Functions

FUNCTIONS - 1ST SEMESTER

LEARNING OBJECTIVES

DESCRIPTION:
The first part of the course is devoted to understand the mechanisms adopted by the human body in order to perceive and adapt to the challenges induced by the interactions with the external environment. To this aim lectures will be focused on the nervous and the endocrine systems illustrating, in details, how these constantly interacting systems coordinate and regulate tissue and organ functions, in order to build up adaptation responses, from the most simple and involuntary reflex reactions to the most complex and behavioral motivational and emotional responses. In order to optimize the interdisciplinary integration some of the topic will be presented with interdisciplinary lecture involving more than one discipline.

MEDICAL PHYSICS
Medical Physics lectures will be devoted to the understanding and the physical laws acting as functional substrates of functions of the body. Students will be trained to critical discussion of physical laws applied to human body.


INTRODUCTION: CONCEPT OF HOMEOSTASIS
Internal environment and the cell. Maintenance of the homeostasis.
Lecture will focus on: 1) the main concept of homeostasis; 2) the concept of internal environment; 3) interplay between external and internal environment through adaptive responses; 4) the needed interplay among the different systems and organs to maintaining the stability of the main parameters of the internal environment assuring the cells life; 5) the main mechanisms of homeostasis control; 6) the different level of complexity of adaptive responses form reflexes to behavioral responses.
FUNCTIONAL PROPERTIES OF THE EXCITABLE CELLS
TOPIC 1. Membrane excitability and communication between excitable cells
Lectures will be focused on the physical principles of bioelectricity and the exchanges of ions across the plasma membrane. Specifically related to excitable cells the following topics will be discussed: 1) the currents underlying the resting membrane potential, the graded potentials, the action potential will be discussed. 2) The electrical model of the axon and the transmission of graded and action potentials will be illustrated. 3) The communication among excitable cells through the electrical and chemical synapses. 4) The activation of the skeletal muscle, the smooth muscle. 5) the currents underlying the pace maker potential and myocardial action potential. 6) the spread of the excitation through the heart.

NERVOUS SYSTEM: HOMEOSTASIS NEEDS TO DETECT RELEVANT STIMULI FROM EXTERNAL AND INTERNAL ENVIRONMENT TO BUILD UP A CORRECT RESPONSE
TOPIC 2. Somatosensory system
Lectures will focus on the somatosensory system highlighting: 1) Functional basis of the receptors function in sensory transduction; 2) anatomy and functional properties of the sensory receptors belonging to the afferent somatosensory pathways; 3) distinction among the different sensory modalities and sensory fibers; 4) anatomo-functional description of the 4 main somatosensory modalities (touch, pain, thermal, proprioception); 5) processing of information in the different stations of the ascending pathways through the relay nuclei (projecting neurons, thalamus and cortex); 6) cortical organization of the sensory afferent information; 7) perceptual aspects and psychophysics of the sensory activation; 8) the relationships of the spinal somatosensory system with the trigeminal system.

TOPIC 3. Special senses
Lectures will focus on the on the special senses devoted to vision, hearing, balance, taste and smell. For each highlighting for each one. For each special sense lectures will discuss: 1) the underlying physical principles 2) type of energy transduced and molecular mechanisms underlying energy transduction; 3) the anatomy of the peripheral sensory organ, the nerve/s conveying information, the central pathways to the cortex; 4) the biochemical and functional properties of the receptors, how the sensory information is processed along the entire pathways and the perceptual aspect related to the activation of the cortex.

THE NERVOUS SYSTEM: HOMEOSTATIC RESPONSES NEED HUMAN MOTION TO INTERACT WITH THE ENVIRONMENT
TOPIC 4. The muscle and neural control of force recruitment
Lectures will focus on the on: 1) the structure of the skeletal muscle; 2) the biochemical processes underlying muscle contraction and force production; 3) mechanical properties of skeletal muscles; 4) motor units properties and the perfect match or the properties of the spinal motoneurons driving the muscle units; 5) the neural mechanism controlling force production.

TOPIC 5. Spinal cord functions
Following an introduction on the hierarchical organization of the motor system, lectures will focus on the functions exerted by the spinal cord and specifically: reflexes and automatisms with particular regard to locomotion, its neural control and its biomechanical substrate.

TOPIC 6. Control of voluntary movement
Lectures will focus on the on the anatomo-functional organization of the descending pathways controlling the voluntary movements and in particular on: 1) descending systems for the brainstem (tecto-, reticulo-, vestibulo-, rubro-spinal systems), their anatomy and functional properties and interaction with spinal motoneurons; 2) the corticospinal system, its anatomy and functional properties subserving the voluntary movement with specific regard to the acquisition of the human hand dexterity; 3) the corticobulbar tract and its control on brains tem descending systems and on cranial motor nuclei; 4) the extrapyramidal systems assisting corticospinal system in motor control: cerebellum and basal ganglia, their structure and function and interplay with motor descending pathways in motor control, their involvement in non-motor functions; 5) the grasping circuit as perfect example of sensori-motor integration needed for movement control.

TOPIC 7. Supporting voluntary movement
Lectures will focus on the neural mechanisms controlling posture, the main sensory systems involved and the main reflexes subserving postural control and specifically: 1) spinal control of posture; 2) visual control of posture; 3) vestibular control of posture; 5) vestibular reflexes contributing posture (vestibulo-ocular and vestibulo-spinal); 6) ocular movements and their involvement in movement control.

OVERVIEW OF THE ANATOMOFUNCTIONAL ORGANIZATION OF THE NERVOUS SYSTEMS
TOPIC 8: From spinal cord to the cortex
Lectures will focus on the on the functional organization of the spinal cord white and grey matter, the brain stem functional organization, the anatomo-functional subdivision of the neocortex, all in light of the functions analysed in the course.

TOPIC 9: Humans' cortex goes beyond the homeostasis
Lectures will focus on the on the human neocortex, its organization in unimodal, polymodal and associative areas hosting cognitive functions that will be presented only as overview in that the detailed analysis is scheduled in the 5th year.


HOMEOSTASIS NEEDS TO MONITOR THE INTERNAL ENVIRONMENT AND CORRECT FOR DEVIATIONS FROM THE EXPECTATIONS
TOPIC 10: Blood-brain interactions and autonomic nervous system
Lectures will focus on the on the complex exchanges between the nervous tissue and the blood through the interstitial fluid and the cerebrospinal fluid. The vascularization of the brain, the blood-brain and blood-cerebrospinal fluid barriers will be discussed and the brain metabolism analyzed in details. The general anatomo-functional organization of the vegetative nervous system will be discussed in particular highlighting the similarities and differences with somatic nervous system.

HOMEOSTASIS NEEDS A WIRELESS SYSTEM FOR A LONG-TERM CONTROL
TOPIC 11: The endocrine system
An overview of the organization of the endocrine system will be followed by lectures focusing on: 1) general concepts of hormones, their chemical classes and functions; 2) the interplay between brain and endocrine system through the hypothalamic-hypophysial axis; 3) the detailed analysis of the anterior and posterior pituitary systems and hormones; 4) the anatomy and functions of he endocrine glands under pituitary control; 5) the complex brain/endocrine interplay supporting growth and reproduction.

HOMEOSTASIS MAINTAINED WHEN WE SHAPE BODY FUNCTIONS ON THE ENVIRONMENTAL CHANGES
TOPIC 12: Circadian rhythms and behavioral homeostatic responses
Lectures will focus on the higher level of organization of homeostatic responses, meaning the motivational states driving the instinctual behavior and the temporal organization of the physiological function driven by the suprachiasmatic nucleus in charge of timing the body functions to the changes of the environment assuring a perfect feedforward homeostatic control.


EXPECTED LEARNING OUTCOMES

TOPIC 1. Membrane excitability and communication between excitable cells
The concept of electric charge and electrostatic interactions, electric potential, conducting and dielectric materials. Electric current, impedence and RC circuits.
Membrane potential. Membrane properties, cell membranes and ion distributions, Nernst equation and Donnan equilibrium, the electrical model of an axon.
Meaning of the Nernst equation, Nernst equation and calculation of membrane potentials, Electrical charges across the cell membrane, the Gibbs-Donnan equilibrium.
Properties and types of ion channels and active transporters in neurons. Control of ion channels and functional states of gated channels. Role of trans-membrane ion movements in electrical excitability, signal propagation, and neurotransmission. Molecular composition, organization, and roles of myelin lipids and proteins. Selective channel distribution in myelinated axons and related function. Importance of intrinsic and adaptive myelination.
Ion movements across the membrane of excitable cells: Na+, K+, Ca++, Cl- ion channels, the electrochemical gradient and the equilibrium potential of different ions. The resting membrane potential: ions and currents, the contribution of each of the different ions and of the Na+/K+ ATP transport in establishing and maintaining the resting membrane potential. Depolarizing and hyperpolarizing currents. Passive responses of the plasma membrane: the local sub-threshold responses and the electrotonic conduction. Active responses of the plasma membrane: the action potential. Time course, ion fluxes underlying action potential and its conduction along the axon. Mechanisms underlying sensory transduction and receptors properties.
Synapse. Electrical and chemical synapses: molecular mechanisms and functional differences. Classification of synaptic transmission by functional type, mechanism of transmission, & mediators of transmission. Neurotransmitters structure, chemical and functional types. Bioactive peptides and their role in neurotransmission. The major neurotransmitters: metabolism, action mechanisms and regulation, neurotransmitter receptors, their types, action mechanisms and regulation. Mechanisms for terminating the actions of neurotransmitters.
Electric synapse: gap junctions, ion currents, synaptic modulation and bidirectionality. Chemical synapse: role of the action potential in the neurotransmitter release. Post-synaptic changes in membrane potentials giving rise to the "excitatory" and "inhibitory" responses. Synaptic integration, current-to-frequency coding and mechanisms underlying the modulation of the synaptic gain. Different neuronal target actions by means of synapsis: neuronal communication, contraction and secretion.
Muscle excitation. Neuromuscular junction, the end plate potential, the striate muscle action potential and the current-to-frequency coding. Smooth muscle action potential and the functional syncytia. Heart muscle action potentials: ion fluxes underlying pace maker. Heart action potentials: ion fluxes underlying contractile cells action potential. Spread of cardiac excitation.

TOPIC 2. Somatosensory system
General features of afferent (sensory) pathways. Sensory modalities and sensory fibers classification. Structure and location of sensory receptors in relation to the transduction of different forms of energy, the location of sensory ganglia and the description of primary sensory neurons. Medial and lateral division of the dorsal root as the origin of ascending pathways in the spinal cord: the conscious and unconscious pathways. Pathways of the anterolateral system: pain, touch and temperature. Dorsal column pathway: conscious proprioception and discriminative touch. Trigeminal pathway: information from the head. Pathways to the cerebellum: the non-conscious pathways of somatosensory information. Routes of visceral sensory information. Thalamic nuclei classification in relation to their target. Primary and secondary somatosensory cortical areas and structure of the somatosensory cortex. Overview: course and anatomic structures involved in the dorsal column pathway; course and anatomic structures involved in the anterolateral system; course and anatomic structures involved in the trigeminal pathway; course and anatomic structures involved in the solitary tract.
Sense of touch. Receptive field, functional properties of fast and slow adapting mechanoreceptors in the skin. Processing of afferents through the dorsal column system to the sensory cortices. Cell properties and the functional organization of the primary sensory cortex. Mechanisms underlying the ability of coding of spatial characteristic of objects. Main psychophysical laws.
Temperature and nociception. Functional and adaptation properties of the thermal warm and cold receptors. Processing of thermal afferents through the anterolateral system to the sensory cortices. Functional properties of the specific, polymodal and silent nociceptors. Mechanisms underlying pain: acute vs slow pain, afferents processing in the dorsal horn and mechanisms underlying sensitization and hyperalgesia. Major ascending pathways mediating specific and diffuse pain, autonomic, endocrinal and emotional reactions. Non-opioid and opioid central mechanisms controlling pain.
Proprioception. limb position sense and kinaesthesia. Functional and adaptation properties of joint receptors and the central coding of the angular excursion. Muscle spindles structure: afferent and efferent innervations; functional and adaptation properties. Golgi tendon organs' functional and adaptation properties of the and their afferent innervations. Role of the skin receptors as proprioreceptors.
Functional processing of proprioceptive information through ascending systems and the body schema representation in parietal cortex.


TOPIC 3. Special senses.
Wave pulses, periodic waves, sinusoidal waves. Main properties of waves (wavelength, amplitude, phase, velocity, frequency, polarization, energy, intensity,...). Fourier analysis for the decomposition of an arbitrary wave into sinusoidal components.
Sound. Define sound waves and their propagation. Basics of sound waves (speed of sound, intensity and other properties). Standing sound waves Doppler effect. Ultrasound waves. The ear as a physical instrument: functional role of the outer ear as acoustic filter. Standing waves. Functional role of the middle ear as mechanical transformer. Functional role of inner ear as spectrum analyser. Anatomical overview of the three compartments of the ear: external, middle and inner. Structures of the middle ear relevant to sound transduction. Structure of the acoustic labyrinth: the cochlea and anatomy of acoustic pathway. Functional circuitry of acoustic signals. Function of the external ear. Function of the middle ear and reflexes. Function of the inner ear: cochlear mechano-electrical transduction. Neural processing of auditory input.
Vision Light: rays, waves or particles? Refraction, reflection and transmission. Lenses, image formation and magnification. Effects of the ray nature of light on vision: the eye as a compound lens. The eye as the "perfect" performance-limited detector: the retina and its "pixels". Effects of the wave nature of light on vision: diffraction and aberrations. Effects of the particle nature of light on vision: counting single photons. Organization of the eyeball: layers, chambers, dioptric devices. Extraocular muscles. Physiology of the lens of the eye, accommodation and common vision disorders. The inversion of the visual field in the retinal image.
Organization of the retina: a piece of brain in the periphery. Explain why the visible region of the sun spectrum works for vision. Different types of photoreceptor molecules, their different location and sensitivity. Biochemical properties of opsins and their differences between rods and cones. Role and location of 11-cis retinal in the photoreceptor structure. Molecular mechanism and electrical events of phototransduction. Retinal ribbon synapse: structure and roles. Termination of the phototransduction, and mechanisms of the regeneration of the photopigment. Role of rods and cones in the foveal and peripheral retina. Mechanisms underlying dark and light adaptation. Functional properties of the ganglion and bipolar cells: the center-surround organization of receptive fields. Neural processing of visual inputs: functional models in primary visual cortex. The "computational" differences between the foveal and the peripheral vision.
Course of the optic nerve, optic chiasm and its surrounding. Course of optic pathways and the anatomic structures involved in pupillary reflex. Medial and lateral component of the optic tract. Neuroanatomy of pathway of the lateral optic tract to the visual cortex: anatomy of the lateral geniculate body, optic radiation and visual cortex. Overview of transcortical pathways fed by visual cortex: visuomotor transformation and objects-face and space recognition. Mechanisms underlying color vision.

Equilibrium The vestibular labyrinth and vestibular pathways. Medial longitudinal fasciculus. Functional circuitry of vestibular signals. Receptors in the vestibular labyrinth: functional properties in mechano- electrical transduction. Movements eliciting complex pattern of vestibular stimulation: the macular system and the semicircular canals system.
Taste and Olfaction Neuroanatomy of gustative and olfactory systems: anatomical structures and pathways. Odorants and how chemical stimuli are perceived and transformed. Molecular structure of olfactory receptors and associated signal transduction mechanisms. Signal transduction for odorants and processing of information in the olfactory system. Taste stimuli, taste receptors and signal transduction for perception of different tastes. Hormonal modulation of taste and interconnections between taste and smell. Regulatory mechanisms of taste information at peripheral taste organs. Functional interaction between taste and olfactory pathway in perception.
Insular lobe: a multisensory cortex.


TOPIC 4. The muscle and neural control of force recruitment
Muscle contraction. Chemical composition of skeletal muscle and its peculiarities. Structure and properties of key sarcomere proteins, their molecular arrangements and functional properties. Neuronal signals to skeletal muscle, the sliding filament model of muscle contraction, and the molecular mechanisms underlying muscle relaxation. Integration of skeletal muscle contraction and metabolism, and coordinated regulation. Role of myoglobin, phosphocreatine and glycogen metabolism during exercise. Key molecules and metabolic integrations in aerobic and anaerobic exercise. Role of muscle proteins in glucose homeostasis.
Mechanical properties of skeletal muscle. Experimental approach to the study of the mechanical properties of the skeletal muscle: from the anatomical organization of the parts of the skeletal muscle to its biomechanical model. Functional behavior of the muscle during relaxation and contraction (total, active and passive force) in isometric condition. Modalities of skeletal muscle activation in experimental conditions and in situ: twitch, incomplete and complete tetanus and their relations with the active state. Functional behavior of the skeletal muscle in dynamic condition that is the relation between velocity of shortening and lengthening and the force exerted by the muscle. Skeletal muscle as a motor and as a brake.
Neural control of force. The Motor Unit: innervation ratio in different muscles. Classification of three types of motor units and based on the functional properties of different muscular fibers. The motoneurons properties: synaptic current to frequency coding: the rate match. Neural mechanisms controlling muscular force: recruitment order of motor units, the size principle and tetanic activation. Role of agonist and antagonist muscles at joint level, the coordinated work of different muscles on skeletal joints and the role of muscles in determining joint stiffness.

TOPIC 5. Spinal cord functions
Overview of the hierarchical organization of motor system.
General concept of reflex. Reflex arc components: somatic and visceral reflexes in spinal cord/brain stem. Main spinal reflexes in adults and in neonates.
Locomotion. Spinal automatism: general neural network underlying automatic functions. Phases of human locomotion: sequence of muscle contraction required for stepping. Spinal rhythm generating system, the neural control of locomotion and the processes active in learning locomotion. Total work during locomotion partitioned in internal and external work. External work measured using a force platform. Inverted pendulum mechanism for walking and the bouncing ball mechanism for running. Mechanisms decreasing the energy requirements for walking and running.

TOPIC 6. Control of voluntary movement
Brain stem descending pathways and corticospinal system. Neuroanatomy of the descending pathways: the medial and lateral system. Origin and course of the pyramidal tract. Location of the primary and secondary motor areas. Structural features of the motor cortex. Pathways from the reticular formation, red nucleus, tectum and vestibular nuclei. Course and anatomic structures involved in the corticospinal tract. Course and the anatomic structures involved in the corticonuclear tract. Course and the anatomic structures involved in the tectospinal and reticulospinal tracts. Course and the anatomic structures involved in the rubrospinal and vestibulospinal tracts. Functional properties acquired during evolution by the cerebral cortex and the corticospinal tract. Role exerted by the brain stem descending pathways on spinal cord. Corticospinal influences on spinal cord machinery for movement control. Illustrate the relation between the sensation and movement and the descending control of afferent inputs to sensory cortex. Output functions of the motor cortices: primary, premotor and supplementary motor cortices. Cortical circuits underlying sensori-motor transformation: reaching and grasping.
Cerebellum. Anatomo-functional organization of the cerebellum into different regions. Origin of sensory inputs to cerebellum. Cerebellar output pathways. Content of the cerebellar peduncles. Microcircuitry of the cerebellar cortex. Course and anatomic structures involved in the spinocerebellar tract. Course and anatomic structures involved in the pontocerebellar and olivocerebellar tracts. Functional properties of the basic cerebellar circuit module: the simple spikes and complex spikes. Role exerted by the Spinocerebellum on body and limb movements: interaction with the vestibular system and with the spinal cord. Role exerted by the Cerebrocerebellum on the cortical motor program: interaction with the cortex.
Functional role of the afferents from the Inferior olive and the role of cerebellum in motor learning. Involvement of cerebellum in postural tone control.
Basal ganglia. Structures belonging to the basal ganglia circuitry. Inputs to the basal ganglia, outputs from the basal ganglia and intrinsic connections.
Circuitry involving the corpus striatum. Course of the pallidofugal fibers and circuitry involving the substantia nigra. General outline of the four parallel channels passing through the basal ganglia. Functional properties of the basal ganglia-thalamocortical circuitry. Skeletomotor, the oculomotor, the prefrontal and the limbic circuit. Role of the basal ganglia in cognition, mood and non-motor behaviour.

TOPIC 7. Supporting voluntary movement
Ocular movements. Main mechanisms of gaze control: the mechanisms for gaze stabilization and the me chanisms for gaze shifting. Gaze stabilization mechanisms: the vestibulo- system and the optocinetc system. Gaze shifting mechanisms: the saccadic system and the smooth pursuit system. Vergence movements and the Hering's law of equal innervation.
Posture and its biomechanical constraints. Different components of the postural control: spinal, vestibular and visual components. Spinal mechanisms acting in postural control and the main role of the stretch reflex. Vestibular mechanisms acting in postural control: the vestibulospinal and tonic neck reflexes. Visual action in postural control: closed vs opened eyes, lateral shift of retinal images and optocinetic nistagmus.


TOPIC 8. From the spinal cord to the cortex
Spinal cord. Functional organization of spinal cord: the gray matter and the white matter
Brain stem. Main functional organization of brainstem: the base or foot (pes), the tegmentum and the tectum
Cortex. Different features of human cerebral cortices according to evolutionary emergence The circuitry of neocortex. Main anatomo-functional subdivision of neocortex.


TOPIC 9. Humans' cortex goes beyond the homeostasis
EEG recording. Principle of EEG recording and EEG analysis. Correlation between the main cortical waves and the behavioral state. Free running recording vs evoked potentials and event related potentials.
Sleep. Classification of sleep and awake state based on the main physiological parameters Correlation of EEG-EMG and EOG and different sleep stages. Neural network underlying asleep vs awake state.


TOPIC 10. Blood-brain interactions and autonomic nervous system
Vascularization of the brain. Circle of Willis: anterior and posterior circulation. Course and territory of supply of the three main cerebral arteries and revise main functional areas of the cerebral cortex. Most important penetrating vessels and their territory of supply. The vascular supply to the brainstem and revise internal structure. Superficial and deep venous drainage of the cerebral hemispheres. Dura meningeal venous sinuses. Anastomoses between intra and extra-cranial circulations.
Brain metabolism. Brain molecular composition and differences between the grey and white matter. Energy requirements and fuels of the nervous system. Importance of glucose as the obligatory energy substrate for neurons. Brain glucose transporters, glucose metabolic fates and differences among neurons and astrocytes. Metabolic and functional cross-talk between neurons and glial cells. Rational for, and clinical importance of the functional glucose imaging of the brain. Brain monocarboxylate transporters and role in brain metabolism. Key role of ketone bodies as brain fuel. Role of brain amino acid metabolism and mechanisms underlying brain ammonia neurotoxicity. Role and metabolism of cholesterol in the nervous system.
BBB and BCFB. Structure and functions of Blood- Brain Barrier. Blood and Cerebrospinal fluid (CSF) Barrier. Cerebrospinal Fluid: amount, composition, production, circulation, reabsorption and functions. Structural and functional relationships between the intracranial compartments and blood-brain and blood-CSF barriers. Interplay between the two barriers.
Autonomic nervous system. Functional organization of the autonomic nervous system: properties of the mechanoreceptors and chemosensory receptors innervating viscera and modalities of visceral perception. Visceral reflexes: slow and rapid visceral responses and the neuroendocrine reflexes.


TOPIC 11. The endocrine system
Hormones. Hormones based on their chemical nature, mechanism of action, nature of action, effects on target cells. Transport of hormones in blood, their distribution, inactivation and clearance. Time course of hormone secretion: pulsatile vs episodic secretion. Feedback/feedforward mechanisms underlying hormonal secretion. Hypothalamus-hypophyseal axis. Hypothalamus and Posterior Pituitary gland as a neuroendocrine unit. Describe the Hypothalamus and Anterior Pituitary gland as a functional unit: the hypothalamus-hypophyseal portal system. Hypothalamic releasing and inhibiting hormones acting on the anterior pituitary gland. Mechanism underlying control of hormonal secretion. Action of the nervous and endocrine system in controlling body functions.
Anterior hypophysis hormones. Mechanism underlying control of Thyroid Gland trophism and hormonal secretion. Biological effect of Thyroid Hormones. Mechanism underlying control of Adrenal Gland trophism and hormonal secretion. Biological effect of adrenal gland hormones.
Growth. Complementary action of Thyroid and Adrenal gland hormones. Tissutal and metabolic events underlying physiological Growth. Factors affecting growth, the growth curves and growth rate at different ages. Events occurring in the skeletal growth. Growth Hormone production, its direct and indirect action by means of somatomedine and the regulation of GH secretion: role of GHRH, Somatostatin and IGFs. Role of the "permissive hormones" in growth: thyroid hormones, cortisol, insulin and gonadal hormones.
Reproduction. Hormonal control of male reproduction: maturation of male seminal cells and role of LH, FSH and testosterone in spermatogenesis. Functional properties of the male reproductive tract and of the accessory sex glands. Hormonal control of female reproduction: role of FSH, LH and ovarian estrogen and progesterone on the ovarian cycle and on the events occurring in the menstrual cycle. Feedback control of the hypothalamus-hypophysis-gonads axis on male and female, the puberty and GnRH activity. Physiological features of menopause. Principal pregnancy, parturition and post-pregnancy events.


TOPIC 12. Circardian rhythms and behavioral homeostatic responses
Circadian rhythms. Circadian rhythms and nervous structure underlying them. Functional properties of the clock proteins and of the pineal gland (melatonin). Role of the suprachiasmatic nucleus in synchronization of biological rhythms with external environmental cues.
Hypothalamus. Functional partition of hypothalamus and its "driving" role of the hypothalamus in controlling the autonomic system. Introduction to the "driving" role of the hypothalamus in integrating endocrinal and autonomic functions with behaviour. Motivational states and their neural control.

MEDICAL PHYSICS OFF TOPICS
Physics. Radioactivity. Binding energy and the nuclear stability. Different types of radiation (α, β, γ, x). Half-life for radioactive dating. Possible interactions of radiation with matter. Basics of dosimetry and biological effects of radiation.


FUNCTIONS - 2nd SEMESTER

LEARNING OBJECTIVES

This part of the course deals with the functions of cardiovascular, gastrointestinal, respiratory and renal systems. A particular attention will be paid to the complex interplay between the different organs of each system and between the different systems. Given the non-linearity of many of the biological systems considered, a semiquantitative description will be provided using graphical analysis.


SYSTEMS

TOPIC 1: Cardiovascular system
Understand and be able to critically discuss how the cardiovascular system is able to exert its functions, with reference to the role of its parts, and to the interactions of the cardiovascular system with the other systems of the body

TOPIC 2: Respiratory system
Understand and be able to critically discuss how the respiratory system is able to exert its functions, with reference to the role of its parts, and to the interactions of the respiratory system with the other systems of the body

TOPIC 3: Gastrointestinal system
Understand and be able to critically discuss how the gastrointestinal system is able to exert its functions, with reference to the role of its parts, and to the interactions of the gastrointestinal systems with the other system of the body

TOPIC 4: .Urinary system
Understand and be able to critically discuss how the urinary system is able to exert its functions, with reference to the role of its parts, and to the interactions of the urinary system with the other systems of the body

INTEGRATION BETWEEN DIFFERENT SYSTEMS

TOPIC 5: Physiological effects of postural changes
Understand and be able to critically discuss the cardiovascular and respiratory effects of postural changes.

TOPIC 6: Exercise
Understand and be able to critically discuss the cardiovascular and respiratory effects of exercise.

TOPIC 7: Calcium and phosphorus homeostasis
Understand and be able to critically discuss how calcium and phosphorus is maintained by the interplay of different systems.

TOPIC 8: Skin and thermoregulation
Understand and be able to critically discuss the functions of the skin and how thermoregulation is maintained.

TOPIC 9: Stress response
Understand and be able to critically discuss the stress response.

TOPIC 10: Acid-base balance
Understand and be able to critically discuss how acid-base balance is maintained by the interplay of different systems and which are the factors potentially able to disrupt it.

EXPECTED LEARNING OUTCOMES

CARDIOVASCULAR SYSTEM

Blood. Molecular and ion composition of plasma. Similarities and differences among plasma, extracellular and intracellular fluids. Major plasma components: types, turnover and functional roles. Plasma carbohydrates, lipids, amino acids. Structure and function of albumin. Hypoalbuminemia. Plasma proteins: classes, turnover, functional properties, and diagnostic importance. Albumin structure, distribution, metabolism and functional properties. Glycated albumin and hypoalbuminemia. Hormonal control of erythropoiesis. Structural and functional properties of hemoglobin. Heme structure, roles, biosynthesis and catabolism, including bilirubin conjugation and excretion. Oxygen binding to hemoglobin and physiological factors that influence it. Hemoglobin switching in human development, its control and the physiological variants of hemoglobin. Hemoglobin transport of carbon dioxide, carbon monoxide, nitric oxide, and the buffer role of hemoglobin. Membrane and cytoskeletal properties of the erythrocytes. Erythrocyte metabolism and relation to oxygen transport. Function of iron and maintenance of its homeostasis in humans. Iron transporters in plasma and cells and cellular iron stores. Toxicity of free iron, its consequences, and the body defenses against it. Measurement of blood viscosity. Determinants of blood viscosity in vitro and in vivo: temperature, hematocrit, red blood cells aggregation, axial migration. Effects of plasma proteins on red blood cells aggregations in normal and pathological conditions. Effects of axial migration on white cells-endothelial cells interactions. Erythrosedimentation rate. Polycythemia. Transport of oxygen and of carbon dioxide. Structure and function of hemoglobin and their relationships. Cooperative oxygen binding to heme and the physiological factors that influence it. Hemoglobin switching in human development, its control and role. Physiological variants of hemoglobin. Transport of carbon dioxide, carbon monoxide and nitric oxide by hemoglobin. Sickle cell anemia. Blood equilibrium curves for oxygen and carbon dioxide. Bohr and Haldane effects. Function and phases of hemostasis. Megakaryocyte maturation, platelets release and control. Molecular specialization of platelets, membrane and vesicle components, and their role in homeostasis. The different steps of hemostasis. Blood clotting factors. Formation of hard clot. Role of vitamin K in blood coagulation. Fibrinolysis and natural anticoagulants.
Vessels. Molecular and functional characteristics of endothelial cells, endothelial barrier, endothelial glycocalyx. Metabolic features of endothelial cells, and major mechanisms of endothelial transport. Endothelial endocrine properties and endothelial and control of vascular smooth muscle . Nitric oxide metabolism in endothelial cells and its local and systemic effects. Mechanical and electrical properties of the smooth muscle, including examples of hormones and drugs interacting with their receptors to modulate smooth muscle function. Connective tissues: molecules of the extracellular matrix, and their cell interactions. Collagen structure, types, and roles. Biosynthesis of collagen, with particular reference to assembly and factor requirement. Structural features and functional properties of elastin and proteoglycans. Elastic and resistive properties of the systemic and pulmonary circulation and of their parts. Role of passive and active tension in determining the radius of a vessel. Critical closing pressure and vascular instability Organization of the systemic and pulmonary circulation, with particular reference to the functional relations between the different parts. Physiological shunt. Distribution of blood volume and of surface area in the systemic and pulmonary circulation. Flow, pressure, blood velocity and cumulative cross-section in the different parts of the systemic and pulmonary circulation, also in the light of the equation of continuity, Bernoulli and Poiseuille equations. Turbulence and its hemodynamic effects. Carotid stenosis. Systolic, diastolic, pulse and mean arterial pressures and their determinants. Measurement technique for systolic and diastolic pressures. Mechanical behavior of arterial compartment using a simple RC model, and relation between the model's parameters (compliance and resistance) and arterial pressure. Age-related changes of arterial compliance and their consequences. Radial pulse, pulse wave velocity, its change in the arterial tree and its determinants. Role of arterial compliance and peripheral resistance in the genesis of a continuous capillary blood flow in the systemic circulation. Mechanisms of transcapillary exchange: diffusion, filtration, pinocytosis. Starling hypothesis and filtration changes in physiological and pathological situations. Lymphatics. Edema. Regulation of microcirculation by intrinsic and extrinsic mechanisms, and their relative importance in the different parts of the body. The veins as capacitance vessels. Starling resistor. Varicose veins. Mean systemic, pulmonary and circulatory filling pressures, and their determinants. Effects of venoconstriction, venodilation, changes in blood volume of mean systemic, pulmonary and circulatory filling pressures. Vascular function curves (also called venous return curves) and their determinants. Invasive assessment of hemodynamics. Characteristics and regulation of the cerebral, coronary, splanchnic, and skin circulation. Coronary stenosis. Hemodynamics of pulmonary circulation with particular reference to the effects of gravity and surrounding environment. Dependence of overall pulmonary vascular resistance on lung volume. Pulmonary hypertension. Characteristics of the renal circulation and their relations with renal blood flow distribution between the cortical and medullary part of the kidneys. Estimation of effective renal plasma flow and of renal blood flow by the clearance of p-amino-hyppuric acid. Relations between glomerular blood flow, the resistances of the afferent and efferent arterioles and the pressure in the peritubular capillaries. Intrarenal and extrarenal mechanisms of blood flow regulation. Tubuloglomerular feedback. Autoregulation.

Heart. Contractile proteins and ion channels in the myocardium (also in comparison with the skeletal muscle). Cardiac metabolism (energetic fuels, regulation, and specialization). Fatty acid metabolism and regulation in the heart, and the cardiac role of lipoprotein lipase, carnitine, and creatine kinase. Cardiac metabolic adaptation in physiological conditions and hypoxia. Structure and action mechanism of natriuretic peptides and control of their secretion by the heart. Conditions/stimuli leading to heart remodeling, and its consequences. Electrical properties of the myocardium and of its parts. Genesis and conduction of the cardiac action potential in physiological conditions. Principles of electrocardiography. Common alterations of heart rhythm investigated with electrocardiography, atrioventricular conduction blocks, premature depolarizations, ectopic tachyarrhythmias, flutter and fibrillation. Mechanical events in terms of the main hemodynamic parameters, and their relations with the electrocardiogram. Effects of heart rate on the duration of the systole and diastole (and therefore of diastolic filling). Cardiac valves. Sounds and murmurs detected by auscultation. Major valvular heart diseases. Description of the cardiac events of the cardiac cycle in terms of pressure-volume (PV) loops. Relation between the PV loops and the mechanical characteristics of the ventricle described in terms of isovolumic, isobaric maxima curves and end-diastolic pressure-volume relation, or in terms of end-systolic pressure-volume relation and end-diastolic pressure-volume relation. Pericardium. Determinants of stroke volume, end-diastolic and end-systolic volume for the left and right ventricle. Preload and afterload. Contractility and its clinical estimators. Ejection fraction. Heterometric regulation of the heart: the Frank Starling mechanism and its relevance in the cardiovascular system in physiological and pathological conditions. Use of the PV plane to explain the Frank Starling mechanism. Cardiac function curves and their determinants, including pleural pressure. Cardiac output as the product of heart rate and stroke volume. Measurement of cardiac output (indicator dilution methods, Fick's method and echocardiography). Control of heart rate and contractility (intrinsic and extrinsic, heterometric and homometric).

Coupling between the different parts of the cardiovascular system, regulation and integrated responses. Coupling between the systemic circulation and the heart-lung. Use of Guyton's equilibrium diagram in order to represent the cardiovascular system in conditions of increased or decreased pre or post capillary resistance, constriction or dilation of capacitance vessels, changes of intravascular volume, changes of heart rate or contractility, changes of the passive properties of the heart or of the pericardium. Coupling between the right and left ventricle through the pulmonary circulation. Effects of alterations of the right and left ventricles and of the systemic and pulmonary circulation on the cardiovascular system. Reflexes and hormones controlling the function of the cardiovascular system, baroreflex, Bainbridge reflex, reflexes originating from the low pressure receptors, adrenaline, angiotensin II, atrial peptides. Physiopathology of heart failure and shock. Compensation of hypovolemia.

GASTROINTESTINAL SYSTEM AND ADIPOSE TISSUE

Motility. Motility of esophagus, stomach, small and large intestine. Intrinsic and extrinsic regulation of motility. Effects of nervous and hormonal stimulation. Expulsive maneuvers. Defecation. Gastroesophageal reflux.

Exocrine and endocrine properties of the gastrointestinal system. Composition, elaboration, and control mechanisms of the digestive secretions including saliva, gastric, pancreatic and intestinal juice, and bile. Metabolic properties of the gastro-enteric system. Structural properties, regulation and physiological actions of gastro-enteric hormones. Cystic fibrosis at the pancreas.

Role of the digestive apparatus and adipose tissue in the metabolic homeostasis. Digestive and absorption processes. The integrative role of the CNS in caloric homeostasis and food intake. Overview of nutritional requirements and the role of nutrition in homeostasis. Factors influencing food intake and energy expenditure. Molecular mechanisms underlying hunger and satiety and their function in homeostasis. Energy balance, caloric homeostasis and its neuro- and hormonal regulation. Key properties and molecular specialization of the liver. Hepatic metabolism of carbohydrates, lipids, amino acids and proteins and role in homeostasis. Compartmentalization of hepatic metabolism. Detoxification pathways in the liver. Phase I reactions, role and regulation of the microsomal electron transport chain.. Phase II reactions, and different types of conjugation reactions. Ethanol structure, absorption, and tissue distribution. Enzymatic mechanisms of ethanol oxidation and their properties. Effects of ethanol oxidation on the liver and the toxic effects of chronic ethanol consumption. The ndocrine properties of the islets of Langerhans. Structure, biosynthesis and secretion of insulin, glucagon, amylin, somatostatin, pancreatic polypeptide and ghrelin. Mechanisms controlling the release of pancreatic hormones and their interconnections. Adipose tissue: storage role and key functions in body's homeostasis. Origin and properties of different adipocytes. Lipogenesis and lipolysis in the white adipose tissue, and their hormonal control. Endocrine properties of adipose tissue, . Biochemical and functional differences between white, beige and brown adipocytes. Contribution of brown adipocytes to thermogenesis, and their nervous control.

RESPIRATORY SYSTEM

Statics of the respiratory system. Spirometric and plethysmographic measurements of clinical interest. Quasi-static properties of the respiratory system: pressure-volume curves the respiratory system as a whole and partitioning of quasi-static elastic properties in those of the lung and of the chest-wall. Respiratory, pulmonary and chest wall compliance. Volume changes and elastic work of breathing at rest and during exercise. Surface phenomena in the lungs. Molecular composition, properties, synthesis and assembly of airway mucus components and the mucociliary escalator. Surfactant composition, metabolism, secretion and dynamics. Lung ion channel types and roles. Functions, of the surfactant, with particular reference to the regulation of surface tension and maintenance of mechanical homogeneity of lung units. Respiratory distress syndrome in the newborn. Pulmonary interdependence. Mechanics of the pleural space and the mechanisms of gases and fluids removal. Changes of the lung PV curves in emphysema and fibrosis.

Dynamics of the respiratory system. Organization of the airways. Molecular composition and properties of airway mucus. Structure, synthesis and assembly of airway mucins. Mechanisms for removal of foreign particles in the lungs Components and mechanism of the mucociliary escalator. Role of ion channels in lung properties. Lung CFTR and its properties. Cystic fibrosis in the lung. Characteristics of upper and lower airways. Contributions of different airways generation to total airway resistance. Effect of pulmonary interdependence on airway diameter. Respiratory mechanics during spontaneous ventilation and measurement and partitioning of respiratory work. Campbell diagram. Organization and characteristics of respiratory muscles. Distribution of ventilation and perfusion in relation to posture. Onion skin diagram. Expiratory flow limitation in health and disease. Obstructive and restrictive syndromes. COPD and emphysema. Effects of orthosympathetic and parasympathetic stimulation on the tracheobronchial tree.

Gas exchange. Composition of inspired, expired and alveolar air. Anatomical and physiological dead space and their measurement (Fowler's and Bohr's methods). Total, dead space and alveolar ventilation. Characteristics and function of the alveolar-capillary barrier. Respiratory gases diffusion across the alveolar-capillary barrier during rest and exercise. Diffusion capacity for carbon monoxide. Measurement of oxygen consumption, carbon dioxide production and respiratory exchange ratio by indirect calorimetry. Relation between respiratory exchange ratio and metabolism. Estimation of energy consumption by indirect calorimetry. "Ideal" lung. Alveolar gases equations. Representation of gas exchange in the Fenn's diagram. Effects of changes of metabolism, ventilation and cardiac output on the alveolar air, arterial blood, and mixed venous blood points. "Real" lung. Ventilation-perfusion ratio and its distribution in health and disease. Hypoxic vasoconstriction and hypercapnic bronchodilation. Three compartment model. Ideal point. Alveolar-arterial oxygen gradient. Gas exchange during disease. Hypoxemia, its definition and its causes: shunt, diffusion limitation, ventilation perfusion mismatch and hypoventilation. Effects of oxygen enriched mixtures on hypoxemia. Cyanosis. Gas exchange during exercise. ARDS.

Control of breathing. Neural mechanisms responsible for the generation of the breathing pattern. Modulation of the output of the central pattern generator by information from central and peripheral chemoreceptors, slow adapting, fast adapting, irritant and J pulmonary receptors, muscle and joints proprioceptors and temperature. Hering Breuer reflex. Ventilatory response to changes of arterial carbon dioxide, oxygen partial pressures and pH. Ventilatory adaptation to high altitude.

URINARY SYSTEM

Renal functions and role of the kidneys in the body's homeostasis. Energy requirements of the kidney, and its adaptations in physiopathological conditions. Importance of the kidney in the biosynthesis of nitrogenous compounds. Role of the kidney in glucose homeostasis in physiological conditions, during starvation, and its hormonal regulation. Renal metabolism of amino acids and mechanisms of ammonia excretion. Renal participation in hormonal regulation. Renal glycosuria.

Glomerular filtration, tubular reabsorption and secretion. Molecular strategies for glomerular filtration. Molecular structure and organization of the glomerular filter. Glomerular filtration rate, net filtration pressure and coefficient of ultrafiltration and their determinants. Relations between glomerular blood flow, resistances of the afferent and efferent arterioles and glomerular filtration rate. Intrarenal and extrarenal mechanisms of glomerular filtration rate regulation. Tubuloglomerular feedback. Clearance. Measurement of glomerular filtration rate by inulin clearance, by creatinine clearance and estimation of glomerular filtration rate by creatinine plasma level. Comparison between the clearance of a freely filtered substance with that of inulin in order to gain information about net secretion or absorption of that substance. Changes of ultrafiltrate osmolarity and volume along the nephron. Major inorganic and organic components of the urine and importance of their excretion. Molecular strategies for tubular specialization: compartmentalization of specific transporters in proximal tubule, Henle's loop, distal tubule and collecting duct. Molecular mechanisms of renal reabsorption of organic molecules (proteins, amino acids, vitamins, monosaccharides, urea, uric acid), ions (sodium, chloride, bicarbonates, potassium, calcium, magnesium and inorganic phosphorus) and water. Extracellular matrix of the kidney. Renal treatment of urea and ammonia. Renal elimination of exogenous and endogenous organic acids and bases and the role of pH. Sodium balance and the role of the kidneys in its maintenance. Primary aldosteronism. Proteinuric kidney disease. Nephrotic syndrome. Regulation of sodium reabsorption by intrarenal and extrarenal factors. Renin-angiotensin-aldosterone system and its renal and systemic actions. Water balance and the role of antidiuretic hormone in its maintenance. Countercurrent medullary multiplier. Regulation of antidiuretic hormone secretion by osmoreceptors and baroreceptors. Potassium homeostasis. Distribution of potassium in the body compartments and how redistribution of potassium can maintain a constant plasma concentration. Hypo and hyperkalemia and their effects. Determinants of potassium secretion in the cortical collecting duct. Mechanisms of action of the main classes of diuretics. Effects of diuretics on potassium balance. Regulatory mechanisms of arterial pressure in short, middle and long term. Micturition.

PHYSIOLOGICAL EFFECTS OF POSTURAL CHANGES
Effects of gravity on the cardiovascular, respiratory and urinary systems. Concept of hydrostatic indifference point/level. Hydrostatic indifference point/level in the systemic and pulmonary circulation. Hemodynamic changes and reflex activation during the postural change. Role of the skeletal muscles. Effects of postural changes on urine production. Effects of postural changes on pulmonary perfusion and ventilation.

EXERCISE
Cardiovascular and respiratory responses to physical exercise. Types of exercises of clinical utility. Anaerobic threshold and its measurement. Respiratory compensation point.

CALCIUM AND PHOSPHORUS HOMEOSTASIS

Molecular composition of bone. Bone mineral. Molecular mechanisms underlying bone remodeling and their regulation. Collagen I biosynthesis, assembly and factor requirement, including the role of vitamin C. Molecular specialization and metabolic properties of osteoclasts and osteoblasts. Formation of hydroxyapatite crystals, the role of matrix vesicles and alkaline phosphatase in bone mineralization. Role of osteocalcin and osteonectin in bone remodeling, and the hormonal properties of uncarboxylated osteocalcin. Role of bone molecules as biochemical markers of bone remodeling. Structure, properties and metabolism of cartilages. Vitamin C deficiency. "Brittle" bone disease. Calcium balance and homeostasis. Importance of dietary calcium. Calcium absorption and factors influencing it. Renal treatment of calcium. Different forms of calcium in plasma and their functional roles. Structure, regulation and action mechanisms of calcitonin, parathyroid hormone, and calcitriol. Role of intestine, bone and kidney in calcium homeostasis. Phosphorus homeostasis. Differences between calcium and phosphate in plasma and in cells. Role of intestine, bone and kidney in phosphate homeostasis. Renal treatment of inorganic phosphorus. Hormonal control of phosphate homeostasis. FGF23-Klotho signaling as endocrine axis in plasma phosphate regulation.


SKIN AND THERMOREGULATION

Key properties of the skin. Structure and function of skin keratins and desmosomes. Protein and lipid molecules of the cornified envelope and their functional properties. Mechanisms of the epidermal barrier and skin permeability. Different mechanisms of skin perception. Skin interrelationships with other organs/tissues and the skin endocrine properties. Molecular pathways of skin pigmentation and control. Photoaging. Internal core temperature. Balance between heat input and output to maintain body core temperature. Principles of heat exchange: radiation, conduction, convection and evaporation. "Sweating" as a regulated evaporative process. "Shivering" as primary involuntary mechanism of heat production. Role of blood flow in thermal regulation. Concept of "set point" and the role of the hypothalamus in thermal control. Fever vs Hyperthermia.

BIOLOGICAL RESPONSE TO STRESS

Definition of stress response and stressors. Pattern of reactions evoked by stressants. Role of sympathetic nervous system in stress. Role of hypothalamus-hypophysis-adrenal gland system in stress. Role of blood pressure in sustaining the stress response. Role of the hypothalamus in coordinating the response. Psychosocial stressors.

ACID-BASE BALANCE
Chemistry of acids and bases in aqueous solutions. Dependence of the ionization state and transmembrane distribution of weak electrolytes on the pH of the solution. Passive reabsorption and secretion of weak acids and bases. Definition of buffer solution and related properties. Intracellular and extracellular buffer systems of the body. Differences between an open and a closed buffer system. Representation of the acid base status on the Davenport diagram and its use to describe the acid-base disorders and their compensations. Open and close buffer systems. Bicarbonates, hemoglobin, proteins and inorganic phosphorus. Respiratory compensation for a non-respiratory acid base disorder. Non-respiratory compensation for a respiratory acid base disorder. Role of the kidneys in the maintenance of acid-base balance. Renal treatment of bicarbonates. Ex-novo production of bicarbonates: titrable acids and glutamine metabolism. Role of the liver in glutamine metabolism. Effects of kidney or liver disease on acid-base balance. Conditions which may induce the kidneys to maintain or produce a state of metabolic alkalosis. Effects of diuretics on acid-base balance. Hemogasanalysis and interpretation acid-base and respiratory disorders. Measurement of blood gas components: pH, pCO2, HCO3-.

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module Physiology.

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module Physiology.

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module Physiology.

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module Physiology.