Integrative physiology

The course provides students with a unified and integrated view of the functions of the organism under nervous and endocrine control. The body's functions are coordinated as a whole and do not act in isolation. Since students already have a basic knowledge of the functions of the various organs and systems, the course covers these only in part: it examines in depth how they are integrated, with particular attention to the nervous system and to the mechanisms by which homeostatic regulation, sensory processing, motor control and higher functions are realised as a single process.

Knowledge and understanding. By the end of the course, students will be familiar with: the principles of homeostatic regulation and their current developments (variable set points, allostasis, anticipatory or feedforward control); the functional organisation of the central and peripheral nervous system and the main methods used to study it; the integrated nervous, endocrine and behavioural mechanisms controlling the principal homeostatic functions (fluid and electrolyte balance and arterial pressure, energy balance, thermoregulation, growth, the stress response, reproductive functions); the organisation of the sensory systems, including interoception, and of the motor systems, from reflexes to voluntary control; the physiological basis of higher functions, including perception, emotion, memory, language and consciousness.

Applying knowledge and understanding. Students will be able to explain an integrated physiological response, tracing it back from the signals that generate it to the circuits that produce it; to predict the consequences of a lesion or of an experimental or pharmacological manipulation of a regulatory system; and to interpret in physiological terms the experimental and clinical findings discussed during the course. They will also be able to read the data of a neuroscience experiment and recognise the type of evidence it provides.

Making judgements. Students will learn to approach physiology as a dynamic discipline, recognising that many questions remain open and that several of the topics covered represent the most current interpretations, subject to revision as research advances. They will be able to critically assess the limitations of an established model, to compare alternative hypotheses about the same phenomenon, and to recognise the methodological problems that make it difficult to attribute complex functions to individual brain structures.

Communication skills. Through classroom discussion of open questions, students will acquire the ability to describe an integrated physiological mechanism using appropriate terminology, to present the results of an experimental study, and to argue a position while distinguishing data from their interpretation.

Learning skills. Students will develop the ability to keep up independently with the physiological and neuroscientific literature, to connect knowledge from different fields (physiology, cell and molecular biology, pathology, pharmacology), and to use the general principles they have learned to address topics not explicitly covered in class.

The course consists of 49 hours of lectures, organised into six thematic modules.

The lectures present the content in a way that guides students towards an understanding of the discipline and towards more in-depth study with the help of the recommended textbooks. Each lecture opens with a question or a physiological problem, which is addressed during the lecture and returned to at the end: the aim is to train students to reconstruct a mechanism starting from the function to be explained, rather than to memorise descriptions.

Since the course presupposes the basic knowledge of anatomy and physiology listed among the prerequisites, these topics may only be briefly revisited during the lectures.

Classroom discussion of one or more scientific articles may also be included, chosen to illustrate how experimental data are obtained, what conclusions they allow, and which questions remain open. Some lectures include the comparison of alternative hypotheses about the same phenomenon and the discussion of models currently under revision.

The content of the lectures will be made available on Studium or through other institutional channels.

Should new legal provisions or particular circumstances of force majeure require the course to be delivered remotely or in blended mode, the necessary changes may be made to what is stated here, in order to comply with the planned program.

Basic knowledge of Physiology and Anatomy.

Students are expected to have already acquired knowledge of cell physiology, including transport mechanisms across the plasma membrane and the ionic basis of the membrane potential and the action potential. They should have a basic knowledge of synaptic transmission, of neurotransmitters and hormones, together with their receptor systems and the main signal transduction mechanisms. Knowledge of the fundamental mechanisms of sensory transduction and muscle contraction, and of the main functions of the musculoskeletal, digestive, respiratory, cardiovascular and excretory systems, is also required. As regards anatomy, students are expected to be familiar with the general organisation of the central and peripheral nervous system: the subdivisions of the brain, the meninges and cerebrospinal fluid, the organisation of the spinal cord, and the cranial and spinal nerves. A basic knowledge of metabolism and the ability to read a scientific text in English are useful.

Module 1 – Homeostasis and predictive regulation (lecture 1)

The organism as an integrated system: homeostasis and physiological systems of regulation and control. Negative and positive feedback; limitations of the fixed set point model; variable set points and rheostasis. Anticipatory (feedforward) control and allostasis; allostatic load. The organism as an open system far from equilibrium and the energy cost of regulation. Interoception: pathways and role in regulation. The nervous system as an organ of predictive regulation.

Module 2 – Functional architecture of the nervous system (lectures 2-3)

2. Functional organisation of the central nervous system: hierarchical and parallel processing, topographic maps, recurrent circuits, balance between excitation and inhibition. Cerebral cortex: cytoarchitecture and functional organisation; cortical areas; intracortical connections, afferents and efferents. Glial cells and their functional role. Cerebrospinal fluid: physicochemical properties and functions; blood-brain barrier; glymphatic system and meningeal lymphatic drainage. Non-invasive investigation methods in humans and experimental methods in animals: recording and manipulation of neuronal activity, identification of cell types, connectomics.
3. Diffuse modulatory systems: nuclei of origin, neurotransmitters and functions. The level of vigilance: measurement of cortical electrical activity, electroencephalographic rhythms, sleep and its stages. Nervous centres involved in the regulation of sleep and organisation of the sleep-wake switch. Homeostatic and circadian regulation of sleep. Hypotheses on the functions of sleep and open questions. Circadian rhythms: suprachiasmatic nucleus, molecular clock, entrainment and peripheral clocks.

Module 3 – Integrated homeostatic regulation (lectures 4-9)

4. The integrating systems: hypothalamus, autonomic nervous system, endocrine system. Sympathetic and parasympathetic systems: organisation, neurotransmitters and receptors; enteric nervous system. Afferent component of the autonomic system and ascending visceral pathways (nucleus of the solitary tract, parabrachial nucleus). Circumventricular organs. Functional anatomy of the hypothalamus and its organisation by neuronal populations. Neuroendocrine systems: hypothalamus and neurohypophysis; hypophysiotropic hormones; anterior pituitary hormones and endocrine axes. Common principles of endocrine axes: pulsatile secretion, rhythmicity, multilevel feedback, transport and availability, permissive effects, peripheral conversion. Definition and classification of hormones; biosynthesis, secretion, transport, activation and inactivation; mechanisms of action.
5. Integrated control of fluid and electrolyte balance and of arterial pressure. Sensors of osmolarity and volume. Thirst circuits and salt appetite. Vasopressin: regulation of secretion, renal effects, outline of pathophysiology. Renin-angiotensin-aldosterone system; functions of aldosterone. Baroreflex and its functional resetting; natriuretic peptides. Integrated responses to standing up and to haemorrhage.
6. Integrated control of energy balance. The endocrine pancreas and the regulation of blood glucose; insulin and glucagon; incretins. Adiposity signals and meal-related signals; hypothalamic circuits of hunger and satiety; the gut-brain axis. Outline of pathophysiology: obesity and diabetes mellitus, with reference to the mechanisms of action of incretin-based drugs.
7. Energy expenditure and thermoregulation. Peripheral and central thermal sensors; effectors; shivering and non-shivering thermogenesis; brown adipose tissue. Fever as a shift of the thermal set point. Thyroid hormones: synthesis, transport, mechanism of action and functions; local regulation by deiodinases; hyper- and hypothyroidism. Endocrine control of growth: GH and IGF-1; interaction with thyroid and sex hormones; growth disorders. Calcium and phosphate homeostasis and bone physiology: parathyroid hormone, vitamin D and calcitonin.
8. Stress responses. Sympathoadrenal axis: catecholamines and the adrenal medulla. Hypothalamic-pituitary-adrenal axis; adrenal gland; functions of cortisol and the permissive role of glucocorticoids; receptors and tissue specificity; Cushing's syndrome. Interactions between the nervous, endocrine and immune systems: sickness behaviour and the inflammatory reflex. Consequences of chronic activation. Outline of prostaglandins, endorphins and endocannabinoids.
9. Physiology of reproduction. Neuroendocrine control of the hypothalamic-pituitary-gonadal axis: the GnRH pulse generator and the role of kisspeptin. Functions of the female reproductive organs: ovarian, uterine and hormonal cycles; physiology of pregnancy and childbirth; neuroendocrine control of lactation. Functions of the male reproductive organs: functional anatomy of the testis and the spermatic ducts; spermatogenesis; male sex hormones. Integration with energy balance and with the stress response.

Module 4 – Sensory systems (lectures 10-16)

10. General principles of sensory systems: transformation of the stimulus into a bioelectrical event; sensory receptors, classification, sensory modality, threshold, adaptation; classification of nerve fibres. Coding of modality, location, intensity and duration; receptive fields and lateral inhibition; efficient coding and predictive coding. Interoception: types of afferents, visceral mechanoreceptors and chemoreceptors, central pathways.
11. Somatosensory system: tactile and thermal receptors; classes of low-threshold mechanoreceptors; muscle and joint proprioceptors. Epicritic and protopathic sensibility; receptive fields; dermatomes. Ascending pathways. Somatosensory cortex and somatotopic organisation; plasticity of cortical maps.
12. Nociception and pain: nociceptors and transduction mechanisms; ascending pathways; peripheral and central sensitisation. Descending control of pain and modulation by expectation and context. Acute, neuropathic and chronic pain. Itch and its pathways.
13. The eye and vision: optical properties of the eye and pupillary reflexes. The retina and the process of phototransduction; functional organisation of the retina and types of ganglion cells; intrinsically photosensitive ganglion cells. Light and dark adaptation; colour vision. Parallel visual pathways and central projections.
14. Visual cortex: receptive fields, columnar organisation, contextual and top-down influences. Stereopsis. Ventral and dorsal cortical pathways; object recognition. Perception: from sensation to perceptual inference; the role of attention.
15. The ear and auditory function: transmission of sound to the inner ear; the cochlea and the transduction of sound stimuli; cochlear amplification and otoacoustic emissions. Coding of frequency and intensity; central auditory pathways and sound localisation; auditory cortex; auditory stream segregation and selective attention. Outline of hearing loss and cochlear implants.
16. The chemical senses: olfaction and taste. Olfactory receptors and combinatorial coding; olfactory bulb and piriform cortex; retronasal olfaction. Olfactory disorders and their clinical significance. Taste receptors and pathways; taste qualities and valence; formation of food preferences.

Module 5 – Motor system (lectures 17-20)

17. Organisation of motor functions. Motor neurons and motor units. Spinal reflexes: stretch reflexes, the alpha-gamma loop, flexor and crossed reflexes; task-dependent modulation of reflexes. Motor patterns and their control: central pattern generators and the organisation of spinal interneurons; supraspinal control of locomotion. Outline of the clinical applications of spinal cord stimulation.
18. Muscle tone and posture: multisensory integration, postural synergies and anticipatory adjustments. Vestibular apparatus: responses to linear and angular accelerations of the head; vestibular reflexes. Eye movements: classes, saccade generator, cortical control. Efference copy and perceptual stability.
19. Motor cortex and the control of voluntary movement: motor areas and their organisation; from somatotopic maps to representations of actions; population coding and preparatory activity. Descending projection systems: corticospinal, rubrospinal, reticulospinal and vestibulospinal pathways. Posterior parietal cortex and sensorimotor transformations; spatial neglect. The basal ganglia and their anatomical and functional organisation; action selection and the role of dopamine; outline of pathophysiology. Brain-computer interfaces.
20. The cerebellum: functional anatomy of the archi-, paleo- and neocerebellum; cerebellar cortical microcircuit and mechanisms of plasticity. Internal models, prediction of the consequences of movement, and motor learning. Cerebellar contribution to non-motor functions. Cerebellar syndromes.

Module 6 – Higher functions (lectures 21-24)

21. Neurophysiology of behaviour: general principles. Motivated behaviours and their neural basis. The limbic system: meaning and limitations of the concept. Emotions and their functional significance; theories of emotion; the role of the amygdala and of interoception. Motivation, reward and addiction. Emotion and decision-making.
22. Memory and learning: memory systems and their dissociations; conditioned reflexes and non-associative learning. Cellular basis of memory and the concept of the engram; synaptic and systems consolidation; reactivation during sleep; reconsolidation and forgetting. Hippocampus and the representation of space and of relations. Recall as a reconstructive process.
23. Cortical association areas and integrative processes. Language: neural basis of production and comprehension; the classical model and the dual-stream model; the aphasias. Lateralisation and cerebral dominance; functional asymmetries and the callosal disconnection syndrome. Prefrontal cortex and executive functions. The problem of localising higher functions: historical development, limitations of lesion and neuroimaging methods, current network-based approaches.
24. Perception and consciousness. Level and content of consciousness; states of consciousness and disorders of consciousness; neural correlates and experimental measures. Main theories of consciousness and their comparison. Corollary discharge and the distinction between self and environment. Consciousness in other species; criteria for its attribution. The mind-brain relationship: main positions and open questions.

Textbooks 

Recommended for exam preparation

• D. U. Silverthorn. Human Physiology: An Integrated Approach. Pearson, latest edition. 
• E. P. Widmaier, H. Raff, K. T. Strang. Vander's Human Physiology: The Mechanisms of Body Function. McGraw-Hill, latest edition.

For reference and further study

• E. R. Kandel, J. D. Koester, S. H. Mack, S. A. Siegelbaum (eds). Principles of Neural Science. McGraw-Hill, 6th edition. 
• D. Purves, G. J. Augustine, D. Fitzpatrick et al. Neuroscience. Oxford University Press, latest edition. (A more concise alternative to Kandel.)
• M. F. Bear, B. W. Connors, M. A. Paradiso. Neuroscience: Exploring the Brain. Jones & Bartlett, latest edition.
• W. F. Boron, E. L. Boulpaep. Medical Physiology. Elsevier, latest edition. (For the endocrine, autonomic and homeostatic modules.)
• M. S. Gazzaniga, R. B. Ivry, G. R. Mangun. Cognitive Neuroscience: The Biology of the Mind. W. W. Norton, latest edition. (For the module on higher functions, including the methodological limits of lesion and neuroimaging studies.)

Optional further reading

• P. Sterling, S. Laughlin. Principles of Neural Design. MIT Press.
• P. Sterling. What Is Health? Allostasis and the Evolution of Human Design. MIT Press. (On allostasis and allostatic load.)
• A. Seth. Being You: A New Science of Consciousness. Faber & Faber / Dutton. (On perception and consciousness.)

Assessment methods

Learning is assessed by means of a written test, with the possibility of an additional oral examination at the student's request. In certain circumstances, the lecturer may require an oral examination to be taken.

Structure of the written test. The test consists of 20 items, each made up of 4 true/false statements, for a total of 80 statements. The time allowed is 60 minutes. Students who complete the test in less than 30 minutes are awarded a bonus of 2 points (equivalent to 2 additional correct answers).

Marking criteria. Each statement evaluated correctly is worth +1 point, each statement evaluated incorrectly −1 point; statements left blank are worth 0 points and are not counted. The pass mark is a minimum score of 36. The score is then converted into a mark out of 30 and communicated to students through the institutional channels (Studium or other channels indicated by the lecturer) and/or by email to the student representatives.

Outcome and official recording. Students who do not pass the written test will have the outcome recorded as "Non approvato" (fail). Students who pass the written test may choose to accept the mark, which is then officially recorded; to reject it, in which case the outcome is recorded as "Ritirato" (withdrawn); or to take an oral examination as well, in which case the final mark takes both parts into account and may be higher or lower than the mark obtained in the written test. Students must communicate their choice to the lecturer within the deadlines that will be indicated. No mark can be officially recorded without a reply from the student.

Object of assessment. The test assesses primarily the ability to reason in physiological terms and the understanding of the logic of regulatory and integrative systems, and secondarily the knowledge of detailed content. In particular, the following are assessed: the ability to connect different functions and systems; the ability to predict the consequences of a perturbation, a lesion or a pharmacological intervention affecting a regulatory system; and the correct interpretation of the functional significance of the mechanisms studied. In the optional oral examination, command of language, the ability to construct an argument, and the ability to recognise the questions still open in the discipline are also assessed.

Information for students with disabilities and/or specific learning disorders (SLD). To guarantee equal opportunities and in compliance with current legislation, interested students may request a meeting with the lecturer, so that any compensatory and/or dispensatory measures can be arranged on the basis of the teaching objectives and their specific needs. Students may also contact the Department's CInAP referent lecturer or the relevant offices.

Arrangements in extraordinary circumstances. Should force majeure or new legal provisions so require, the examination arrangements may be modified, even temporarily or for individual needs, possibly providing for the examination to be held remotely.

Two examples of the kind of item that may appear in the written test, which will consist of 20 items of this type:

Answer true (T) or false (F)

In the somatosensory system:
__ Meissner corpuscles are slowly adapting receptors
__ the thalamic nuclei of the ventroposterior complex show somatotopic organisation
__ the afferent fibres from muscle spindles run in the dorsal columns
__ cold thermoreceptors are associated mainly with Aδ fibres

(F, T, T, T)

A unilateral lesion of the dorsal columns at the cervical level results in:
__ loss of discriminative touch on the side of the lesion
__ loss of thermal and pain sensitivity on the side of the lesion
__ impaired fine movements of the ipsilateral hand
__ loss of vibratory sensitivity on the side opposite to the lesion

(T, F, T, F)