Physiology I - Cochlear Circulation and Homeostasis PDF

CMSD5280 Audition II Physiology #1: Cochlear Circulation and Homeostasis Dr. Olivier Valentin, Ph.D. LAND ACKNOWLEDGEMENT The Dalhousie University Senate acknowledges that we are in Mi’kma’ki, the ancestral and unceded territory of the Mi’kmaq People and pays respect to the Indigenous...

CMSD5280 Audition II Physiology #1: Cochlear Circulation and Homeostasis Dr. Olivier Valentin, Ph.D. LAND ACKNOWLEDGEMENT The Dalhousie University Senate acknowledges that we are in Mi’kma’ki, the ancestral and unceded territory of the Mi’kmaq People and pays respect to the Indigenous knowledges held by the Mi’kmaq People, and to the wisdom of their Elders past and present. The Mi'kmaq People signed Peace and Friendship Treaties with the Crown, and section 35 of the Constitution Act, 1982 recognizes and affirms Aboriginal and Treaty rights. We are all Treaty people. The Dalhousie University Senate also acknowledges the histories, contributions, and legacies of African Nova Scotians, who have been here for over 400 years. OUTLINE A few words about me Review of the course schedule Reminder of the functioning of the hearing system Presentation of the vascular anatomy of the cochlea Concept of homeostasis Ionic homeostasis in the cochlea Pathophysiology of cochlear circulation and homeostasis A few words about me Originally majoring in nuclear physics A few words about me Originally majoring in nuclear physics Diagnosed with hearing loss and tinnitus in 2004 A few words about me Originally majoring in nuclear physics Diagnosed with hearing loss and tinnitus in 2004 Switched my major for biomedical engineering A few words about me Originally majoring in nuclear physics Diagnosed with hearing loss and tinnitus in 2004 Switched my major for biomedical engineering Moved to Montreal for my PhD A few words about me Originally majoring in nuclear physics Diagnosed with hearing loss and tinnitus in 2004 Switched my major for biomedical engineering Moved to Montreal for my PhD in 2010 Appointed Assistant Professor of Audiology at SCSD in 2024 A few words about me Hearing protectors Acoustics Tinnitus AUDITO ENGINEE Listening Effort RY RING Hearing Devices SCIENCE NEUROSCIE NCE Sound Quality Auditory Brain Computer Electrophysiology Interface A few words about me DUAL-AXIS INDEPENDENT RESEARCH PROGRAM AI A few words about me TRAINING NEXT GENERATION OF BIOMEDICAL SCIENTISTS TO ADDRESS KEY HEALTH CHALLENGES BUILDING A BETTER TOMORROW Review of the course schedule Review of the course schedule Reminder of the functioning of the hearing system THE PERIPHERAL HEARING 1- Pinna SYSTEM 2- Ear canal 3- Tympanic membrane (eardrum) 4- Malleus 5- Incus 6- Stapes 7- Eustachian tube 8- Tympanic cavity (middle ear) 9- Cochlea (inner ear) 10- Cochlear nerve  When a sound reaches a normally functioning ear, it first meets the external ear. The external ear is comprised of the pinna and the external ear canal. The pinna has a peculiar shape that allows both sound localization in the vertical plane and sound amplification: the mid frequencies from 2000 and 7000 Hz are slightly amplified. The sound then travels in the ear canal, another source of sound amplification composed of an external cartilaginous portion and an inner bony portion. At the end of the external auditory canal, the sound reaches a thin translucid membrane called the tympanic membrane, or eardrum. The tympanic membrane is the first structure of the middle ear and is composed of three layers. The condensations and rarefactions of the sound make the tympanic membrane vibrate, and the three middle ear ossicles (called malleus, incus and stapes) are put into motion as well, transforming the acoustical energy into mechanical energy. The three ossicles are linked with one another and the ossicle chain is suspended in the middle ear cavity by ligaments. The last ossicle of the chain, the stapes, transfers the movement to the oval window, a small opening in the inner ear which is covered with a flexible membrane. During the transfer of the movement to the oval window, the ossicles also amplify the movement, mainly around 1-2 kHz. When the stapes presses on the oval windows, it causes the liquid of the inner ear (the perilymph) to move. During this change in medium, the middle ear uses two principles to match the impedance: firstly the tympanic membrane has a much larger surface than the oval window, and secondly the lever action of the incus and malleus. Reminder of the functioning of the hearing system 1- Perilymph 13- Endolymphatic duct 2- Endolymph 14- Oval window 3- Semicircular canals 15- Round window 4- Posterior semicircular 16- Perilymphatic duct canal 17- Cochlea 5- Horizontal semicircular 18- Scala tympani canal 19- Scala vestibuli 6- Superior semicircular 20- Cochlear duct canal 21- Oran of Corti 7- Ampula 22- Middle ear 8- Vesibule 23- Stapes 9- Otolith organs 24- Tympanic cavity 10- Utricule (middle ear) 11- Saccule 12- Vestibular maculae THE INNER EAR  The inner ear, also called the cochlea, is filled with two different kinds of fluids: perilymph and endolymph. These liquids travel in three canals all along the two and a half spires of the cochlea: the endolymph in the cochlear duct and perilymph in the scala vestibuli and scala tympani. The scala vestibuli and the scala tympani are connected at the apex of the cochlea, a point named helicotrema. Along with the oval window, the round window allows perilymph to move when the stapes moves. The movement of the stapes and the presence of the two windows allow a movement of the fluids, resulting in a vibration of the basilar membrane, on which the Organ of Corti rests. Even if the organ of Corti is similar along the two and a half turns of the cochlea, the properties of the basilar membrane differ. It is narrow and stiff at the base. At the apex the basilar membrane is wider, more flexible and has more mass. These properties allow a frequency distribution (low-frequencies being perceived with the stimulation of the apex and high-frequencies being perceived with a base stimulation of the cochlea). Reminder of the functioning of the hearing system 1- Perilymph 2- Endolymph 3- Tectorial membrane 4- Organ of Corti 5- Inner hair cells 6- Outer hair cells 7- Inner pillar 8- Outer pillar 9- Deiter’s cells 10- Hensen’s cells 11- Claudius cells 12- Basilar membrane 13- Cochlear duct 14- Inner tunnel (Corti) 15- Internal spiral tunnel 16- Scala tympani 17- Bony (osseous) sprial lamina 18- Auditory (cochlear) ORGAN OF nerve 19- Efferent fibers  In the organ of Corti, there are hair cells and supporting cells: hearing sensitivity depends on the good function of those cells, and more specifically on inner and outer hair cells. The hair cells are in contact with two different fluids with different ionic composition: perilymph and endolymph. These fluids have a 80 mV potential difference (endocochlear potential). The tip of the hair cells bathes in endolymph and the base bathes in perilymph, allowing a passive entrance of potassium ions (K+) as well as a passive exit of the same ions, following the concentration gradient. This way, rapid successive stimulations are possible in the hair cells. The stria vascularis needs energy to create the endolymph, which is rich in K+, but the presence of the different fluids allows hair cells to save Adenosine triphosphate (ATP). Inner hair cells have stereocilia at their apex and, when there is a vibration, the stereocilia move in the stria vascularis’ direction (driven by the movements of the basilar and tectorial membranes) and pull open potassium channels, allowing for the cell to depolarize. There is a release of neurotransmitters in the synaptic space, thus transforming a mechanical energy into an electrical energy: the sound travels through many auditory relays up to the brainstem or the brain. In the inner ear, outer hair cells also depolarize by the stereocilia movement. Unlike the inner hair cells, the outer hair cells’ electric message feeds energy back to the cochlear partition. The outer hair cells play an amplification role for faint to moderate sounds. These cells contract (by electro-mechano transduction), allowing less powerful soundwaves to stimulate the inner hair cells more easily. Lost external hair cells do not regenerate in humans, nor for all mammals. Reminder of the functioning of the hearing system  When sound waves strike the tympanic membrane, it vibrates, causing the ossicles in the middle ear to move. The footplate of the stapes transmits the vibration to the oval window, which displaces the basilar membrane. Short wavelengths from high-pitch sounds displace the basilar membrane near the oval window. In contrast, long wavelengths from low-pitch sounds displace it farther along the cochlea (toward the apex). These movements are detected by the hair cells and are transmitted to the auditory cortex via the auditory nerve. Presentation of the vascular anatomy of the cochlea BLOOD SUPPLY TO THE INNER EAR Presentation of the vascular anatomy of the cochlea BLOOD SUPPLY TO THE INNER EAR 1- Subclavian arteries 2- Vertebral arteries  The subclavian arteries arise from the brachiocephalic trunk on the right side and directly from the aortic arch on the left side. They provide indirect blood flow to the inner ear via their branches, notably the vertebral arteries, which arise from the subclavian arteries and ascend through the transverse foramina of the cervical vertebrae to enter the cranial cavity. Presentation of the vascular anatomy of the cochlea BLOOD SUPPLY TO THE INNER EAR 1- Subclavian arteries 2- Vertebral arteries 3- Basilar artery 4- Anterior inferior cerebellar artery  The basilar artery is formed by the union of the two vertebral arteries at the base of the pons. It primarily supplies the brainstem, cerebellum, and parts of the inner ear. It gives rise to several branches, including the anterior inferior cerebellar artery (AICA), which provides the labyrinthine artery. Presentation of the vascular anatomy of the cochlea Anterior semicircular BLOOD SUPPLY TO canal THE INNER EAR Horizontal 1- Subclavian arteries semicircular canal 2- Vertebral arteries 3- Basilar artery Saccul Utricle e 4- Anterior inferior cerebellar artery 5- Anterior vestibular artery 6- Common cochlear artery Posterior semicircular 7- Main cochlear artery canal 8- Posterior vestibular  The labyrinthine artery, which supplies the inner ear, branches into the Anterior Vestibular Artery, Common Cochlear Artery, Main Cochlear Artery, and Posterior Vestibular Artery. The Anterior Vestibular Artery supplies blood to the utricle, the anterior part of the saccule, and parts of the semicircular canals. The Common Cochlear Artery provides blood to the cochlea (via the Main Cochlear Artery) and parts of the vestibular apparatus (via the Vestibulocochlear Artery). The Main Cochlear Artery provides blood to the cochlea, and the Posterior Vestibular Artery supplies the posterior part of the saccule and the posterior semicircular canal. Presentation of the vascular anatomy of the cochlea BLOOD SUPPLY TO THE INNER EAR 1- Subclavian arteries 2- Vertebral arteries 3- Basilar artery 4- Anterior inferior cerebellar artery 5- Anterior vestibular artery 6- Common cochlear artery 7- Main cochlear artery 8- Posterior vestibular artery 9- Spiral modiolar artery  The spiral modiolar artery, which arises from the main cochlear artery, supplies the organ of Corti and primary auditory neurons of the modiolus and forms the capillaries of the spiral ligament and stria vascularis in the cochlear lateral wall. The blue vessels represent the venous return route of deoxygenated blood. Presentation of the vascular anatomy of the cochlea SO THE ORGAN OF CORTI IS DIRECTLY VASCULARIZE D?  While the cochlea is intricately supplied by a network of blood vessels, there is no direct contact between these blood vessels and the organ of Corti itself. This is an essential feature, as direct vascularization within the organ of Corti could introduce mechanical vibrations or pulsations from blood flow, potentially interfering with the precision of sound detection. Instead, the organ of Corti is indirectly supported by the cochlear blood supply, with nutrients and oxygen diffusing from nearby vascularized structures such as the basilar membrane and stria vascularis. Concept of homeostasis Claude Bernard Walter Bradford Cannon Joseph Barcroft  Homeostasis, the state of steady internal physical and chemical conditions maintained by living systems, evolved through the contributions of several key scientists. In 1849, Claude Bernard, a French physiologist, introduced the idea of regulating the body’s internal environment for proper function. Walter Bradford Cannon, building on Claude Bernard's work, introduced the term 'homeostasis' in the early 20th century, highlighting the body’s ability to maintain equilibrium. Joseph Barcroft, in 1932, extended the concept by emphasizing the need for a stable internal environment for higher brain function, such as temperature and oxygen levels. Concept of homeostasis KEY PRINCIPLES OF HOMEOSTASIS Homeostasis is the process by which living organisms maintain stable internal conditions (e.g., temperature, pH, fluid balance) despite external changes. The body constantly adjusts its internal systems to remain in a state of balance, allowing optimal function Homeostasis relies on feedback loops that counteract changes to bring systems back to their set point (e.g., body temperature regulation) In some cases, homeostasis involves processes that amplify a change to reach a specific outcome (e.g., blood clotting). In the inner ear, homeostasis maintains the stable ionic composition of fluids, which is essential for hearing and balance. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids  The cochlea is divided into three primary fluid-filled compartments: the scala media, the scala vestibuli, and the scala tympani. The fluid in the scala media is known as endolymph, while the fluids in the scala vestibuli and scala tympani are perilymph. These two fluids have distinct ionic compositions, and maintaining their balance is crucial for proper cochlear function and hearing Ionic homeostasis in the cochlea INNER EAR Endolymp Plasma CSF Perilymph HOMEOSTASIS h Na+ 149 145 1.3 148 1- Cochlear fluids K+ 3.1 5 157 1.2 2- Perilymph vs endolymph Ca2+ 1.2 2.6 0.023 1.3 Cl- 129 106 132 119 HCO3- 19 N/A 31 21 Values in millimoles – mM CSF: Cerebrospinal fluid  Perilymph, found in the scala vestibuli and scala tympani, has a composition similar to cerebro-spinal fluid (CSF), with a high sodium (Na+) concentration and low potassium (K+) concentration. In contrast, endolymph, found in the scala media, is rich in potassium (K+) and has a low sodium concentration. Perilymph is believed to be derived primarily from the cerebrospinal fluid (CSF), as the scala vestibuli and scala tympani are connected to the subarachnoid space via the perilymphatic duct within the cochlear aqueduct. Endolymph is thought to be secreted by the stria vascularis, often referred to as the 'battery of the cochlea,' located on the outer wall of the scala media. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity  Reissner’s membrane, first described by Reissner in 1851, is a thin membrane approximately 2-3 µm thick. It consists of two cellular layers: a single layer of polygonal epithelial cells on the endolymphatic (cochlear duct) side, and flat cells on the perilymphatic (scala vestibuli) side. This membrane separates the scala vestibuli from the cochlear duct, preventing the mixing of endolymph and perilymph. While the exact function of Reissner’s membrane remains unclear, it is believed to facilitate fluid transport between the endolymphatic and perilymphatic spaces due to its permeability. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity  The blood-labyrinth barrier (BLB) in the stria vascularis is a specialized capillary network that regulates the exchanges of substances between the blood and the cochlea. The barrier protects the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in maintening cochlear homeostasis. Anatomically, the BLB is composed of pericytes, endothelial cells and macrophages, and surrounds the capillaries that are embedded within the intermediate cell layers of the stria vascularis. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity 4- Ionic balance in hair cells  When the hair bundle is deflected toward the tallest stereocilium, cation-selective channels open near the tips of the stereocilia, allowing K+ ions from the endolymph to flow into the hair cell down their electrochemical gradient. The resulting depolarization opens voltage-gated Ca2+ channels in the hair cell soma, allowing calcium entry and neurotransmitter release onto the nerve endings of the auditory nerve. Regulation of fluids and ionic environments is essential for cochlear activity. Disruptions in ionic homeostasis can impair hearing and balance. Various structures work together to maintain this balance, ensuring optimal cochlear function. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity 4- Ionic balance in hair cells 5- Battery model of the Cochlea  When von Bekesy first measured the DC potentials within the cochlea, he identified a positive potential in the endolymphatic space (the endocochlear potential, or EP) and a negative potential inside the organ of Corti. These potentials would drive a circulating current, forming the foundation of Davis's mechanicoelectrical "battery theory" of cochlear transduction (1957). The main component of this simplified electrical model, which explain the ionic and electrical gradients that support cochlear function, are: the stria vascularis as the primary energy source, the basilar membrane, reissner's membrane, the spiral limbus, and the spiral ligament as sources of fixed resistances, and the hair cell as sources of variable resistance. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS K+ 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity K+ 4- Ionic balance in hair cells 5- Battery model of the Cochlea 6- One-pump two-cell model  The main ion transport mechanisms in the lateral wall of the cochlea involve four key processes: (1) transport from fibrocytes of the spiral ligament and basal cells of the stria vascularis, (2) transport from intermediate cells to the interstitial space, (3) transport across the basal surface of marginal cells, and (4) transport across the apical surface of marginal cells into the scala media. These processes contribute to the establishment and maintenance of the cochlear ionic balance. Ionic homeostasis in the cochlea INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity 4- Ionic balance in hair cells 5- Battery model of the Cochlea 6- One-pump two-cell model 7- Gap junction functions  Gap junctions are specialized connections between cells that allow the direct exchange of small molecules, ions, and electrical signals. Ionic homeostasis in the cochlea K+ INNER EAR HOMEOSTASIS 1- Cochlear fluids 2- Perilymph vs endolymph 3- Cochlear fluid integrity 4- Ionic balance in hair cells 5- Battery model of the BC, basal cells HC, hair cells Cochlea IC, intermediate cells 6- One-pump two-cell model MC, marginal cells RC, root cells 7- Gap junction functions SC, supporting cells Type 1 FC, type I fibrocytes Type II FC, type II fibrocytes  Sensory transduction in the cochlea and the vestibular labyrinth depends on the cycling of K+. Therefore, K+ recycling is a critical. Gap junctions are thought to play a key role in this process by facilitating the movement of K+ ions between different cochlear cells. One proposed pathway involves the transport of K+ from the hair cells, where it accumulates during depolarization, to the supporting cells and the stria vascularis. The K+ ions then move through gap junctions in the stria vascularis to be reabsorbed by the cochlear lateral wall and returned to the perilymphatic space. This recycling ensures that the ionic environment required for normal auditory signaling is maintained, preventing toxic Pathophysiology of cochlear circulation and homeostasis Normal Cx26 EXAMPLE #1 gene Cx26-Related Deafness (Gap Junction Mutations) Mutated Cx26 gene  Cx26-related deafness is a type of sensorineural hearing loss associated with mutations in the Cx26 gene, which encodes for the Connexin 26 protein. This protein is crucial for the formation of gap junctions in the cochlea, which are responsible for potassium ion recycling. When mutations occur in Cx26, the function of these gap junctions is disrupted, preventing the proper movement of K+ ions between cochlear cells. Without effective K+ recycling, the ionic balance within the cochlear fluids (particularly in the endolymph) is disturbed. This leads to elevated potassium levels and impaired cochlear function, which results in sensorineural hearing loss. The severity of hearing loss depends on the extent of the mutation and its impact on cochlear homeostasis. This condition is one of the most common genetic causes of congenital deafness. Pathophysiology of cochlear circulation and homeostasis Enlarged vestibular aqueduct of patient compared with normal individual EXAMPLE #2 (white arrows) Pendred Syndrome and Cochlear Development Absence of middle turn of the cochlea and smaller cochlea in our patient compared with normal individual (narrow white arrow – apical turn, wide white arrow – middle turn, black arrow – basal turn of the  Pendred syndrome is a genetic disorder typically caused by mutations in the SLC26A4 gene, which encodes the pendrin protein. Pendrin plays a critical role in the ion transport mechanisms of the cochlea and the thyroid gland. In the cochlea, pendrin is involved in regulating the movement of ions, which is essential for maintaining the proper ionic balance required for hearing. When pendrin is deficient or nonfunctional due to a mutation, it can lead to abnormal cochlear development, which may result in fewer turns in the cochlea, a key feature of Pendred syndrome. This anatomical anomaly disrupts normal cochlear function, leading to sensorineural hearing loss. In addition, Pendred syndrome often includes thyroid problems, such as a goiter. Pendred syndrome’s impact on cochlear development, combined with abnormal ion transport, makes it a significant example of how disruptions in cochlear homeostasis can lead to hearing loss. This condition highlights the complex interplay between genetic factors and cochlear fluid regulation, leading to both structural and functional defects in the inner ear. Recap of Today’s Learnings Recap of Today's The Learnings (1/2) inner ear receives its blood supply mainly from the cochlear artery, which branches off from the labyrinthine artery, delivering oxygen and nutrients to cochlear structures The vascular supply to the cochlea is tightly regulated, as disruptions in blood flow can lead to cochlear dysfunction and contribute to hearing loss The cochlea maintains ionic balance through the separation of endolymph and perilymph, with distinct ionic compositions critical for cochlear function Recap of Today’s Learnings Recap of Today's Learnings Ion transport (2/2) mechanisms, including the stria vascularis and gap junctions, ensure proper recycling of potassium (K+) and the maintenance of endocochlear potential (EP) The homeostasis of cochlear fluids is essential for the electrochemical gradients that support sensory transduction and sound perception Genetic mutations, such as Cx26-related deafness, and disorders like Pendred syndrome can impair cochlear ionic balance and lead to sensorineural hearing loss