are involved in modulation of nociceptive inputs, what are their interconnections, their spinal projections, and what actually happens when they are activated ? Brief consideration of opioids and opioid receptors in the brain. Distinguishing between opioid and nonopioid forms of analgesia. Deep brain stimulation. Could there be a Neuroscience of alternative forms of analgesia ie., acupuncture, hypnosis. Chemical Sensory Pathways 1: Olfaction What is the structure of the receptors of the nasal cavity which respond to chemical signals. The neuroanatomy of the olfactory bulb. The brain pathways which relay smell. How is smell decoded in the brain? Chemical Sensory Pathways 2: Gustation This lecture will consider the following issues. The tongue and oral cavity. Tastebuds.: structure and location of these receptors Mechanisms of transduction of different tastes (salt, sweet, bitter, sour, umami). The peripheral and central pathways which relay these signals. How are different tastes coded in the brain. Taste evokes emotional state changes. The brain circuits for taste aversion. Feeding/Thirst/Sex What are motivational states ? Hunger. Thirst. Libido. What brain regions control motivational states. The anatomy of the hypothalamus. The role of the hypothalamus in feeding thirst and sex; regional control and chemical coding. Obesity, adipsia and promiscuity. Sexual differentiation in the hypothalamus and its proposed role in reproductive behaviour, gender identity and sexual orientation. Motor 4: Emotional system A look at the different brain centres that are thought to generate emotions; those that mediate visceral and behavioural responses to these emotions. A flirtation with the limbic system - who are the main players and what are their functions cortex, thalamus, hypothalamus, amygdala. Anger, Angression, Fear, Anxiety and Love - some emotions we will consider. DR CATHERINE LEAMEY Brain Development 1 Overview of brain development why is it interesting? Where does the nervous system come from? Neural Induction and the organiser. Folding of the neural tube. Neural crest cells and their derivatives. Development of the neural tube and its derivatives. How do you build a brain? Brain Development 2 The neural tube is organised along 3 axes. Dorsoventral patterning in the nervous system. Anteroposterior patterning along the neuraxis. Segmentation and rhombomeres. Patterning of the midbrain. DR JOHN MITROFANIS Introduction: Neurones & Glia Welcome to course. Introduction to neural cells. A neurone and its parts (soma, dendrites, axons, synapses, neurotransmitters). A glial cell (astrocytes, microglia, oligodendrocytes). Methods 1: Anatomical techniques Appreciate that structure and organisation often signals function. An examination of classical and more modern techniques that explore the anatomy of the CNS. What is a Nissl stain, the Golgi Method, Intracellular filling, Immunocytochemistry,

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Tract tracing, viral infections? Why use them? Welcome to the spectacular world of neuroanatomical discovery, and beyond Motor 1: Basal ganglia Define the principal components of basal ganglia; caudate, putamen, globus pallidus, subthalamus, substantia nigra. Outline the structure, transmitters and locations of each of these components. Describe the general circuitry of basal ganglia: direct and indirect pathways. What are the functions and clinical manifestations of basal ganglia? Motor 2: Cerebellum General functions and connections of cerebellum. Three major functional subdivisions; vestibulo-, spino- and neocerebellum. What are the peduncles and which major pathways do they carry? What are the deep cerebellar nuclei and what functions are they associated with? The three lovely, but very strict, cerebellar laminae. Familiarise the many different types of cerebellar cells, their projections and transmitters. Climbings and Mossys - what are these and what are their differences?. Discuss some symptoms from cerebellar lesions. Motor 4: Motor Disorders Examining the mechanisms, signs and symptoms of various disorders of the motor pathways. Focus on Parkinson Disease. What are the factors that may generate this disease? What mechanisms underlie the stiffness, slowness of movement and tremor? What are the current treatments of Parkinson Disease, from surgery to transplants and stem cells? Overview and feedback Outline of exam format and provide some of the exam questions. Students fill out questionnaire. DR BILL PHILLIPS Methods 2: Physiological techniques

Explain in your own words what is involved in making intracellular EPSP recordings from a neuron and what sorts of things it can tell us. Explain the terms EPSP, IPSP, miniature EPSP and miniature IPSP. Explain in your own words what a voltage clamp device does, how it works and what sorts of information can be gained from neurons by using it. Explain what is recorded when extracellular electrodes are placed on the surface of the scalp (EEG), close to a neuron in the cortex or on the surface of a muscle (EMG).

Methods 3: Molecular Biological techniques Gain an overview of the range of molecular techniques that can be usefully applied to investigating particular types of questions about the nervous system and how it develops. Give an example illustrating how studies with a simple organisms in which mutagenesis studies are feasible (yeast, flies, zebrafish) has helped to further our understanding of how the mammalian nervous system develops or functions Outline methods that can be used to modify gene expression in cultures of neurons. What sorts of things can be learnt from such studies? Describe the phenotype of a mouse that has been genetically modified and what it has told us about how synapses work or of how the brain develops. GFP, antisense RNAs, RNA interference and dominant negative proteins are all approaches to investigating the roles of specific gene products. Outline how these techniques can be used to study the role of particular proteins in the intact brain. Neuronal reflex circuits and Pattern generators, descending influences and locomotion Explain in your own words what is meant by these phrases: reflex arc, Ia afferent, muscle spindle, functional set, motor task-dependent reflexes Describe with the aid of a drawing the anatomical organisation and the synaptic inputs to spinal motor neurons Describe the characteristic features of AMPA and NMDA type glutamate receptors that help them contribute to excitatory synaptic potentials (EPSPs) at central synapses Describe in your own words factors that influence the summation of excitatory inputs to motor neuron What is meant by the recruitment order of motor neurons? Describe two major classes of inhibitory interneurons: their receptor inputs and key synaptic outputs. Give a brief description of the characteristic features of the glycine and GABAA classes of receptors, explaining how their gating properties and channel permeability contributes to inhibitory synaptic potentials in neurons. Explain how integration of excitatory and inhibitory synaptic currents within the neuron influences firing patterns (output) Describe the phases of locomotion and how these phases are generated by alternate activation of different muscle groups What is meant by the term central pattern generator? Use a diagram to help explain. In what ways and by what means can descending motor nerve tracts modulate reflexes? Describe how feedback from sensory receptors helps a cat to adapt it's gait. In what ways can normal reflex functions be modified following spinal cord damage in animals and humans. Modulation of neurone excitability Outline the major classes of second messenger receptors in the central nervous system Describe the key intracellular pathways by which G-coupled receptors are known to modulate their target ion channels and other effectors within neurons Explain in your own words two examples illustrating how slow signalling via second-messenger receptors can alter neuronal excitability Development of neuronal connections I and II Briefly discuss the following issues concerning formation of neuronal circuits: Determination of neuronal identity Axon path-finding Initiation of a synaptic connection
Matching of neurone pools to their targets and programmed neurone death Activity-dependent refinement of synaptic connections

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Neuromuscular Disorders Muscle weakness may result from problems with the muscle itself, the neuromuscular junction or the motor neurons. Without the use of specific test reagents how might you use physiological techniques to distinguish between these broad possibilities in an individual with muscle weakness? Describe experiments using intracellular electrical recordings from the endplate of the muscle fibre that might be used to distinguish between a fault in the efficiency of acetylcholine release from a potential myasthenia Gravis case where the density of postsynaptic acetylcholine receptors was reduced below normal levels. The most common form of Myasthenia Gravis is an autoimmune disease. Explain how an immune response against the acetylcholine receptor is thought to result in muscle weakness. DR DARIO PROTTI Vision1: Eye Properties of light, optics, macroscopic anatomy of the eye, image formation by the eye, accommodation, optical problems of the eye, eye muscles and eye movements, visual acuity. Vision 2: Retina Structure of the retina and most important classes of retinal neurones: - Photoreceptors: phototransduction - Bipolar Cells - Horizontal Cells - Amacrine Cells - Ganglion Cells: the output cells of retina. Retinal processing Vision 3: Retinal circuits Day-time and night-time vision: Cone and Rod pathways. Ganglion cell responses and receptive fields. Lateral inhibition. Direction selectivity Vision 4: Colour "The rays are not coloured". Mixing light and pigments. Cones and colour. Cones spectral sensitivity. Trichromacy and colour opponency. Colour blindness Vision 5: Higher visual centres - subcortex and cortex Retino-recipient nuclei. Topographic and laminar organisation of the dLGN. Receptive field properties. Visual Cortex: Topographic organisation, laminar organisation. Orientation columns. Putting it all back together in the cortex. Vision 6: Visual processing. Plasticity in the visual system Spatial resolution. Depth and size. Face cells. Ocular dominance columns. Activity dependent synapse formation. Critical period. Effects of sensory deprivation. Topographical maps: stability and plasticity. General objective for vision lectures: To relate the properties of vision in human and other mammals to the properties of neurones and neuronal pathways in the visual system. Specific objectives for vision : Understand the optical principle of the eye and describe the formation of the image on the retina. Understand and use the terms: visual field, binocular field, fovea, optic axis, visual field eccentricity. Draw a simple diagram showing the decussation of optic nerve fibres and relate this to the visual field. Draw a simple diagram showing the layered structure of the retina and the disposition of the main neurones: photoreceptors (outer nuclear layer), horizontal, bipolar and amacrine cells (inner nuclear layer), and ganglion cells (ganglion cell layer). Show the main vertical and lateral pathways of signal flow in the retina. Outline the mechanism of phototransduction, showing the main steps by which changes in local contrast lead to changes in glutamate release by photoreceptors Relate the density of photoreceptors and ganglion cells to spatial resolving ability and the behavioural requirements of different species. Describe the functional and morphological differences between rods and cones. Draw a simple diagram showing the rod and cone circuit and how signals are transferred in each of them. Describe the changes in receptive field properties of neurones at different levels of the visual pathway from retina to extrastriate visual cortex. Understand the principle of retinotopic organisation of the lateral geniculate nucleus and visual cortex. Show how the visual input from the two eyes is segregated at the lateral geniculate nucleus and organised in the primary visual cortex. Summarise the trichromatic theory of colour vision and describe the basis of colour blindness. Understand the concept of ocular dominance columns and plasticity in the nervous system: use it or lose it

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2. NEUROANATOMY TUTORIALS
Each Neuroanatomy tutorial is made up of 2 parts. (1) Introductory Talk: All of the students (~60 per session) will be given a 1hr introductory talk by a member of staff. This talk will outline and highlight the majors issues of the week. This will occur in the dental dissection room (W413). (2) Tutorial Exercises (examination of prosections): After each introductory talk, students will split into smaller groups (~15) adjourning to designated tutorial rooms. There, students will examine and identify all the structures mentioned in the tutorial exercises. This is more of a self-directed session, although 1-2 tutors will be patrolling the tutorial rooms answering questions. To help you along, many of the figures and images provided in this coursebook indicate many of the structures you need to identify. In each tutorial, make it your business to identify, in as many wet specimens and models possible (mentioned in brackets - see Key), all the structures referred to in each session. You should also be aware of the function(s) currently ascribed to each of these structures. It would be very, very handy for you to have a Neuroanatomy Atlas (eg, Colouring Book) by your side for the journey. Key: BS - brainstem model/prosection; CS - coronal section; HS - horizontal section; +HB - positive hippocampal brain; HB - negative hippocampal brain; Ph - Photographs; R - radiographs; SB - sagittal brain; SC - spinal cord prosection; SCe - sagittal cerebellum; SH - sagittal head section; TCe - transverse cerebellum; VM - ventricular model; WB - whole brain; WCe - whole cerebellum WEEK 1-3: NO TUTORIALS WEEK 4: INTRODUCTION frontal lobe (WB,SB); parietal lobe (WB,SB); occipital lobe (WB,SB); temporal lobe (WB,SB); longitudinal fissure (WB); lateral fissure (WB,SB); corpus callosum (SB, CS, HS); caudate nucleus (CS, HS, BS), lentiform nucleus (CS, HS, BS), thalamus (SB, CS, HS, BS); hypothalamus (SB, CS); cerebellum (WB, SB); brainstem - midbrain, pons, medulla - (BS, WB, SB); spinal cord (SC). WEEK 5: SPINAL CORD cauda equina (SC); conus medullaris (SC); filum terminale (SC); ventral & dorsal roots (SC); denticulate lig (SC); dorsal root ganglia (SC); cervical & lumbosacral enlargements (SC); ventral median fissure (anterior spinal artery) (SC, Ph); dorsal median septum (SC, Ph); central canal (Ph); grey matter (dorsal/ventral horns, intermediate grey) (Ph); white matter (dorsal, lateral ventral funiculi) (Ph); dorsal column (SC, Ph); spinothalamic tract (Ph); spinocerebellar tract (Ph); corticospinal tract (Ph); rubrospinal tract (Ph); reticulospinal tract (Ph); vestibulo-spinal tract (Ph); ventral white commissure (Ph); substantia gelatinosa (Ph); nucleus dorsalis (clarke's column) (Ph); nucleus proprius (Ph); ventral horn (Ph); intermediate grey (Ph); lateral horn (Ph) Review all the ascending and descending tracts discussed in lecture and ask yourself these key questions of each tract: - where does it start? Does it cross? If so, where? - where does it finish? - where is it at any given spinal cord level (look at the sections)? WEEK 6: BRAINSTEM General Organisation: auditory decussation (Ph); cerebral peduncle (Ph); corticospinal & pontocerebellar tracts (Ph); cuneate nucleus (Ph); decussation of superior cerebellar peduncles (Ph); fourth ventricle (BS, SB); gracile nucleus (BS); inferior cerebellar peduncle (BS, Ph); inferior olivary complex (olive) (BS, Ph); medial lemniscus (Ph); mesencephalic aqueduct (BS, Ph); middle cerebellar peduncle (BS, Ph, WB); olivocerebellar fibres (Ph); periaqueductal grey matter (Ph); pyramidal (corticospinal) tract (BS, Ph); red nucleus (BS, Ph); reticular formation (Ph); sensory decussation (Ph); spinocerebellar tract (Ph); spinothalamic tract (Ph); substantia nigra (CS, Ph); sulcus limitans (BS); superior & inferior colliculi (BS, Ph, SB). Cranials: abducent nucleus/nerve (BS, Ph); accessory nerve (BS); cochlea nuclei (BS, Ph); dorsal (motor) nucleus of vagus (BS, Ph); Edinger-Westphal nucleus (BS, Ph); facial colliculus (BS, Ph); facial motor nucleus (BS, Ph); glossopharyngeal nerve (BS); hypoglossal and vagal trigones (BS); hypoglossal nucleus/nerve (BS, Ph); mesencephalic trigeminal nucleus (BS, Ph); nucleus ambiguus (BS, Ph); nucleus of the solitary tract (BS, Ph); nucleus of the spinal trigeminal tract (BS, Ph); oculomotor nucleus/nerve (BS, Ph); principal (chief or pontine) trigeminal nucleus (BS, Ph); superior and inferior salivatory nuclei (BS); trigeminal motor nucleus (BS, Ph); trigeminal nerve (BS); trochlear nucleus/nerve (BS, Ph); vagus nerve (BS); vestibular nuclei (inf, lateral, medial, sup) (BS, Ph). WEEK 7: DIENCEPHALON thalamus (BS, CS, HS, +HB, SB, WB); anterior thalamic nuclei (BS, CS, HS, +HB, SB); pulvinar (BS, CS, +HB); ventroposterior nucleus (CS); thalamic reticular nucleus (CS); lateral geniculate nucleus (BS, CS, +HB); medial geniculate nucleus (BS, CS, +HB); internal capsule (ant/post limbs, genu) (CS, HS); interthalamic adhesion (BS, SB); globus pallidus (CS, HS); external capsule (CS. HS), putamen (CS, HS), extreme capsule (CS, HS); claustrum (CS, HS); subthalamic region (CS); hypothalamus (CS, SB); hypothalamic sulcus (SB); lamina terminalis (SB); mammillary body (BS, +HB, SB, WB); optic nerve/chiasma/tract (BS, +HB, SB, WB); habenula (BS, +HB, SB); pineal gland (BS, SB); stria medullaris (BS, +HB, SB). this tutorial may be viewed as a little lighter than the preceding ones. Use any extra time that you have here to revise the spinal cord and brainstem structures that you were introduced to in the last tutorials.

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WEEK 8: CEREBRAL CORTEX central sulcus (-HB, SB, WB); precentral sulcus (-HB, SB, WB); postcentral sulcus (-HB, SB, WB); parieto-occipital sulcus (SB); cingulate sulcus (SB); callosal sulcus (SB); calcarine sulcus (SB); lateral fissure (CS, HS, SB, WB); precentral gyrus (-HB, SB, WB); postcentral gyrus (-HB, SB, WB); superior frontal gyrus (-HB, SB, WB); middle frontal gyrus (-HB, SB, WB); inferior frontal gyrus (-HB, SB, WB); superior temporal gyrus (-HB, SB, WB); middle temporal gyrus (-HB, SB, WB); inferior temporal gyrus (-HB, SB, WB); transverse gyrus of Heschl (-HB); plenum temporale (-HB); insula (CS, HS, SB, WB); Broca's area (SB, WB); Wernicke's area (-HB, SB, WB); corpus callosum (CS, HS, SB); anterior commissure (CS, SB). WEEK 9: BLOOD SUPPLY & MENINGES pia, arachnoid, dura (WB,SH); dural folds (falx cerebri, tentorium cerebelli) (SH); arachnoid granulations (WB); lateral ventricles (anterior, posterior, inferior horns, body) (SB, VM), foramina of Munro (SB, BS, VM), choroid plexus (-HB), 3rd ventricle (SB, BS, VM), mesencephalic aqueduct (SB, VM), 4th ventricle (SB, BS, LVM), central canal (Ph); cisterns (cerebello-medullary, superior, pontine) (SH, SB); foramina of Magendie and of Lushka (SB, LVM); internal carotid artery (WB; R); vertebral artery (WB; R); middle cerebral artery (WB; R); anterior cerebral artery (WB, SB; R); posterior cerebral artery (WB, SB, R); basilar artery (WB, R); Circle of Willis (WB); anterior and posterior communicating arteries (WB); anterior and posterior perforating arteries (WB); anterior and posterior choroidal arteries (WB; R); posterior inferior cerebellar artery (WB; R), anterior inferior cerebellar artery (WB), superior cerebellar artery (WB, R), pontine arteries (WB); transverse, superior & inferior sagittal, sigmoid, straight sinuses (SH); great cerebral vein (of Galen) (SB). WEEK 10: SENSORY PATHWAYS: a general revision of structures Somatosensory: DRG (SC); dorsal horn (Ph); substantia gelatinosa (Ph); clarke's column (Ph); dorsal column (Ph); spinothalamic tract (Ph); spinocerebellar tract (Ph); gracile nucleus (Ph); cuneate nucleus (Ph); medial lemniscus (Ph); spinal tract V nucleus (Ph); principal V nucleus (Ph); VP thalamus (CS); postcentral gyrus (WB, SB); paracentral lobe (+HB, SB). Visual: optic nerves (WB, BS); optic chiasma (SB, WB, BS, +HB); optic tract (WB, +HB, BS); superior colliculus (WB, SB, BS, +HB, CS); lateral geniculate nucleus (CS, +HB, BS); pulvinar (+HB, BS, CS); optic radiation (HS); primary visual cortex (SB); band of Gennari (HS); secondary visual cortex (WB, SB). Auditory: cochlear nerve (BS); dorsal/ventral cochlear nuclei (BS, Ph); inferior colliculus (SB, BS, Ph); brachium of inferior colliculus (BS, Ph); superior olivary nucleus (Ph); trapezoid body (Ph); nucleus of trapezoid body (Ph); lateral lemniscus (Ph); medial geniculate nucleus (CS, BS, +HB); transverse gyrus Heschl (-HB); plenum temporale (-HB). WEEK 11: LIMBIC STRUCTURES amygdala (CS, -HB, WB); anterior thalamic nucleus (BS, CS, HS, SB); anterior perforated substance (WB); cingulate gyrus (SB, -HB); dentate gyrus (-HB); fornix (CS, HS, -HB, SB); gyrus rectus (WB); hippocampus (CS, -HB); olfactory bulb (WB); olfactory tract (WB); parahippocampal gyrus (WB, -HB); stria terminalis (+HB); uncus (-HB, WB, SB). WEEK 12: MOTOR PATHWAYS caudate (BS, SB, +HB, CS, HS), putamen (BS, CS, HS), globus pallidus (CS, HS), external capsule (CS,HS), extreme capsule (CS, HS), lateral medullary lamina (CS, HS), medial medullary lamina (CS, HS), substantia nigra (Ph, CS), subthalamic region (CS); inferior cerebellar peduncle (BS); middle cerebellar peduncle (WCe; TCe, BS); superior cerebellar peduncle (SCe, BS); anterior lobe of cerebellum (WCe; SCe); posterior lobe of cerebellum (WCe; SCe, TCe); tonsil of cerebellum (WCe; SCe, TCe); paravermal zone of cerebellum (SCe, WCe); vermis of cerebellum (WCe; SCe, TCe); lingula of cerebellum (SCe); flocculus of cerebellum (WCe); nodule of cerebellum (SCe); primary fissure of cerebellum (WCe, SCe); dentate nucleus of cerebellum (TCeS). WEEK 13: REVISION Trial Spot Test today. In the meantime, go back over tutorials and make sure you can identify all the structures mentioned in the text.

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Practical classes are held in the Anderson Stuart Teaching rooms. You will be assigned to ONE of Monday 2-6pm Wednesday 2pm-6pm WEEK 1-5 - No practicals WEEK 6 - Vision WEEK 7 - Eye movements WEEK 8 - No practical WEEK 9 - Axovacs WEEK 10 - Axovacs WEEK 11 - Axovacs WEEK 12 - Auditory WEEK 13 - Auditory

3. PHYSIOLOGY PRACTICALS

4. PAPER SESSIONS / MAJOR ESSAY

ABOUT THE PAPER DISCUSSION SESSIONS An important part of the Neuroscience course is the weekly "Paper Discussion Session". For each session, your supervisor will inform you of what is required by him/her during these sessions; style and format of each paper session does vary from group to group. In general, research papers selected from the essay reading lists will be "presented" by members of a group. The group will usually be about 15-20 students together with a staff supervisor. It is intended that the discussions be informal, where interruptions, digressions, objections, and criticisms are encouraged. Note that this does not equate to the presenter being unprepared! Before dealing with advice as to how to prepare for the sessions, consider this list of reasons for the sessions: - You will gain experience in presentation of scientific results (an increasingly important part of most careers in science) - You will develop abilities in the critical evaluation of published data and conclusions drawn from them. - You will develop skills in group discussions about experiments (also increasingly important in most science careers). - You will develop skills in summarising a publication for others (another career requirement). - You will gain insights into the way the overviews in textbooks and lectures are based on individual publications. - The sessions provide an opportunity for informal contact between staff and students. Preparing your presentation You should plan to take advantage of the usual tutorial room aids, especially the overhead projector and/or blackboard. It is easy to photocopy figures from papers onto transparencies. Summarise the points you need to cover, selecting the illustrations or tables from the paper that will help you. Requirements of journals vary somewhat but, generally, scientific papers are organised into the following elements: 1. Title: - states clearly what the paper is about. 2. Authors and addresses:- only people and labs that made a substantial contribution to study should be listed. 3. Abstract: - summarises main findings, usually limited to 100 - 400 words or 5 or 10% of the length of the article. 4. Introduction: - should very briefly describe the state of the field and give reasons why the present work is being done (background & hypothesis to be tested). 5. Methods: - describe techniques so that labs comparable to those of authors could easily repeat the work. 6. Discussion: - fit present study into context of field, relate to previously published work and evaluate its significance. 7. Acknowledgments: - contributors who do not qualify as Authors should be mentioned there. Also financial sources, donations of chemicals and equipment should be listed. 8. References: - list all the works cited in the text. All studies which helped to set the stage for the present work should be included since it is the way of repaying the "intellectual debt" to your predecessors. 9. Discussion - that of the author(s) and your own. Having done the above, the presentation should be a breeze! In the past, some students have found the paper sessions a little daunting in the first instance. On the other hand, most have found them quite valuable and participate enthusiastically once over the initial uncertainties about what is expected. Cooperation and give-and-take are essential elements. There is no competition. Assessment will be based equally on your presentation, the usefulness and clarity of your "handout", and on your overall contribution to the discussion in the group. Essay writing: plagiarism, correct citation and some hints. The University of Sydney defines plagiarism as: "knowingly presenting another person's ideas, findings or written work as one's own by copying them without due acknowledgment of the source ... at its worst, plagiarism is theft. Plagiarism may involve copying the work of another student, or it may involve paraphrasing or copying a published author's text or argument without giving a reference." (University of Sydney Policy Document, April 1995). You should read the above paragraph carefully, and understand that the University penalties for plagiarism are justifiably severe. In the Neuroscience course you are asked to submit an essay, which is expected to be your own work, and practical reports, which may involve group work with other students. Group work which has been carried out and/or compiled with the help of others must be properly acknowledged on the front page of the report. For your essay submission, you must sign the cover sheet declaration which states that it is entirely your own work. Remember that the person who suffers most from plagiarism is the plagiariser:

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If you are found out, you are liable to be expelled from the course, or from the University. If you escape detection, you still will suffer, because you will not have learned or produced anything new if you simply copy down what others have written. In the table below are some simple examples of mistakes which are made when first writing an essay based on original scientific papers. If your lecturer judges that your essay has not been properly referenced, you may be asked to resubmit. Make sure you understand the example D below: this is a common mistake. You should not adopt citations made by others, or include them in your reference list. This is called "secondary citation". You should only cite and include in your reference list those original papers which you have personally read. More details on the basics of citations and reference lists can be found in the Dept of Physiology Document "Essay writing and reference lists", which is reproduced as an appendix at the end of this course guide. Source document (Bloggs and Dingsbum, 1987) Essay text ... with a melon. By contrast, the Cheshire cat is A : Bloggs and Dingsbum (1987) state that the particularly well camouflaged in twilight conditions, and Cheshire cat is very difficult to see at dusk... (Good! the is practically invisible against dark foliage. reference is properly acknowledged) B : By contrast, the Cheshire cat, is particularly well camouflaged in twilight conditions, and is practically invisible against dark foliage (Bloggs and Dingsbum, 1987)BAD! the reference is cited, but the text is simply copied from the original. This is an offence. Don't do it. C : By contrast, Bloggs and Dingsbum (1987) state that " the Cheshire cat ... is practically invisible against dark foliage"(GOOD! This is correctly cited. the text excerpt is enclosed in inverted commas and set off from the main body of text.) .... Only 5 Cheshire cats were observed in the present D : The cheshire cat is very common in that part study, although Keensight et al (1945) claim that these of the country (Keensight et al, 1945)(Almost certainly cats are the prevalent breed in this part of the country. bad! You should never use "secondary citations" if you havent read the paper cited., in this case the paper by Keensight et al.) E : The Cheshire cat is very common in that part of the country (Keensight et al, 1945, cited by Bloggs and Dingsbum, 1987)(This is the correct way to make secondary citations. But you are much better off to go and find the original paper in the library. You will learn more, and you will impress your essay marker much more!)
ESSAY TOPICS

Friday 3-5pm (unless stated otherwise)

Grievous bodily harm is it good or bad for you? (Dr Vladimir Balcar) Carslaw Tutorial Room 352 Audition (A/Prof Simon Carlile) Carslaw Tutorial Room 353 Making Memories (Dr Karen Cullen) Carslaw Tutorial Room 355 Sexual brain (Dr Kevin Keay) Carslaw Tutorial Room 359 Brain development (Dr Cathy Leamey) Carslaw Tutorial Room 360 SickBrain (Dr John Mitrofanis) Anderson-Stuart lab E401 Tuesday 10-12 Control of postsynaptic differentiation in neurones (Dr Bill Phillips) Carslaw Lecture Room 350 Setting the internal clock (Dr Dario Protti) Carslaw Lecture Room 251

4. PAPER SESSIONS / MAJOR ESSAY

Grievous bodily harm is it good or bad for you?

Dr Vladimir Balcar
4-Hydroxybutyrate (gamma-hydroxybutyrate, GHB, sometimes spelled as GBH for grievous bodily harm in the recreational drug milieu) is actually present in small amounts in the normal mammalian brain tissue presumably as a metabolite of gamma-aminobutyrate (GABA). GHB passes readily through the blood brain barrier and can be, therefore, easily administered to experimental animals or selfadministered by humans. In vivo, GHB decreases body temperature, at higher doses produces euphoria and hallucinations, severely distorts judgment and may result in a prolonged coma-like state followed by a loss of memory. It has been, however, claimed that controlled administration of GHB may help patients suffering from drug dependency, including alcoholism. It has even been contemplated as a possible anaesthetic or a natural sleeping pill. Recently, there have been reports of an explosive growth in the exploitation of GHB as an illegal substance distributed mainly at techno-parties or, as widely publicized by media in the US and Europe, used in criminal activities ranging from daterape to a perfect murder. At the same time, there is a rumour that somebody is about to apply for a controlled clinical trial of GHB. Authorities are confused and worried and a special committee composed of senior public servants and scientists has just been set up in Canberra to deal with the matter. Using keywords neurotransmitters, neurochemistry and neurodegeneration they identified you as an expert who should be listen to and are urgently seeking your scientific advice. In

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your report you have to be objective, stick to your field of expertise but you are at liberty to stress which scientific findings should be considered as crucial when the Committee makes their final decision. References Carter LP, Wu H, Chen W, Cruz CM, Lamb RJ, Koek W, Coope A & France CP: Effects of GHB on schedule-controlled responding in rats: role of GHB and GABA-B receptors J Pharm Exp Ther 308 182-188 (2004) Gibson KM, Gupta M, Pearl PL, Tuchman M, Vezina LG, Carter Snead O III, Smit LME & Jakobs C: Significant behavioural disturbances in SSADH deficiency (GHB aciduria) Biol Psychiatry 54 763-768 (2003) Hechler V, Ratomponirina C & Maitre M: GHB conversion into GABA induces displacement of GABA-B binding that is blocked by valproate and ethosuccimide. J Pharmacol Exp Ther 281 753-760 (1997) Kaupman K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, Schnutz M, Froestl W, van der Putten H, Mosbacher J, Brauner-Osborne, Waldmeier P & Bettler B: Specific GHB binding sites but loss of pharmacological effects of GHB in GABA-B(1)-deficient mice Eur J Neurosci 18 2722-2730 (2003) Muller C, Viry S, Miehe M, Andriamampandry C, Aunis D & Maitre M: Evidence for GHB uptake by rat brain synaptic vesicles J Neurochem 80 899-904 (2002) Ottani A, Saltini S, Bartiromo M, Zaffe D, Botticelli AR, Ferrari A, Bertolini A & Genedani S: Effect of GHB in two rat models of focal cerebral damage Brain Research 986 181-190 (2003) Tancredi DN & Shannon MW: Case 30-2003: A 21 year-old man with sudden alteration of mental status New Eng J Med 349 1267-1275 (2003) Wong CGT, Gibson KM & Carter Snead O III: From the street to the brain: neurobiology of the recreational drug gammahydroxybutyric acid Trends in Pharm Sci 25 29-33 (2004)

Audition

A/Prof Simon Carlile

The existence of a 'map' of auditory space in the brain has been problematic. At the perceptual level, maps of auditory space are easily demonstrated. However neurally, auditory space mapping is seen as a computational phenomenon, especially when compared to the other sensory systems such as vision and somatosensation (touch). In your discussion, consider what important aspects of sound direction are encoded by afferent auditory system, from the ear to the brain, and how this information is processed to encode auditory space. Consider why it might be difficult to compare perceptual and neural data in terms of the mapping of auditory space. Are maps important? Background reading Moore B.C.J. (1989) "An introduction to the psychology of hearing", Academic Press, Chapter on space perception. Carlile S (1996) "Auditory space" in Virtual Auditory Space: Generation and applications Ed. S Carlile, Landis, Austin. Butler, R.A., R.A. Humanski, and A.D. Musicant, Binaural and monaurallocalization of sound in two- dimensional space. Perception, 1990.19: p. 241-256. Carlile, S. and D. Pralong, The location-dependent nature of perceptuallysalient features of the human head-related transfer function. J Acoust SocAm, 1994. 95(6): p. 3445-3459. Shu, Z.J., N.V. Swindale, and M.S. Cynader, Spectral motion produces anauditory after-effect. Nature, 1993. 364: p. 721-723. Middlebrooks, J.C., Narrow-band sound localization related to externalear acoustics. J. Acoust. Soc. Am., 1992. 92(5): p. 2607-2624. Butler, R.A., The bandwidth effect on monaural and binaural localization.Hear. Res., 1986. 21: p. 67-73. Goldberg, J.M. and P.B. Brown, Response of binaural neurons of dogsuperior olivary complex to dichotic tonal stimuli: some physiologicalmechanisms of sound localization. J. Neurophysiol, 1969. 32: p.613-636. Young, E.D., et al., Neural organization and responses to complexstimuli in the dorsal cochlear nucleus. Philos. Trans. R. Soc. London B,1992. 336(1278): p. 407-413. Smith, P.H., P.X. Joris, and T.C. Yin, Projections of physiologicallycharacterised spherical bushy cell axons from the cochlear nucleus of cat:evidence for delay lines to the medial superior olive. J. Comp. Neurol.,1993. 331(2): p. 245-260. Palmer, A.R. and A.J. King, A monaural map in the guinea pig superiorcolliculus. Hear. Res. 1985 17:267-280 Wise, L.Z. and D.R.F. Irvine, Topographic organization of interauralintensity difference sensitivity in deep layers of cat superior colliculus:Implications for auditory spatial representation. J. Neurophysiol., 1985.54: p. 185-211. Olsen, J.F., E.I. Knudsen, and S.D. Easterly, Neural maps of interauraltime and intensity differences in the optic tectum of the owl. J.Neurosci., 1989. 9(7): p. 2591-2605. Carlile, S. and A.J. King, Monaural and binaural spectrum level cues inthe ferret: acoustics and the neural representation of auditory space. JNeurophys, 1994. 71: p. 785-801. 13. Imig, T.J. and H.O. Adrian, Binaural columns in the primary field (A1)of cat auditory cortex. Brain Research, 1977. 138: p. 241-257. Middlebrooks, J.C., R.W. Dykes, and M.M. Merzenich, Binauralresponse-specific bands in primary auditory cortex (AI) of the cat: topographicorganization orthogonal to isofrequency contours. Brain. Res., 1980.181: p. 31-48. Middlebrooks, J.C., et al., A panoramic code for sound locationby cortical neurons. Science (Washington, D.C.), 1994. 264(5160): p.842-844. Knudsen E I The role of auditory experience in the development andmaintainence of sound localization. TINS, 1984 September, p326-330 Hofman PM, van Riswick JGA. Re-learning sound localization with new ears. Nature Neuroscience 1998 1(5): 421 Wightman F and Kistler D. Of vulcan ears, human ears and 'ear prints' Nature Neuroscience 1998 1(5):337-339

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Making Memories
Dr Karen Cullen
The question of how and where memories are stored has puzzled neuroscientists for the better part of last century. Answering the how question has been guided by Hebbs 1949 proposal that memories are held in the cortex, first by reverberating circuits and then by lasting changes in firing patterns that stably link neural representations of the memory. A variety of cellular mechanisms have been proposed for consolidating this memory code. Early theories of where memories are stored, such as Galls phreneology, viewed memory as part of various faculties localised in different cortical areas. While phreneology has been relegated to the position of an amusing parlour game, more sophisticated studies have supported the notion that stable memories are dispersed across the cortex, with different aspects of a given memory localised to specific cortical regions. Memory processing can be divided into distinct systems: declarative (remembering who what when where) and procedural (remembering how) memory. The hippocampal-entorhinal structures are essential during the acquisition of new declarative memories; damage results in an inability to remember new information (anterograde amnesia). Retrograde amnesia, or loss of previously stored memories, can be produced with ablation of the cortex, with the class of information lost dependent on the functional area affected. Alzheimers disease is a progressive disorder, predominantly amnestic in early stages but later characterised by impairment in attention, language, perception, reasoning and comportment. The progression of neuronal degeneration from medial temporal lobe structures to neocortex parallels clinical symptoms of the disease. In this theme session, we will discuss journal articles on: (1) cellular mechanisms involved in memory encoding, (2) the role of the medial temporal lobe and prefrontal cortex in new memory formation, (3) cortical functional areas in neurologically -healthy humans and (4) conditions such as Alzheimers disease as examples of memory dysfunction. Well look some of the advances and controversies in this complex area of neuroscience through a critical review of recent literature. Before the first meeting, everyone should read Chapters 62 & 63 of Principles of Neuroscience, Kandel Schwartz & Jessel and the following review articles: Tsien JZ. 2000. Building a brainier mouse. Scientific American April:62-68. McGaugh JL. 2000. Memory - Century of Consolidation. Science 287:248-251. Another useful review: Eichenbaum H. 2000. A cortical-hippocampal system for declarative memory. Nature Reviews Neuroscience:41-50. The format for the essay assignment will be discussed at the first meeting. 1. Bliss T, Errington M, Fransen E, Godfraind JM, Kauer JA, Kooy RF, Maness PF, Furley AJ. 2000. Long-term potentiation in mice lacking the neural cell adhesion molecule L1. Current Biology. 10:1607-1610. 2. Curtis CE, Zalda DH, Pardoa JV. 2000. Organization of working memory within the human prefrontal cortex: a PET study of self-ordered object working memory. Neuropsychologia 38:1503-1510. 3. Dolan RJ, Fletcher PC. 1997. Dissociating prefrontal and hippocampal function in episodic memory encoding. Nature 388:582-585. 4. Ficca G, Lombardo P, Rossi L, Salzarulo P. 2000. Morning recall of verbal material depends on prior sleep organization. Behavioural Brain Research. 112:159-163. 5. Fischer S, Hallschmid M, Elsner AL, Born J. 2002. Sleep forms memory for finger skills. Proceedings of the National Academy of Sciences of the United States of America. 99:11987-11991. 6. Giannakopoulos P, Gold G, Duc M, Michel J, Hof P, Bouras C. 2000. Neural substrates of spatial and temporal disorientation in Alzheimer's disease. Acta Neuropathologica 100:189-195. 7. Kelley Hudson AJ, Grace GM. 2000. Misidentification syndromes related to face specific area in the fusiform gyrus. Journal of Neurology, Neurosurgery & Psychiatry 69:645-648. 8. Kelley WM. 1998. Hemispheric specialization in human dorsal frontal cortex and medial temporal lobe for verbal and non-verbal memory encoding. Neuron 20:927-936. a. King JA, Burgess N, Hartley T, Vargha-Khadem F, OKeefe J. 2002. Human hippocampus and viewpoint dependence in spatial memory. Hippocampus 12, 811-812 9. Lee AK, Wilson MA. 2002. Memory of sequential experience in the hippocampus during slow wave sleep. Neuron. 36:1183-1194. 10. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith CD. 2000. Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences of the United States of America. 97:4398-4403. 11. Maguire EA, Valentine ER, Wilding JM, Kapur N. 2003. Routes to remembering: the brains behind superior memory. Nature Neuroscience:90-95. 12. Maquet P, Laureys S, Peigneux P, Fuchs S, Petiau C, Phillips C, Aerts J, Del Fiore G, Degueldre C, Meulemans T, Luxen A, Franck G, Van Der Linden M, Smith C, Cleeremans A. 2000. Experience-dependent changes in cerebral activation during human REM sleep. Nature Neuroscience. 3:831-836. 13. Neylan TC. 2000. Memory and the medial temporal lobe: Patient H. M. The Journal of Neuropsychiatry and Clinical Neurosciences 12:103. 14. Peigneux P, Laureys S, Delbeuck X, Maquet P. 2001. Sleeping brain, learning brain. The role of sleep for memory systems. NeuroReport. 12:A111-124. 15. Stoop R, Pralong E. 2000. Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brain. European Journal of Neuroscience 12:3651-3663. 16. Sybirska E, Davachi L, Goldman-Rakic P. 2000. Prominence of direct entorhinal-CA1 pathway activation in sensorimotor and cognitive tasks revealed by 2-DG functional mapping in nonhuman primate. Journal of Neuroscience 20:5827-5834.

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17. Strekalova T, Wotjak CT, Schachner M. 2001. Intrahippocampal administration of an antibody against the HNK-1 carbohydrate impairs memory consolidation in an inhibitory learning task in mice. Molecular & Cellular Neurosciences. 17:1102-1113. 18. Tsien JZ, Huerta PT, Tonegawa S. 1996. The essential role of hippocampal CA1 NMDA receptor -dependent synaptic plasticity in spatial memory. Cell 87:1327-1338. 19. Vargha-Khadem F, al e. 1997. Differential effects of early hippocampal pathology on episodic and semantic memory. Science 277:376-379. 20. Wheeler M, Petersen S, Buckner R. 2000. Memory's echo: Vivid remembering reactivates sensory-specific cortex. Proceedings of the National Academy of Sciences of the United States of 97:11125-11129. 21. Wittenberg GM, Sullivan MR, Tsien JZ. 2002. Synaptic reentry reinforcement based network model for long-term memory consolidation. Hippocampus. 12:637-647. 22. Wood E, Dudchenko P, Eichenbaum H. 1999. The global record of memory in hippocampal neuronal activity. Nature 397:613-616. 23. Wright JW, Masino AJ, Reichert JR, Turner GD, Meighan SE, Meighan PC, Harding JW. 2003. Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases. Brain Research. 963:252-261. 24. Young B, Otto T, Fox G, Eichenbaum H. 1997. Memory representation within the parahippocampal region. Journal of Neuroscience 17:5183-5195. 25. Zola-Morgan S, Squire LR, Ramus SJ. 1994. Severity of memory impairment in monkeys as a function of locus and extent of damage within the medial temporal lobe system. Hippocampus 4:483-495. 26. Sutherland GR, McNaughton B. 2000. Memory trace reactivation in hippocampal and neocortical neuronal ensembles. Current Opinion in Neurobiology. 10:180-186. 27. Miller E. 2000. The prefrontal cortex and cognitive control. Nature Reviews Neuroscience:59-65. 28. Wilson MA. 2002. Hippocampal memory formation, plasticity, and the role of sleep. Neurobiology of Learning & Memory 78:565-569. 29. Stickgold R, Hobson JA, Fosse R, Fosse M. 2001. Sleep, learning, and dreams: off-line memory reprocessing. Science. 294:1052-1057.

Sexual Brain
Dr Kevin Keay
What are the brain circuits and mechanisms which produce sexual behaviour? How do these circuits and mechanisms differ between males and females? What can animal studies tell us about human sexual behaviour? Suggested Pre-Discussion Reading (1) Agmo, Pfaff (1999) Research on neurobiology of sexual behavior at turn of millennium. Behav Brain Res 105, 1-4. (2) Breedlove (1992) Sexual dimorphism in the vertebrate nervous system. Journal of Neuroscience. 12, 4133-42. (3) Breedlove, Cooke and Jordan (1999) The orthodox view of brain sexual differentiation. Brain Behav Evol 54, 8-14. (4) Frohlich, Ogawa, Morgan, Burton and Pfaff (1999) Hormones, genes and the structure of sexual arousal. Behavioural Brain Research. 105, 5-27. Human Papers you may wish to use in the Essay Comparison (1) Allen, Hines, Shryne and Gorski (1989) Two sexually dimorphic cell groups in the human brain. Journal of Neuroscience. 9, 497-506. (2)Allen and Gorski (1990) Sex difference in the bed nucleus of the stria terminalis of the human brain. Journal of Comparative Neurology. 302, 697-706. (3) Allen, Richey, Chai and Gorski (1991) Sex differences in the corpus callosum of the living human being. Journal of Neuroscience. 11, 933-42. (4) Allen and Gorski (1991) Sexual dimorphism of the anterior commissure and massa intermedia of the human brain. Journal of Comparative Neurology. 312, 97-104. (5) Allen and Gorski (1992) Sexual orientation and the size of the anterior commissure in the human brain. Proceedings of the National Academy of Sciences of the United States of America. 89, 7199-202. (6) Breedlove (1994) Sexual differentiation of the human nervous system. Annual Review of Psychology. 45, 389-418. (7) Swaab and Fliers (1985) A sexually dimorphic nucleus in the human brain. Science. 228, 1112-5 Animal Studies for Discussion Sessions (we will not cover ALL these papers, they are suggestions) (1) Anderson, Rhees and Fleming (1985) Effects of prenatal stress on differentiation of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the rat brain. Brain Research. 332, 113-8. (2) Aou, Oomura and Yoshimatsu (1988) Neuron activity of the ventromedial hypothalamus and the medial preoptic area of the female monkey during sexual behavior. Brain Research. 455, 65-71. (3) Breedlove, Jacobson, Gorski and Arnold (1982) Masculinization of the female rat spinal cord following a single neonatal injection of testosterone propionate but not estradiol benzoate. Brain Research. 237, 173-81. (4) Breedlove and Arnold (1983) Hormonal control of a developing neuromuscular system. I. Complete Demasculinization of the male rat spinal nucleus of the bulbocavernosus using the anti-androgen flutamide. Journal of Neuroscience. 3, 417-23. (5) Breedlove and Arnold (1983) Hormonal control of a developing neuromuscular system. II. Sensitive periods for the androgen-induced masculinization of the rat spinal nucleus of the bulbocavernosus. Journal of Neuroscience. 3, 424-32. (6) Cherry and Baum (1990) Effects of lesions of a sexually dimorphic nucleus in the preoptic/anterior hypothalamic area on the expression of androgen- and estrogen-dependent sexual behaviors in male ferrets. Brain Research. 522, 191-203. (7) Cherry, Basham and Baum (1991) Neonatal testosterone masculinizes sexual behavior without affecting the morphology of the dorsal preoptic/anterior hypothalamic area of female ferrets. Brain Research. 546, 321-8.

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(8) Cooke, Chowanadisai and Breedlove (2000) Post-weaning social isolation of male rats reduces the volume of the medial amygdala and leads to deficits in adult sexual behavior. Behavioural Brain Research. 117, 107-13. (9) Dellovade, Chan, Vennstrom, Forrest and Pfaff (2000) The two thyroid hormone receptor genes have opposite effects on estrogen-stimulated sex behaviors. Nature Neuroscience. 3, 472-5. (10) Fleming, Anderson, Rhees, Kinghorn and Bakaitis (1986) Effects of prenatal stress on sexually dimorphic asymmetries in the cerebral cortex of the male rat. Brain Research Bulletin. 16, 395-8. (11) Fraile, McEwen and Pfaff (1988) Comparative effects of progesterone and alphaxalone on aggressive, reproductive and locomotor behaviors. Pharmacology, Biochemistry & Behavior. 30, 729-35. (12) Gradwell, Everitt and Herbert (1975) 5-hydroxytryptamine in the central nervous system and sexual receptivity of female rhesus monkeys. Brain Research. 88, 281-93. (13) Halem, Cherry and Baum (2001) Central forebrain Fos responses to familiar male odours are attenuated in recently mated female mice. European Journal of Neuroscience. 13, 389-99. (14) Hennessey, Wallen and Edwards (1986) Preoptic lesions increase display of lordosis by male rats. Brain Res370, 21-8. (15) Hennessey, Camak, Gordon and Edwards (1990) Connections between the pontine central gray and the ventromedial hypothalamus are essential for lordosis in female rats. Behavioral Neuroscience. 104, 477-88. (16) Hines, Allen and Gorski (1992) Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis of the rat. Brain Research. 579, 321-6. (17) Hughes, Everitt and Herbert (1987) Selective effects of beta-endorphin infused into the hypothalamus, preoptic area and bed nucleus of the stria terminalis on the sexual and ingestive behaviour of male rats. Neuroscience. 23, 1063-73. (18) Hughes, Everitt and Herbert (1990) Comparative effects of preoptic area infusions of opioid peptides, lesions and castration on sexual behaviour in male rats: studies of instrumental behaviour, conditioned place preference and partner preference. Psychopharmacology. 102, 243-56. (19) Kaufman, McEwen and Pfaff (1988) Cholinergic mechanisms of lordotic behavior in rats. Physiol & Behav 43, 507-14. (20) Kow, Brown and Pfaff (1994) Activation of protein kinase C in the hypothalamic ventromedial nucleus or the midbrain central gray facilitates lordosis. Brain Research. 660, 241-8. (21) Kow and Pfaff (1998) Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system. Behavioural Brain Research. 92, 169-80. (22) McCarthy, Pfaff and Schwartz-Giblin (1991) Midbrain central gray GABAA receptor activation enhances, and blockade reduces, sexual behavior in the female rat. Experimental Brain Research. 86, 108-16. (23) McGregor and Herbert (1992) Differential effects of excitotoxic basolateral and corticomedial lesions of the amygdala on the behavioural and endocrine responses to either sexual or aggression-promoting stimuli in male rat. Brain Res574, 9-20. (24) McGregor and Herbert (1992) Specific effects of beta-endorphin infused into the amygdala on sexual behaviour in the male rat. Neuroscience. 46, 165-72. (25) Meisel, Dohanich, McEwen and Pfaff (1987) Antagonism of sexual behavior in female rats by ventromedial hypothalamic implants of antiestrogen. Neuroendocrinology. 45, 201-7. (26) Monaghan, Arjomand and Breedlove (1993) Brain lesions affect penile reflexes. Hormones & Behavior. 27, 122-31. (27) Ogawa, Taylor, Lubahn, Korach and Pfaff (1996) Reversal of sex roles in genetic female mice by disruption of estrogen receptor gene. Neuroendocrinology. 64, 467-70. (28) Ogawa, Chester, Hewitt, Walker, Gustafsson, Smithies, Korach and Pfaff (2000) From the cover: abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO). [see comments]. Proceedings of the National Academy of Sciences of the United States of America. 97, 14737-41. (29) Oomura, Yoshimatsu and Aou (1983) Medial preoptic and hypothalamic neuronal activity during sexual behavior of the male monkey. Brain Research. 266, 340-3. (30) Perachio, Marr and Alexander (1979) Sexual behavior in male rhesus monkeys elicited by electrical stimulation of preoptic and hypothalamic areas. Brain Research. 177, 127-44. (31) Pfaff and Sakuma (1979) Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. Journal of Physiology. 288, 203-10. (32) Romano, Mobbs, Lauber, Howells and Pfaff (1990) Differential regulation of proenkephalin gene expression by estrogen in the ventromedial hypothalamus of male and female rats: implications for the molecular basis of a sexually differentiated behavior. Brain Research. 536, 63-8. (33) Slimp, Hart and Goy (1978) Heterosexual, autosexual and social behavior of adult male rhesus monkeys with medial preoptic-anterior hypothalamic lesions. Brain Research. 142, 105-22.1996

Brain development
Dr Catherine Leamey
The brain is a complex and mysterious organ whose circuitry is the basis of all behaviour. Developmental neurobiology tries to understand how this marvelous structure, with all its intricate circuitry, is formed. Sensory pathways are useful for this as they are characterised an orderly representation of the peripheral sensory organs. This type of organisation is called a topographic map. One of the most widely studied maps is the projection from the retina to the optic tectum or superior colliculus. Work done over 40 years ago proposed that gradients of molecules provide positional information to permit the formation of an appropriate map of visual space. Recent work in this pathway is starting to reveal what these molecules are, and hence some of the mechanisms that underlie the formation of topographic maps in the brain. In this theme session we will examine the scientific literature which initially postulated the presence of molecules which regulate mapping, through until the current time. Does this knowledge explain mapping in the retinotectal pathway? What about activity does it play a role? A recent review article is provided here as background. A full list of papers will be provided at the first session.

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McLaughlin, T., Hindges, R. and OLeary, D.D.M. (2003) Regulation of axial patterning of the retina and its topographic mapping in the brain. Current Opinion in Neurobiology 13: 57-69

SickBrain
Dr John Mitrofanis
Brains are really wonderful when they are working well. They are the marvel of biology. Unfortunately, they get sick sometimes, either by disease or injury. This can result in major disturbances in sensory perception, behaviour, memory, movement, visceral activities, thought and cognition. This seminar series explores the neural mechanisms thought to underlie the symptoms of 4 principal brain dysfunctional states; Epilepsy, Parkinson Disease, Alzheimer Disease and Schizophrenia. You will be assessed in the following way. You and a partner will choose to present one recent journal article - selected from list below - dealing with one of these states. Each week, all of you will answer 2 short questions on each of the articles to be discussed for that week (3 papers per week; see below). For your essay, you will explore issues of interest to you - relating of course to one of the 4 major dysfunctional states. In essence, you will set your own question and agenda. Epilepsy 1 Porter BE. Brooks-Kayal A. Golden JA. Disorders of cortical development and epilepsy. Archives of Neurology. 59(3):361-5, 2002 2 Ben-Ari Y. Cell death and synaptic reorganisations produced by seizures. Epilepsia 42 Suppl 3: 5-7 2001 3 Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 42 Suppl 3:8-12, 2001. 4 Kostopoulos GK. Involvement of the thalamocortical system in epileptic loss of consciousness. Epilepsia. 42 Suppl 3:13-9, 2001. 5 Carlen PL. Skinner F. Zhang L. Naus C. Kushnir M. Perez Velazquez JL. The role of gap junctions in seizures. Brain Research - Brain Research Reviews. 32(1):235-41, 2000 6 Vezzani A. Hoyer D. Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis. European Journal of Neuroscience. 11(11):3767-76, 1999 Parkinson Disease 7 Crossman AR. Functional anatomy of movement disorders. Journal of Anatomy. 196: 519-525 2000 8 Stein JF, Aziz TZ. Does imbalance between basal ganglia and cerebellar outputs cause movement disorders. Current Opinion in Neurology 12: 667-669 1999 9 Pahapill PA. Lozano AM. The pedunculopontine nucleus and Parkinson's disease. Brain. 123 ( 9):1767-83 2000 10 Drobny M. Kurca E. Possible extrapyramidal system degradation in Parkinson's disease. Brain Research Bulletin. 53(4):425-30, 2000 11 Bevan MD. Magill PJ. Terman D. Bolam JP. Wilson CJ. Move to the rhythm: oscillations in the subthalamic nucleusexternal globus pallidus network. Trends in Neurosciences. 25(10): 525-31 2002 12 Tintner R. Jankovic J. Treatment options for Parkinson's disease. Current Opinion in Neurology. 15(4):467-76 2002 Alzheimer Disease 13 Cummings JL. Cole G. Alzheimer disease. JAMA. 287(18):2335-8, 2002 May 8. 14 de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 33(4):1152-62, 2002 15 Smith MA. Drew KL. Nunomura A. Takeda A. Hirai K. Zhu X. Atwood CS. Raina AK. Rottkamp CA. Sayre LM. Friedland RP. Perry G. Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochemistry International. 40(6):527-31, 2002 16 Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Experimental Gerontology. 35(9-10):1363-72, 2000 17 Louis ED. A new twist for stopping the shakes? Revisiting GABAergic therapy for essential tremor. Archives of Neurology. 56(7):807-8, 1999 18 Johnson WG. Late-onset neurodegenerative diseases--the role of protein insolubility. Journal of Anatomy. 196( 4):60916, 2000. Schizophrenia 19 Jones EG. Cortical development and thalamic pathology in schizophrenia. Schizophrenia Bulletin. 23(3):483-501, 1997. 20 Maynard TM. Sikich L. Lieberman JA. LaMantia AS. Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia. Schizophrenia Bulletin. 27(3):457-76, 2001. 21 Finlay JM. Mesoprefrontal dopamine neurons and schizophrenia: role of developmental abnormalities. Schizophrenia Bulletin. 27(3):431-42, 2001. 22 Jones LB. Recent cytoarchitechtonic changes in the prefrontal cortex of schizophrenics. Frontiers in Bioscience. 6:E14853, 2001 23 Stevens JR. Schizophrenia: reproductive hormones and the brain. American Journal of Psychiatry. 159(5):713-9, 2002 24 Heckers S. Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus. 11(5):520-8, 2001.

Synapse Formation
Dr Bill Phillips
During development presynaptic nerve terminals make contact with postsynaptic cell and at the point of contact both become specialized. The nerve terminal becomes more efficient at releasing transmitter in response to action potentials. The postsynaptic membrane forms a cluster of neurotransmitter receptors to respond more effectively to the released transmitter. Many central synapses remain "plastic" throughout life. They can adapt to new functional demands becoming stronger or weaker depending upon patterns of activation. Neuroscientists speak of activity-dependent Hebbian-type changes like LTP where a synapse becomes stronger when the presynaptic and postsynaptic parts of it are active at the same time. They also

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talk about non-Hebbian plasticity, where this co-activation rule may not be followed. Thus it is important to unravel the cell biological processes responsible for making synapses stronger and weaker. We also need to clarify how these processes may be influenced by neuron activity and other signals to develop or adapt the synapse. This is a big question so here we will concentrate mainly on the mechanisms that organize the postsynaptic receptors into clusters beneath developing transmitter release sites. The Report Write a short article in which you first outline what is known about mechanisms for organizing glutamate, glycine and GABAA receptors into clusters at their respective synapses. Critically review recent experimental studies that have attempted to understand how neuronal activity might act though these mechanisms to modify synaptic strength. Finally, based on what you have read, speculate on how these mechanisms might work together to refine the strength of synaptic connections in a simple spinal reflex pathway during postnatal development. Papers Introductory review- everyone to read before first session: 1. Barry, M.F. and Ziff, E.B. (2002) Receptor trafficking and the plasticity of excitatory synapses. Current Opinion in Neurobiology 12: 279-286. -----------------------Pre- and postsynaptic matching during synapse formation 2. Craig, A. M., C. D. Blackstone, R. L. Huganir and G. Banker. 1994. Selective clustering of glutamate and g-aminobutyric acid receptors opposite terminals releasing the corresponding transmitters. Proc. Natl Acad. Sci. (USA) 91:12373-12377. Activity effects on development of synapses 3. Desai, N.S. Cudmore, R.H., Nelson, S.B. and Turrigiano, G.G. (2002) Critical periods for experience-dependent synaptic scaling in visual cortex. Nature Neuroscience 5: 783-789. 4. Rosato-Siri, M., Granolfo, M. and Ballerini, L. (2002) Activity-dependent modulation of GABAergic synapses in developing rat spinal networks in vitro. European J. of Neuroscience 16: 2123-2135. Postsynaptic density proteins Inhibitory Synapses 5. Feng, G., H. Tintrup, J. Kirsch, M. C. Nichol, J. Kuhse, H. Betz, and J. R. Sanes (1998) Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282: 1321-1324. also read the introduction piece: Froehner, S. C. (1998) Gathering glycine receptors at synapses. Science 282: 1277-1279. 6. Kneussel,M., Brandstatter,J.H., Laube,B., Stahl,S., Muller,U. and Betz,H. (1999) Loss of postsynaptic GABAA receptor clustering in gephyrin-deficient mice. J. Neurosci. 19: 9289-9297. 7. Kins,S., Betz,H. and Kirsch,J. (2000). Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Nature Neurosci. 3:22-9. also read the introduction piece: Fallon JR. (2000) Building inhibitory synapses: exchange factors getting into the act? Nature Neurosci. 3:5-6. 8. Kins et al. 2000 on trafficking of GABAA receptors by gephyrin/collybistin interactions Nature Neurosci 3: 22-28 9. Christie, S. B., Miralles, C. P., and De Blas, A. L. (2002). GABAergic innervation organizes synaptic and extrasynaptic GABAA receptor clustering in cultured hippocampal neurons., Journal of Neuroscience 22, 684-697. 10. Kittler, J. T., Delmas, P., Jovanovic, J. N., Brown, D. A., Smart, T. G., and Moss, S. J. (2000). Constitutive Endocytosis of GABAA Receptors by an Association with the Adaptin AP2 Complex Modulates Inhibitory Synaptic Currents in Hippocampal Neurons, Journal of Neuroscience 20, 7972-7977. .Excitatory synapses 11. GarnerC, NashJ, Huganir RL (2000) PDZ domains in synapse assembly and signalling Trends in Cell Biology 10: 274280. 12. Migaud, M., P. Charlesworth, M. Dempster, L. C. Webster, A. M. Watabe, M. Makhinson, Y. He, M. F. Ramsay, R. G. M. Morris, J. H. Morrison, T. J. O'Dell, and S. G. N. Grant (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density -95 protein. Nature 396: 433-439. 13. Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M (1999) AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses Nature Neurosci. 2: 972-977. 14. Chen L, Chetkovich DM, Petralla RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nichol RA (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408: 936-943 15. Durand,G.M., Kovalchuk,Y. and Konnerth,A. (1996) Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381: 71-75. 16. Kacharmina JE, Job C, Crino P, Eberwine J (2000) Stimulation of glutamate receptor protein synthesis and membrane insertion within isolated neuronal dendrites. Proc Natl Acad Sci (USA): 97: 11545-50 17. Lu W, Man H, Ju W, Trimble WS, MacDonald JF, Wang YT (2001) Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29: 243-54. 18. Beique, J.-C. and Andrade, R. (2002) PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J. Physiology 546: 859-867. 19. Poncer, J.C., Esteban, J.A. and Malinow, R. (2002) Multiple mechanisms for the potentiation of AMPA receptor mediated transmission by a-Ca2+/calmodulin-dependent protein kinase II. J. Neuroscience 22: 4406-4411. 20. Thiagarajan,T.C., Piedras-Renteria,E.S. and Tsien, R.W. (2002) a and bCaMKII: inverse regulation by neuronal activity and opposing effects on synaptic strength. Neuron 36: 1103-1114.

Setting the internal clock

Dr Dario Protti

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These paper sessions will review the most recent evidence for a newly discovered retinal subsystem and its links to circadian rhythms and other environmental variables. Many human physiological variables, ranging from body temperature to cognitive performance, are governed by internal circadian clocks, which keep pace with the 24 hour cycle of day and night. A pacemaker located in the hypothalamus drives these rhythms and has an intrinsic oscillator whose period is approximately 24 hours. Light is the main sensory input which matches the internal clock with the solar day. For many years, rods and cones have been thought to be the only photoreceptors of the mammalian eye. More recently, however, a subset of intrinsically photosensitive ganglion cells has been shown to constitute an independent photoreceptor system that projects to the hypothalamus and thus, help to synchronise circadian rhythms with the solar day. Background reading. D.M. Berson et al., Phototransduction by retinal ganglion cells that set the circadian clock. Science 295 (2002), pp. 10701073. R.G. Foster et al., Circadian photoreception in the retinally degenerate mouse (rd/rd). J. Comp. Physiol. [A] 169 (1991), pp. 3950. M.S. Freedman et al., Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284 (1999), pp. 502504. J.J.Gooley et al., Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001) J. Hannibal et al., The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptidecontaining retinal ganglion cells of the retinohypothalamic tract. J. Neurosci. 22 (2002), p. RC191. S. Hattar et al., Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295 (2002), pp. 10651070. S. Hattar et al., Melanopsin and rodcone photoreceptive systems account for all major accessory visual functions in mice Nature 424 (2003), 75-81 E.B. Klerman et al., Photic resetting of the human circadian pacemaker in the absence of conscious vision. J. Biol. Rhythms 17 (2002), pp. 548555. R.J. Lucas et al., Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav. Brain Res. 125 (2001), pp. 97102. R.J.Lucas et al., Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245-247 (2003) D.E. Nelson and J.S. Takahashi, Comparison of visual sensitivity for suppression of pineal melatonin and circadian phaseshifting in the golden hamster. Brain Res. 554 (1991), pp. 272277. S.Panda et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213-2216 (2002) I. Provencio et al., Photoreceptive net in the mammalian retina. Nature 415 (2002), p. 493. I. Provencio et al., Melanopsin: An opsin in melanophores, brain, and eye. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), pp. 340345. I. Provencio et al., A novel human opsin in the inner retina. J. Neurosci. 20 (2000), pp. 600605 N.F. Ruby et al. Role of melanopsin in circadian responses to light. Science 298, 2211-2213 (2002) J.S. Takahashi et al., Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308 (1984), pp. 186188.