L-type Ca2+ Channel Oligomerization in Hearts and Minds
In ventricular myocytes, excitation-contraction (EC) coupling occurs via a Ca2+ induced Ca2+ release mechanism such that the depolarization created by an action potential (AP) triggers Ca2+ influx through voltage-dependent L-type Ca2+ channels (i.e., Cav1.2 channels), which in turn stimulates further Ca2+ release from ryanodine receptors (RyRs) on the nearby junctional sarcoplasmic reticulum. The simultaneous activation of multiple RyRs across the myocyte results in a cell-wide increase in intracellular Ca2+ and triggers contraction. This process is remarkably reproducible despite the confounding fact that, at the membrane potential reached during the AP plateau, the driving force for Ca2+ entry through a single Cav1.2 channel is not sufficient to reliably activate RyRs. Instead it has been proposed that up to ten Cav1.2 channels must open simultaneously during the AP plateau to achieve this coupling fidelity. The mechanism that permits coordinated opening of multiple Cav1.2 channels during EC-coupling, however, has not yet been elucidated. Using electrophysiological, and optical approaches, we have found that an allosteric interaction between the C-terminal domains of voltage-gated CaV1.2 channels induces an increase in the open probability of the channels that amplifies Ca2+ influx during the AP and contributes to reproducible EC-coupling. We have also discovered that Cav1.3 channels that regulate excitability in neurons often display the same cooperative behavior. The objectives of this presentation are to summarize the molecular details of the channel interactions that we have resolved thus far and to highlight the significance of these findings to the cardiac and neuronal field
Rose Dixon, Ph.D.
University of Washington
Chalk talk, Friday, January 22nd, at 9:30 in G-417.
Where the kidney meets the heart: calcium signaling, cardiomyopathies and polycystic kidney disease
Ivana Yih-Tsue Kuo, PhD,
Chalk talk, Friday, January 29th, at 9:30 in G-417.
A molecular mechanism of acute oxygen sensing
While the molecular mechanism for slower adaptations to low oxygen (hypoxia) is known, mechanisms for rapid oxygen sensing are not well understood. Located at the bifurcation of the carotid artery in the neck, the mammalian carotid body is a chemosensory organ that senses decreases in blood oxygen to stimulate breathing within seconds. I will present the identification of an acute oxygen-sensing pathway in the mouse carotid body that senses hypoxia indirectly through detection of a metabolite.
Andy J. Chang, PhD
Chalk Talk on Friday, February 5th, 9:30am in G-417.
Seminar Title: Thoughts (and Experiments) on Microtubule Nucleation
Abstract: Microtubules are born and reborn continuously, even during quiescence. These polymers are nucleated from templates, namely γ-tubulin ring complexes (γ-TuRCs) and severed microtubule ends. Interestingly, the rate of microtubule nucleation increases as cells enter mitosis, and all cells nucleate microtubules in distinct regions of their cytoplasms. How are these spatial and temporal profiles for microtubule nucleation established? I will discuss my lab’s recent attempts to answer this question using a mix of single-molecule biophysics, cell biology, and structural biology.
Host: Chip Asbury
Circuit Mechanisms for Flexible Sensory Processing
In a complex and dynamic environment, animals must constantly vary their behavior to accommodate changing circumstances and contingencies. Yet, how associative brain centers flexibly couple the same sensory input to alternative behavioral pathways remains unclear. My lab takes advantage of the relative simplicity of the Drosophila olfactory system to gain insight into the synaptic and circuit mechanisms through which context and experience can modify odor processing. In Drosophila, the mushroom body is a higher brain center that integrates olfactory and neuromodulatory reinforcement signals to generate learned and adaptive behaviors. I will describe recent work in which we used functional synaptic imaging and electrophysiology to show that the mushroom body functions like a switchboard in which dopaminergic neuromodulation can reroute the same odor signals to different behavioral circuits depending on the state and experience of the fly. Our data suggest a circuit mechanism for behavioral flexibility in which neuromodulatory networks act with exquisite spatial precision to transform a single sensory input into different patterns of output activity.
Gabrielle H. Reem and Herbert J. Kayden Assistant Professor
Laboratory of Neurophysiology and Behavior
Host: John Tuthill
The restricted and dynamically regulated subcellular localization of signaling proteins in highly differentiated cells such as mammalian neurons defines intra- and inter-cellular signaling events. Among neuronal proteins exhibiting the most highly compartmentalized expression are ion channels, whose localization at specific sites can both define signaling in that neuronal compartment, but also allow for discrete regulation of the population of channels found at these sites. I will describe the diverse mechanisms that establish, maintain and dynamically regulate ion channel expression at specific sites to support neuronal function and confer plasticity to neuronal signaling.
UC Davis, Departments of Physiology and Membrane Biology and Neurobiology, Physiology and Behavior
host: Nicholas Poolos
Higgins Professor of Molecular and Cellular Biology
Howard Hughes Medical Institute Investigator
host: Stan Froehner
Big Time for BK: Mechanisms of Circadian Rhythm in Neuronal Activity
Andrea L. Meredith Ph.D.
University of Maryland, Physiology
host: Sharona Gordon
Inactivation gating is an intrinsic property of several types of voltage-dependent ion channels, closing the conduction pathway during membrane depolarization and dynamically regulating neuronal activity. BK large conductance voltage- and Ca2+-activated K+ channels undergo N-type inactivation via their β2 subunit, but the physiological significance has not been clear. To understand the role of BK channel inactivation in neuronal excitability, we identified a circuit where β2 is expressed and where dynamic regulation of the BK current is critical for neural coding, the suprachiasmatic nucleus (SCN) ‘clock circuit’ of the hypothalamus. BK channel regulation of SCN action potentials is dynamic, with a significant effect on nighttime firing, but little effect during the day. Correlated with this dynamic role in SCN excitability, we found that inactivating BK currents predominate during the day, reducing steady-state current levels. At night inactivation is diminished, resulting in larger BK currents. Loss of β2 eliminates BK channel inactivation, abolishing the diurnal variation in both BK current magnitude and SCN firing, and disrupting behavioral rhythmicity. Selective restoration of inactivation via the isolated β2 N-terminal ‘ball-and-chain’ domain rescues BK current levels and firing rate, unexpectedly contributing to the sub-threshold membrane properties that shift SCN neurons into the daytime ‘upstate’. These findings reveal that the intrinsic clock employs inactivation gating as a biophysical switch to set the diurnal variation in SCN excitability that underlies circadian rhythm.
Exploring the nature of spinal cord plasticity: Neurobiological mechanisms and implications for recovery after injury
Prior research has shown that pain (nociceptive) circuits within the spinal cord are affected by environmental relations and support some simple forms of learning (e.g., sensitization, instrumental conditioning). Further, learning can induce a modification in the capacity for learning (a form of metaplasticity); controllable stimulation enables learning through a process that depends upon brain derived neurotrophic factor (BDNF) while uncontrollable stimulation induces a lasting learning impairment that has been linked to the development of central sensitization and the cytokine tumor necrosis factor (TNF). I review data that show temporal predictability also affects spinal function by engaging an internal oscillator. Spinal injury disrupts descending serotonergic fibers that appear to quell nociceptive sensitization. This process is related to a change in the co-transporters that regulate spinal GABA function. It is also shown that nociceptive stimulation impairs recovery after a contusion injury. This effect is related to increased cell death and alterations in BDNF/TNF. Potential therapeutic treatments will be discussed.
Assistant Professor of Biochemistry, University of Washington
host: Greg Horwitz
How are load-bearing soft tissues built?
Force-structure causality in the matrix
Jeffrey W. Ruberti
host: Chip Asbury
Abstract: Shockingly, there exists no established model that can explain how a cluster of vertebrate cells which are expressing matrix proteins manage to produce, refine and grow load-bearing structures that are organized over much longer length scales than the cells themselves. The current best guess model, which was proposed in the mid-1980s by David Birk and Robert Trelstad (subsequently carried forward by Karl Kadler’s group) suggests that cells extrude formed collagen fibrils into the extracellular space via structures which are termed “fibripositors”. Thus, one imagines that the cells, working together, somehow weave the collagen into the matrix, thread by thread with the necessary exposed loose ends finding each other and fusing to form long-range, organized connective tissue. However, gathering evidence to support this model is severely hampered because it is nearly impossible to observe cells in the act of producing matrix while observing the collagen fibril deposition directly at the nanoscale (but we sure are trying to do that in the lab). In addition, the fibripositor model does not contemplate either matrix refinement or growth. Thus, we are not only in need of experimental evidence to support the fibripositor theory, we are short of a comprehensive testable hypothesis in general for how tissue is built. To address this dearth, we have chosen to make a simple (and risky) assumption: We reject the idea that the cells directly manipulate individual collagen monomers or fibrils to make tissue. Instead, we assume the cell has spent much of its time (~billion years) refining specific molecular systems (secretomes) that are designed to “settle” into their appropriate configuration simply by “reading” the energetic landscape. To generate load-bearing connective tissues, we suggest that the cells provide appropriate geometry by self-organizing and then produce an appropriate secretome that has been designed to assemble in opposition to the locally and globally applied mechanical forces which threaten to dissipate animal structure. In effect, we predict that mechanical strain is actually a long-range structure producing signal which works via mechanical allostery to modulate both collagen fibril assembly and retention. Because collagen is generally found resisting tension in load-bearing soft-connective tissue, we expect that the mechanical environment directly shifts the molecular energetics such that collagen’s inherent stability and assembly kinetics are enhanced in the direction of applied tensile forces. I will present the current state and limitations of our investigation of this risky assumption and entertain your thoughts, concerns and comments.
Vocal motor control and sensorimotor learning: behavior, neurophysiology, and biomechanics
The brain uses sensory feedback to calibrate the performance of complex behaviors. However, the neural and computational bases of sensorimotor learning remain mysterious. Our lab uses behavioral, physiological, biomechanical, and computational techniques to investigate the biological underpinnings vocal learning in songbirds. My talk will cover three ongoing lines of investigation into how songbirds correct vocal errors and precisely coordinate the acoustics of vocal production. First, our behavioral studies demonstrate that songbirds use vocal variability to constrain the speed and extent of vocal learning, and that the dynamics of learning across a number of experimental conditions can be understood as the result of an iterative process of Bayesian inference. Second, recent behavioral and anatomical studies demonstrate a crucial role for dopaminergic inputs to a basal ganglia nucleus in mediating vocal reinforcement learning. Third, neurophysiological recordings and computational analyses suggest that cortical motor neurons employ a millisecond-resolution spike timing code to regulate vocal behavior. Recent single-unit recordings from muscle tissue in behaving animals and in vitro measures of vocal biomechanics further suggest that millisecond-scale spike timing is an essential component of motor control, suggesting that reorganization of fine temporal spiking patterns might underlie vocal plasticity.
Assistant Professor of Biology, Emory University
Host: David Perkel
Examining neural circuits mediating social behaviors and motor learning using the CANE technology
Fan Wang, Ph.D.Associate Professor,
Department of Neurology
host: John Tuthill
NMDA Receptors: learning from singles and beyond
Gabriela Popescu, PhD
ProfessorDepartment of Biochemistry, Jacobs School of Medicine and Biomedical SciencesUniversity of Buffalo
NMDA receptors are members of the tetrameric ionotropic glutamate receptor family that fulfill unique and critical roles during the normal development and function of the central nervous system. These roles are supported by characteristic kinetic attributes of the glutamate-evoked output, which in turn reflect the receptor’s operation. In this talk, I will review the biologically salient features of the NMDA receptor response and describe recent mechanistic insights afforded by kinetic modeling of one channel currents. In addition, I will present unpublished data on novel modalities of gating
host: Andres Barria
“Seven Transmembrane Receptors”
James B. Duke Professor of Medicine
Investigator, Howard Hughes Medical Institute
Duke University Medical Center
Seven transmembrane receptors (7TMRs), also known as G protein coupled receptors (GPCRs) represent by far the largest, most versatile, and most ubiquitous of the several families of plasma membrane receptors. They regulate virtually all known physiological processes in humans. As recently as 40 years ago, the very existence of cellular receptors for drugs and hormones was highly controversial, and there was essentially no direct means of studying these putative molecules. Today, the family of GPCRs is known to number approximately 1,000, and crystal structures have recently been solved of approximately 25 members of the family and even of a receptor-G protein complex. In my lecture, I will briefly review how the field has evolved over the past 40 years, hanging some of the story on my own research throughout this period. Then I will discuss recent developments in the field, which are changing our concepts of how the receptors function and are regulated in fundamental ways. These include the duality of signaling through G-proteins and β-arrestins; the development of “biased ligands”; and the possibility of leveraging this new mechanistic and molecular information to develop new classes of therapeutic agents. Finally, I will discuss recent biophysical and structural studies of receptor-barrestin interactions.
Dwight Bergles, Ph.D.
The Solomon H. Snyder Department of Neuroscience
Johns Hopkins University
Sounds in silence: How glial cells in the ear promote development of the auditory system.
Spontaneous electrical activity is a prevalent feature of the developing nervous system, which has been shown to influence the maturation and survival of neurons, as well as the refinement of circuits in the brain. In the auditory system, bursts of activity are initiated in the cochlea when ATP is released by supporting cells that lie adjacent to inner hair cells (IHCs). This periodic release of ATP induces inward currents, crenations (cell shrinkage), and Ca2+ waves in supporting cells, events that are associated with periodic depolarization of inner hair cells and subsequent bursts of action potentials in primary auditory neurons. This activity is prominent during the first two postnatal weeks in mice, prior to hearing onset, suggesting that it may influence development of the cochlea and maturation of central auditory circuits. In this lecture, I will describe how glial cells in the inner ear have adapted a pathway used for fluid secretion in other organs to induce excitation of hair cells, define several key molecular components of this pathway and show using in vivo imaging how these peripheral glial cells control neural activity in auditory centers of the CNS.
host: Ed Rubel
Anastasios V. Tzingounis
University of Connecticut
Seizing the brake: defining the role of KCNQ2/3 channels in the brain
My seminar will focus on KCNQ channels, a potassium channel family implicated in multiple neonatal epileptic encephalopathy disorders. I will first discuss the role of KCNQ2/3 channels in interneurons. Previous research on the function of KCNQ2/3 channels nearly exclusively focused on excitatory neurons, but in fact these channels are also expressed by inhibitory interneurons. Insight regarding the function of KCNQ2/3 channels in interneurons has become critical as some newly identified epilepsy-associated KCNQ2/3 mutations have a gain-of-function effect on channel activity, and such mutations may lead to seizures through diminished inhibitory neuron activity. Second, I will present data regarding the molecular components that underlie the slow afterhyperpolarization (sAHP) in hippocampus and the role of KCNQ2/3 channels in the sAHP.
Host: Andres Barria
An ion channel on steroids: the unconventional pathway of calcium regulation by endogenous cannabinoids
Polina Lishko, PhD
Assistant Professor of Cell and Developmental Biology
Department of Molecular and Cell Biology
Host: Sharona Gordon
Ion channels control sperm activity by regulating intracellular levels of calcium, which stimulates cell motility and fertility. Steroid hormone progesterone produced by an ovulated egg promotes the entry of calcium through sperm channel CatSper- an event so central for fertilization that men lacking these channels are infertile. We have demonstrated that human CatSper is associated with a membrane progesterone receptor, which makes human spermatozoa controlled by the female reproductive cycle. The identity of this receptor has been recently revealed to be serine hydrolase ABHD2 that degrades endogenous CatSper inhibitor 2-arachidonoylglycerol upon progesterone exposure. ABHD2 is ubiquitously expressed, and the pathway we have discovered in spermatozoa, is likely a universal pathway that defines membrane steroid signaling in other tissues.
Feedback control of sodium and calcium channels – from shared
molecular underpinnings to synthetic modulation.
Manu Ben-Johny, Ph.D.
Department of Bioengineering
Johns Hopkins University
The voltage-gated sodium (NaV) and calcium (CaV) channels constitutes two major ion-channel superfamilies with custom molecular attributes that enable a multitude of unique biological functions. For example, the NaV channels support brisk spatial propagation of action potentials while the CaV channels couple excitability to contraction, secretion, and transcription. Yet, one similarity of these channels is their homologous carboxy-tail, a segment that is a hotspot for diverse cardiac arrhythmogenic and neurological disorders. If this region were to support like-functions, deep mechanistic insights could be gleaned from the joint investigation of these channels, and shared principles derived for approaching related channelopathic diseases. For CaV channels, dynamic interactions between their tail domains and calmodulin elaborate rapid and recognizably similar forms of Ca2+-feedback regulation. However, for NaV channels, Ca2+ effects have long-appeared to be subtle and variable with divergent purported mechanisms, dimming prospects for unification. Here, using quantitative Ca2+-photouncaging and single-channel recordings, we show that these differences are only apparent and that Ca2+ regulatory function and mechanism are fundamentally conserved across the two channel families. Despite this high similarity and dependence on a modular structural element, we demonstrate how cells employ distinct auxiliary proteins to selectively switch feedback control of NaV versus CaV channels and vice versa. Overall, these results help substantiate the persistence of an ancient Ca2+-regulatory design across channel superfamilies, unravel the sophisticated mechanisms by which cytosolic proteins tune cellular excitability and calcium signaling, and reveal new strategies to engineer the molecular function of ion channels.
host: Stan Froehner
Unexpected lessons on neuromodulator action from imaging molecular signals
Yao Chen, Ph.D.
Department of Neurobiology
Harvard Medical School
Neuromodulators such as acetylcholine and dopamine have profound effects on neural circuits and behavior. However, how neuromodulator-induced molecular signals influence behavior represents an outstanding gap in our understanding of neuromodulator action. In order to go beyond the identity to the action of molecular signals, we need to know the subcellular and cellular specificity as well as temporal dynamics of neuromodulator-induced molecular signals. One of the major challenges to uncover these features is the lack of methods to dynamically monitor the molecular signals induced by G protein-coupled receptor (GPCR) activation with high spatial resolution. A critical intracellular integrator of GPCRs is protein kinase A (PKA). PKA activity is stimulated by Gαs-coupled and inhibited by Gαi-coupled neuromodulator receptors, and this push-pull relationship can bidirectionally modulate synaptic function as well as transcription. In order to monitor PKA activity in the brain, we modified a PKA activity sensor and developed optical approaches that enable quantitative analysis of endogenous GPCR signaling in brain tissue with two-photon fluorescence lifetime imaging microscopy. Using this reporter, we have found that, contrary to the canonical model of GPCR signaling, endogenous Gαq-coupled neuromodulator receptors elevate phosphorylation by PKA in the mouse hippocampus. I will present this discovery that highlights PKA as a central integrator of three major types of GPCR signals. Furthermore, I will share ongoing work suggesting that the same neuromodulator input (e.g. acetylcholine) can produce different PKA signals depending on the context of cellular physiology and animal experience. Finally, I will outline my future directions that aim to examine the spatial location, temporal dynamics and context dependence of neuromodulator-induced molecular signals, and how these features of molecular signaling contribute to cellular physiology and animal behavior.
host: Stan Froehner
Collective endothelial cell migration – cadherin fingers lead the way
Arnold L. Hayer, Ph.D.
Department of Chemical and Systems Biology
The development and maintenance of the vasculature requires collective cell movement, during which neighboring cells coordinate the polarity of their migration machineries. We addressed the unresolved question of how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, using an in vitro model of collective endothelial cell migration.
We found that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, ‘cadherin fingers’, which leading cells extend from their rear and follower cells engulf at their front. In follower cells, engulfment of cadherin fingers occurs along with the formation of a lamellipodia-like zone with low actomyosin contractility, and requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization. Lateral accumulation of cadherin fingers in follower cells precedes turning, and increased actomyosin contractility can initiate cadherin finger extension as well as engulfment by a neighboring cell, to promote follower behavior. Cadherin fingers create positively curved membrane surfaces only in the front of follower cells, which selectively recruit and polarize curvature sensing regulatory proteins. Thus, engulfment of cadherin fingers at the cell front converts symmetric cadherin junctions into polarized structures that support collective cell guidance.
Further, I will discuss our recent identification of a BAR domain and RhoGAP protein, which is required both for coordinated endothelial cell movement and vascular sprouting in vitro, and therefore establishes an intriguing mechanistic link between the asymmetric cadherin finger structure and RhoGTPase signaling.
host: Stan Froehner
Moving and Removing Axonal Mitochondria
Thomas L. Schwarz, PhD
F.M. Kirby Center for Neurobiology
Children’s Hospital, Boston
and Dept. of Neurobiology, Harvard Medical School
Location: Foege Auditorium, GNOM S060
seminar abstract: Mitochondria are dynamic organelles. In every cell they move and undergo fission and fusion. Their distribution and associations with the cytoskeleton change in response to many signals, including the mitotic cell cycle. In addition, because neurons look like no other cell in the organism, with axons of up to a meter in humans, mitochondrial motility is particularly crucial to the survival of the neuron. The neuron also needs to clear away damaged mitochondria efficiently wherever in the cell they may arise. Not surprisingly then, defects in the transport machinery of neurons and in their mechanisms for removing damaged mitochondria have been linked to several neurodegenerative diseases, including ALS and Parkinson’s disease. This talk will present the evidence for a motor/adaptor complex that is responsible for and regulates the movement of mitochondria and will discuss how that movement is regulated by the cell cycle, Ca++, and glucose. We will look at the operation of two proteins PINK1 and Parkin that are mutated in forms of Parkinson’s disease and examine how these proteins operate in axons to clear away damaged mitochondria that might otherwise compromise the health of the cell. Particularly in the case of mitophagy, we will consider the special challenges posed for neurons by their extended geometry and the difficulty of having a PINK1-dependent pathway operating far from the soma.
From body to brain: control of autonomic physiology by the sensory vagus nerve
Rui Chang, Ph.D.
Department of Cell Biology
Harvard Medical School
Cardiac, respiratory, and other autonomic functions are precisely controlled by the nervous system, yet many autonomic reflexes remain poorly characterized at a molecular and cellular level. The sensory vagus nerve is a major conduit between body and brain, and is critical for many autonomic physiology. Using a genetic approach, we molecularly deconstructed the vagus nerve, and successfully identified neuron populations that are critically involved in respiratory physiology and digestive functions. We further elucidated the molecular mechanism for lung inflation-mediated apnea. Together, these findings lay the groundwork for a molecular dissection of respiratory and gastrointestinal physiology.
Couple, amplify, fire!
Coupling of L-type calcium channels and excitability
L-type CaV1.2 and CaV1.3 calcium channels are key players in the generation and regulation of electrical activity in different cell types, including neurons and myocytes. In the pacemaker cells of the heart, the spike of the action potential that initiates each heartbeat depends entirely on the entry of calcium through these channels. Recently, we discovered a novel cooperative gating mechanism, on both CaV1.2 and CaV1.3 channels, which facilitates calcium entry and modulates the excitability of ventricular cardiomyocytes and neurons. We found that these channels establish a calcium-dependent physical interaction via their c-termini, which results in an increase in their open probability. Our more recent project aims to answer two new questions: Do CaV1.2 and CaV1.3 channel undergo functional coupling in the pacemaking cells of the heart? And, if so, is this coupling modulated by physiological stimuli? Our new results point to a mechanism by which beta-adrenergic signaling increases the coupling of CaV1.2 channels in the pacemaker cells. These exciting results add to our understanding on how the sympathetic nervous system increases heart rate.
Claudia Moreno, Ph.D.
Department of Physiology and Membrane Biology
School of Medicine
University of California, Davis
host: Stan Froehner
“Molecular Signaling Mechanisms of Cardiac Remodeling and Heart Failure”
University of Washington
Dept of Physiology & Biophysics
host: Stan Froehner
“Molecular physiology of cold-activated TRP channels”
Instituto de Neurociencias de Alicante Institute of Neurosciences, Alicante (Spain)
Visiting Scholar in the Department of Biological Structure, UW
Transient receptor potential (TRP) channels are a family of cationic channels with important roles in many aspects of sensory physiology, from vision to taste. Several of these channels are highly sensitive to temperature and have been shown to play critical roles in thermoreception, thermoregulation and pain. I will provide an overview of our work with two cold-activated channels, TRPA1 and TRPM8, highlighting their differential function in cold transduction, thermoregulation and nociception, and some newly discovered pathophysiological roles outside the nervous system.
host: Bertil Hille
Rebooting sensory processing after afferent loss: probing the capabilities and limitations of adult cortical plasticity
Harvard Medical School
Massachusetts Eye and Ear Infirmary
host: Ed Rubel
Following a near-complete loss of auditory nerve fibers that convey signals from the cochlea to the brain, all evidence of central sound processing grinds to a halt. Over the ensuing weeks, neurons at higher stages of central auditory processing increase the gain on the small fraction of remaining inputs and restore perceptual awareness and normative rate coding, even when markers of brainstem processing indicate complete deafness. I will describe our efforts to understand the mechanisms and limitations of this “cortical amplifier” that supports a partial compensatory plasticity. The second half of the talk will address whether further gains of function might be possible through auditory training tasks that activate cholinergic neurons in the basal forebrain. In particular, we are motivated to discover ways to ‘de-noise’ cortical representations of stimuli embedded in high levels of background noise. These experiments describe a multiplexed encoding of auditory stimuli and behavioral reinforcement signals in cholinergic neurons of Nucleus Basalis that project to the auditory cortex. We ask how these neurons are activated during auditory learning, first through simple auditory fear conditioning and ultimately through complex audiomotor tasks that generate high levels of sensory prediction errors. We conclude by showing how training on closed-loop audiomotor behavioral tasks can broadly enhance cortical and perceptual processing of faint sounds near the noise floor both in unit recordings from the mouse auditory cortex and through measurements of speech processing in elderly human subjects with profound hearing loss.