The ability of neurons to regulate their activity (homeostatic plasticity) is thought to be responsible for changes in neural responsiveness/gain induced by sensory deprivation, or augmented stimulation. For example, following auditory deprivation, excitatory and inhibitory synaptic transmission is strengthened and weakened, respectively. Abnormally high neural gain results in an 'over amplification' of spontaneous and stimulus-evoked firing rates, and may result in aberrant auditory perceptions including tinnitus and/or hyperacusis, respectively. The first manuscript in the thesis 'Pump up the Volume' (Chapter Three) provides a summary of the neural gain mechanism in the adult auditory system. Aspects of neural gain, including temporal characteristics and frequency specificity, had not been systematically investigated. Therefore, the aim of this thesis was to investigate characteristics of the neural gain mechanism. The thesis comprises three related studies involving normal hearing adult listeners: two studies involved short term sensory deprivation and one study involved short term augmented stimulation. The main outcome measures were the acoustic reflex threshold (ART), auditory brainstem response (ABR) and loudness. In Study One, the time course, frequency specificity and anatomical location of changes in the ART, following 6 days of unilateral earplug use (ca 30 dB attenuation at 2-4 kHz), were investigated. The reduction in ART in the treatment ear was greatest at day 4 and at frequencies most attenuated by the earplug. Ipsilateral and contralateral ARTs were similar when stimuli were presented to the treatment ear. ARTs were not statistically significant from baseline when measured 4 and 24 hours after earplug removal. In Study Two, the ART and ABR were measured at baseline and after 7 days of unilateral and bilateral hearing aid use (13-17 dB real ear insertion gain), to compare the effect of symmetrical and asymmetrical inputs. There was no change in ART and ABR after treatment, suggesting that the augmented stimulation was insufficient to modify neural gain. In Study Three, ARTs, ABRs and loudness were investigated after 4 days of unilateral earplug use (30 dB attenuation at 2-4 kHz). There was a significant reduction in ART (ca 6 dB) in the treatment ear, which returned to baseline within 1-2 hours of earplug removal. There was an unexpected but significant 35 nV decrease in the ABR wave V peak-to-trough amplitude in the treatment ear, and a 12 nV increase in the control ear. The change in ABR was opposite in direction to the change in ART. There was no change in loudness. The thesis has provided information on the threshold of deprivation/stimulation required to elicit a change in neural gain, along with the frequency specificity and temporal characteristics of the gain control mechanism. The anatomical location for changes in neural gain is around the level of the cochlear nucleus. The change in ABR was in the opposite direction to those predicted, but could be due a difference in the compensatory changes of contralateral and ipsilateral inputs at the level of the inferior colliculus.

Stroke is the third leading cause of death and the primary cause of adult long-term disability in Canada. Despite advances in rehabilitation research, stroke survivors experience an unusually high incidence of depressive symptoms which undermine recovery outcomes by reducing patient motivation levels. Human and animal studies have linked the incidence of post-stroke depression and the extent of prefrontal cortex (PFC) damage. The PFC and the lateral habenula (LHb) are limbic structures that are strongly connected to the serotonergic dorsal raphe nucleus (DRN), a key neuronal hub for mood regulation. We hypothesized that PFC stroke produces a depressive phenotype by triggering maladaptive reorganization in mood-related networks. We used viral and optogenetic strategies to functionally characterize PFC and LHb projections to DRN. Moreover, we found that PFC stroke causes a time-dependent remodeling of LHb inputs to DRN 5-HT neurons which results in altered postsynaptic glutamate receptor number and subunit composition. This remodeling likely reflects a homeostatic upregulation of LHb-DRN synapses in response to stroke-induced challenge to network activity. Since these synapses encode stress and aversion, potentiation of this pathway could contribute to depressive symptoms following stroke. However, more work will be needed to identify the behavioral and network-level consequences of altered LHb-DRN dynamics. Thus, a deeper understanding of circuit mechanisms implicated in post-stroke depression will provide insights into this disease and open new treatment avenues to improve recovery.

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No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Stroke is the second leading cause of mortality worldwide, accounting for 5.5 million deaths annually. In addition to its high mortality rate, stroke is the most common cause of acquired epilepsy. Three to thirty percent of stroke survivors develop post-stroke epilepsy. Although currently available therapies such as thrombolytics and mechanical thrombectomy prevent immediate mortality by restoring blood flow after stroke, these treatments do not target the cellular and molecular mechanisms that lead to post-stroke epileptogenesis. With the increasing number of stroke survivors, there is an urgent need for therapies that prevent epilepsy development in this population. Here, we showed that homeostatic plasticity is involved in the development of hyperexcitability after stroke and can be targeted to prevent the development of post-stroke epilepsy. Using two-photon calcium imaging, we found that homeostatic regulation leads to cortical hyperexcitability after stroke. We also found that activity enhancement by optogenetic and pharmacological approaches can target homeostatic plasticity to prevent post-stroke epilepsy. This study demonstrates the high translational potential of activity enhancement as a novel strategy to prevent post-stroke epilepsy through regulating cortical homeostatic plasticity. Sudden premature death is a leading cause of death in patients with medically refractory epilepsy. This unanticipated death of a relatively healthy person with epilepsy in which no structural or toxicological cause of death can be identified after postmortem analysis is referred to as sudden unexpected death in epilepsy patients (SUDEP). Respiratory failure during seizures is an important underlying mechanism of SUDEP. Here, we showed that LPS-induced peripheral inflammation is protective against SUDEP. This protection is mediated at least in part via enhancing serotonergic function in the brain stem. To the best of our knowledge, this is the first study demonstrating the relationship between peripheral inflammation and SUDEP prevention. / 2024-11-01

<p>Tinnitus is an auditory disorder characterized by the perception of a ringing, hissing or buzzing sound with no external stimulus. Because the most common cause of chronic tinnitus is hearing loss, this neurological disorder is becoming increasingly prevalent in our noise-exposed and ageing society. With no cure and a lack of effective treatments, there is a need for a comprehensive understanding of the neural underpinnings of tinnitus. This dissertation outlines the development and validation of a comprehensive theoretical model of cortical correlates of tinnitus that is used to shed light on the development of tinnitus and to propose improvements to tinnitus treatment strategies.</p> <p>The first study involved the development of a computational model that predicts how homeostatic plasticity acting in the auditory cortex responds to hearing loss. A subsequent empirical study validated a more biologically plausible version of this computational model. The goal of these studies was to determine whether and how a form of plasticity that maintains balance in neural circuits can lead to aberrant activity in the auditory cortex. The final study extends the validated computational model to develop a comprehensive theoretical framework characterizing the potential role of homeostatic and Hebbian plasticity in the development of most major cortical correlates of tinnitus.</p> <p>These theoretical and empirical studies provide a novel and complete description of how neural plasticity in adult auditory cortex can respond to hearing loss and result in the development of tinnitus correlates.</p> / Doctor of Philosophy (PhD)

No description available.

Tinnitus, die Wahrnehmung eines Phantomgeräuschs, geht in den meisten Fällen mit Hörverlust einher. Es ist jedoch unbekannt, wie Hörverlust zu Tinnitus führen könnte. In Tierversuchen wurde gezeigt, dass Verhaltensanzeichen für Tinnitus nach Hörverlust mit erhöhten spontanen Feuerraten von Neuronen im zentralen auditorischen System korreliert sind. Zunächst untersuchen wir ob sich bei lärmbedingtem Hörverlust die Audiogramme von Patienten mit und ohne Tinnitus unterscheiden. Im Vergleich zu Patienten ohne Tinnitus haben Tinnituspatienten im Mittel weniger Hörverlust, einen steileren Abfall des Audiogramms, und die Audiogrammkante befindet sich bei höheren Frequenzen. Mit einem theoretischen Modell zeigen wir, wie tinnitusartige Hyperaktivität durch eine Stabilisierung der mittleren Feuerrate von Neuronen im zentralen Hörsystem mittels homöostatischer Plastizität entstehen kann: verringerte Aktivität von Hörnervfasern nach Hörverlust wird kompensiert durch eine Erhöhung der neuronalen Verstärkung. Dies stabilisiert die mittlere Rate, kann jedoch zu einer Erhöhung der spontanen Feuerraten führen, die dann von Art und Stärke der cochlearen Schädigung abhängen. Wir testen das Modell, indem wir es auf die Audiogramme von Patienten mit tonalem Tinnitus und Lärmschwerhörigkeit anwenden. Für jedes Audiogramm sagen wir mit dem Modell Veränderungen in der Spontanaktivität von auditorischen Neuronen vorher. Das resultierende Hyperaktivitätsmuster hat typischerweise eine deutliche Spitze, die mit einem steilen Abfall des Audiogramms einhergeht. Wenn solch eine Spitze als Grundlage für einen tonalen Tinnitus interpretiert wird, dann sagt das Modell Tinnitusfrequenzen nahe den empfundenen Tinnitustonhöhen vorher. Unser Modell stellt also eine plausible Hypothese, wie Hörverlust zu Tinnitus führen könnte, dar. Basierend auf dem Modell zeigen wir außerdem wie Hyperaktivität und somit eventuell auch Tinnitus, durch zusätzliche akustische Stimulation reduziert werden könnte. / Tinnitus is a phantom auditory sensation that is associated with hearing loss, but how hearing loss can lead to tinnitus has remained unclear. In animals, hearing loss through cochlear damage can lead to behavioral signs of tinnitus and can increase the spontaneous firing rates of central auditory neurons. To study the relation between hearing loss and tinnitus, we first analyze audiometric differences between patients with hearing loss and tinnitus and patients with hearing loss but without tinnitus. We find that tinnitus patients have on average less hearing loss, a steeper slope of the audiogram, and the audiogram edge is located at higher frequencies compared to patients without tinnitus. We then derive a computational model that demonstrates how tinnitus-related hyperactivity could arise as a consequence of a stabilization of the mean firing rates of central auditory neurons through homeostatic plasticity: decreased auditory nerve activity after hearing loss is counteracted through an increase of the neuronal response gain. This restores the mean rate, but can also lead to increased spontaneous firing rates, which depend on the type and degree of cochlear damage. Finally, we test the ability of our model to predict tinnitus pitch by applying it to audiograms from patients with noise-induced hearing loss and tone-like tinnitus. Given an audiogram, the model is used to predict changes in the spontaneous firing rates of central auditory neurons. The resulting hyperactivity pattern typically exhibits a distinct peak that is associated with a steep drop in the audiogram. If such a peak is interpreted as the basis for a tone-like tinnitus sensation, the model predicts a tinnitus frequency that is close to the patient''s tinnitus pitch. Thus, our model presents a plausible hypothesis of how hearing loss could lead to tinnitus. Based on this model, we also show how hyperactivity, and possibly also tinnitus, could be alleviated through additional acoustic stimulation.

Neuronal activity in the brain is tightly regulated. During operation in real time, for instance, feedback and feedforward loops limit excessive excitation. In addition, cell autonomous processes ensure that neurons’ average activity is restored to a setpoint in response to chronic perturbations. These processes are summarized as homeostatic plasticity (Turrigiano in Cold Spring Harb Perspect Biol 4:a005736–a005736, 2012). In the basal ganglia, information is mainly transmitted through disinhibition, which already constraints the possible range of neuronal activity. When this tightly adjusted system is challenged by the chronic decline in dopaminergic neurotransmission in Parkinson’s disease (PD), homeostatic plasticity aims to compensate for this perturbation. We here summarize recent experimental work from animals demonstrating that striatal projection neurons adapt excitability and morphology in response to chronic dopamine depletion and substitution. We relate these cellular processes to clinical observations in patients with PD that cannot be explained by the classical model of basal ganglia function. These include the long duration response to dopaminergic medication that takes weeks to develop and days to wear off. Moreover, dyskinesias are considered signs of excessive dopaminergic neurotransmission in Parkinson’s disease, but they are typically more severe on the body side that is more strongly affected by dopamine depletion. We hypothesize that these clinical observations can be explained by homeostatic plasticity in the basal ganglia, suggesting that plastic changes in response to chronic dopamine depletion and substitution need to be incorporated into models of basal ganglia function. In addition, better understanding the molecular mechanism of homeostatic plasticity might offer new treatment options to avoid motor complications in patients with PD.

A fundamental goal in neurobiology is to understand the development and organization of neural circuits that drive behavior. In the embryonic spinal cord, the first motor activity is a slow coiling of the trunk that is sensory-independent and therefore appears to be centrally driven. Embryos later become responsive to sensory stimuli and eventually locomote, behaviors that are shaped by the integration of central patterns and sensory feedback. In this thesis I used a simple vertebrate model, the zebrafish, to investigate in three manners how developing spinal networks control these earliest locomotor behaviors. For the first part of this thesis, I characterized the rapid transition of the spinal cord from a purely electrical circuit to a hybrid network that relies on both chemical and electrical synapses. Using genetics, lesions and pharmacology we identified a transient embryonic behavior preceding swimming, termed double coiling. I used electrophysiology to reveal that spinal motoneurons had glutamate-dependent activity patterns that correlated with double coiling as did a population of descending ipsilateral glutamatergic interneurons that also innervated motoneurons at this time. This work (Knogler et al., Journal of Neuroscience, 2014) suggests that double coiling is a discrete step in the transition of the motor network from an electrically coupled circuit that can only produce simple coils to a spinal network driven by descending chemical neurotransmission that can generate more complex behaviors. In the second part of my thesis, I studied how spinal networks filter sensory information during self-generated movement. In the zebrafish embryo, mechanosensitive sensory neurons fire in response to light touch and excite downstream commissural glutamatergic interneurons to produce a flexion response, but spontaneous coiling does not trigger this reflex. I performed electrophysiological recordings to show that these interneurons received glycinergic inputs during spontaneous fictive coiling that prevented them from firing action potentials. Glycinergic inhibition specifically of these interneurons and not other spinal neurons was due to the expression of a unique glycine receptor subtype that enhanced the inhibitory current. This work (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggests that glycinergic signaling onto sensory interneurons acts as a corollary discharge signal for reflex inhibition during movement. v In the final part of my thesis I describe work begun during my masters and completed during my doctoral degree studying how homeostatic plasticity is expressed in vivo at central synapses following chronic changes in network activity. I performed whole-cell recordings from spinal motoneurons to show that excitatory synaptic strength scaled up in response to decreased network activity, in accordance with previous in vitro studies. At the network level, I showed that homeostatic plasticity mechanisms were not necessary to maintain the timing of spinal circuits driving behavior, which appeared to be hardwired in the developing zebrafish. This study (Knogler et al., Journal of Neuroscience, 2010) provided for the first time important in vivo results showing that synaptic patterning is less plastic than synaptic strength during development in the intact animal. In conclusion, the findings presented in this thesis contribute widely to our understanding of the neural circuits underlying simple motor behaviors in the vertebrate spinal cord. / Un objectif important en neurobiologie est de comprendre le développement et l'organisation des circuits neuronaux qui entrainent les comportements. Chez l'embryon, la première activité motrice est une lente contraction spontanée qui est entrainée par l'activité intrinsèque des circuits spinaux. Ensuite, les embryons deviennent sensibles aux stimulations sensorielles et ils peuvent éventuellement nager, comportements qui sont façonnées par l'intégration de l'activité intrinsèque et le rétrocontrôle sensoriel. Pour cette thèse, j'ai utilisé un modèle vertébré simple, le poisson zèbre, afin d'étudier en trois temps comment les réseaux spinaux se développent et contrôlent les comportements locomoteurs embryonnaires. Pour la première partie de cette thèse j'ai caractérisé la transition rapide de la moelle épinière d'un circuit entièrement électrique à un réseau hybride qui utilise à la fois des synapses chimiques et électriques. Nos expériences ont révélé un comportement embryonnaire transitoire qui précède la natation et qu'on appelle « double coiling ». J'ai démontré que les motoneurones spinaux présentaient une activité dépendante du glutamate corrélée avec le « double coiling » comme l'a fait une population d'interneurones glutamatergiques ipsilatéraux qui innervent les motoneurones à cet âge. Ce travail (Knogler et al., Journal of Neuroscience, 2014) suggère que le « double coiling » est une étape distincte dans la transition du réseau moteur à partir d'un circuit électrique très simple à un réseau spinal entrainé par la neurotransmission chimique pour générer des comportements plus complexes. Pour la seconde partie de ma thèse, j'ai étudié comment les réseaux spinaux filtrent l'information sensorielle de mouvements auto-générés. Chez l'embryon, les neurones sensoriels mécanosensibles sont activés par un léger toucher et ils excitent en aval des interneurones sensoriels pour produire une réponse de flexion. Par contre, les contractions spontanées ne déclenchent pas ce réflexe même si les neurones sensoriels sont toujours activés. J'ai démontré que les interneurones sensoriels reçoivent des entrées glycinergiques pendant les contractions spontanées fictives qui les empêchaient de générer des potentiels d'action. L'inhibition glycinergique de ces interneurones, mais pas des autres neurones spinaux, est due à l'expression d'un sous-type de récepteur glycinergique unique qui augmente iii le courant inhibiteur. Ce travail (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggère que la signalisation glycinergique chez les interneurones sensoriels agit comme un signal de décharge corolaire pour l'inhibition des réflexes pendant les mouvements auto- générés. Dans la dernière partie de ma thèse, je décris le travail commencé à la maîtrise et terminé au doctorat qui montre comment la plasticité homéostatique est exprimée in vivo aux synapses centrales à la suite des changements chroniques de l'activité du réseau. J'ai démontré que l'efficacité synaptique excitatrice de neurones moteurs spinaux est augmentée à la suite d’une diminution de l'activité du réseau, en accord avec des études in vitro précédentes. Par contre, au niveau du réseau j'ai démontré que la plasticité homéostatique n'était pas nécessaire pour maintenir la rythmicité des circuits spinaux qui entrainent les comportements embryonnaires. Cette étude (Knogler et al., Journal of Neuroscience, 2010) a révélé pour la première fois que l'organisation du circuit est moins plastique que l'efficacité synaptique au cours du développement chez l'embryon. En conclusion, les résultats présentés dans cette thèse contribuent à notre compréhension des circuits neuronaux de la moelle épinière qui sous-tendent les comportements moteurs simples de l'embryon.