This thesis investigates the involvement of primary auditory cortex (A1) in sound localisation. Experiments were carried out both to assess the effect of A1 inactivation on sound localisation, and to measure the sensitivity of single A1 neurons to sound source location. Ferrets were trained to localise bursts of broadband noise, of varying intensity and duration, from an array of loudspeakers that spanned 360 degrees in azimuth. Bilateral A1 inactivation caused an impairment on this task, but only for short-duration stimuli. Unilateral A1 inactivation also resulted in an impairment for short-duration stimuli, but this was limited to the side of space contralateral to the inactivation, and was only seen in animals which had been highly trained prior to surgery. A feature of the impairment in all animals was the increased number of "front-back confusions", where the animal's response was on the correct side of the midline but the wrong side of the interaural axis. Recordings from ferret A1 showed that the firing rate of individual neurons varied little as sound source location was changed. Further, the neurons' location sensitivity was affected by changes in stimulus intensity and duration. However, mathematical techniques were used to measure the information these neurons provided about sound source location, and it was found that this information was not sensitive to intensity or duration changes. The analysis also showed that the amount of information provided by response latency was greater than that carried by firing rate. Similar mathematical treatment tentatively suggested that the information from different neurons was only slightly redundant, so it may be possible to account for whole-animal localisation performance by assuming that the output of large numbers of neurons is considered. It is concluded that A1 is involved in processing the location of sound sources, but it seems unlikely that sound localisation is A1's primary or only role within the auditory system.

No description available.

Tinnitus, ringing in the ears, is a phantom sound percept affecting roughly 10-20% of the total world population. Tinnitus severely impacts the quality of life of 10% of tinnitus sufferers, affecting their sleep, concentration, emotion, social enjoyment, and sometimes leading to depression and suicidal tendencies. In humans, most forms of tinnitus are associated with noise-exposure, leading to compensatory maladaptive plasticity of central auditory neurons. Human and animal studies suggest that tinnitus alters normal adult attentional resources. Human studies by McKenna, Hallam and Surlock 1996, suggested tinnitus-related impairment in sustained attention, vigilance, visual conceptualization and visuo-motor memory. Additionally, tinnitus may impact aspects of selective or divided attention as well as working and long-term memory. The involvement of primary auditory cortex and nicotinic signaling in selective attention, working and long-term memory has been well established. Neuronal nicotinic acetylcholine receptors (nAChRs) are present on presynaptic and postsynaptic inputs that innervate neurons across layers of primary auditory cortex (A1). Layer 5 pyramidal neurons (PNs) in the A1 are major output neurons, conveying auditory information to corticocortical and subcortical nuclei. The excitation of PNs is regulated by a complex microcircuitory of inhibitory neurons with vasointestinal peptide positive (VIP) neurons playing a key role in regulating the excitation. The focus of present studies was to: 1) Characterize tinnitus-related changes in the physiology and nAChR signaling of layer 5 PNs and VIP neurons in the A1 and 2) Determine the ability of nAChR partial/desensitizing agonists to ameliorate tinnitus pathology in subcellular studies. Wild-type, ChAT-Cre and VIP-Cre:Rosa26-loxP-stop-loxP-tdTomato (VIP-Cre:Rosa-tdTomato Long-Evans rats were used in the present study. CHAT-Cre rats allowed us to selectively express cre-inducible AAV-EF1a-DIO-hChR2(H134R)-EYFP and stimulate the cholinergic neurons of basal forebrain (BF). VIP-Cre:Rosa-tdTomato express fluorescent tdTomato protein in the VIP positive neurons allowing us to identify them under fluorescence microscopy using 550 nm wavelength. An established noise-exposure (one hour of 116 dB narrowband noise centered at 16 kHz) was used to induce behavioral tinnitus in a rat model. Approximately 50-60% noise-exposed animals (53/92) exhibited behavioral evidence of tinnitus with significant shifts in hearing threshold contiguous to the exposure frequency. Animals were classified as control, exposed tinnitus and non-tinnitus. In vitro whole-cell patch clamp recordings were performed in control and tinnitus animals. Results: Numerous tinnitus-related changes in the physiology of layer 5 PNs and VIP neurons, and changes in the activity of excitatory and inhibitory input neurons were observed. The resting membrane potential of A1 layer 5 PNs from tinnitus animals was significantly depolarized compared to PNs from unexposed controls. PNs from the A1 of animals with behavioral evidence of tinnitus showed increases in the frequency of excitatory and decreases in frequency of inhibitory spontaneous postsynaptic currents, which directly correlated with the rat’s tinnitus score. Optical stimulation of thalamocortical terminals from PNs in tinnitus animals evoked significantly larger excitatory/inward currents than in currents evoked in PNs from controls. A1 layer 5 PNs showed tinnitus-related decreases in postsynaptic gamma-amino butyric acid (GABA) signaling suggestive of GABA-A receptors (GABA-ARs) subunit switches or loss of GABA-ARs. VIP neurons favoring excitation of layer 5 PNs via disinhibition, were depolarized with significantly lower current to evoke action potentials (rheobase current). The excitability of VIP neurons was significantly increased, with this increase being strongly correlated to the rat’s tinnitus score. Tinnitus-related changes in nAChR signaling were then tested in layer 5 PNs and VIP neurons. Both PNs and VIP neurons receive cholinergic input from basal forebrain and were highly sensitive to nicotinic stimulation. Optical stimulation of basal forebrain (BF) terminals evoked a depolarizing current from VIP neurons. In tinnitus animals, layer 5 PNs showed a significant loss of nAChR signaling, while, VIP neurons showed tinnitus-related increase in responses to nicotinic stimulation. Most of the nAChR responses in auditory cortex are believed to be mediated via volume transmission of acetylcholine (ACh). Continuous voltage clamped recordings were used to examine the activity of excitatory and inhibitory neurons impacting PNs in the presence of bath applied ACh. We observed significant tinnitus-related changes in nAChR signaling with layer 5 PNs showing significantly larger GABAergic input after prolonged bath application of ACh. This led us to hypothesize that desensitization of nAChRs could increase/normalize the activity of GABAergic input neurons. To test this hypothesis, nAChR partial desensitizing agonists sazetidine-A and varenicline were used in cellular and behavioral studies. Immediately after bath application of sazetidine-A or varenicline, a dramatic increase in the activity of inhibitory input neurons onto PNs was observed. In a behavioral tinnitus test, both sazetidine-A and varenicline were effective in lowering the tinnitus-like behavior. In conclusion, we identified a significant tinnitus-related disruption in intrinsic physiology of layer 5 PNs and VIP neurons, with strong evidence of dysregulated cholinergic signaling. Partial/desensitizing agonists sazetidine-A and varenicline increased the activity of inhibitory input neurons, showing therapeutic potential in both subcellular and behavioral studies.

<p>Dendritic spines are mushroom-shaped appendages on the dendritic branches of neurons. They are invaluable to the function of the brain as they form the major site for excitatory signal transmission in the mammalian brain. These ubiquitous structures have several invaluable and unique characteristics – namely that their morphological and functional characteristics are activity-dependent and undergo remodeling as the spine experiences stimulation. This activity-dependent regulation then in turn modulates the excitatory postsynaptic potential that propagates into the adjacent parent dendrite, and which ultimately reaches the somatic compartment. The mediation of this modulatory effect on the postsynaptic signal by dendritic spines renders them invaluable to the brain’s ability to change neuronal circuits as it learns. The relationship between the structural and functional change in dendritic spines as plasticity is induced remains poorly understood; while efforts have been made to examine the morphology of dendritic spines during plasticity as well as the change to receptor insertion on the postsynaptic density, a comprehensive methodology to interrogate the concomitant changes to several aspects of dendritic spine structure and function as plasticity occurs has not been established. In this study, such a methodology was developed in order to facilitate future study of how a dendritic spine’s diffusional neck resistance, head volume, calcium-sensitive channels (on the postsynaptic density), and excitatory postsynaptic potential amplitude change concurrently as the spine undergoes activity-dependent regulation. This activity-dependent regulation also occurs in groups of spines called “clusters” <em>in vivo</em>, and the structural and functional dynamics of spines as these groups are formed also remains unknown. In order to to facilitate future <em>in vivo</em> studies on how clustered dendritic spines may change dynamically in both structure and function, a methodology for surgically accessing and recording calcium-based activity from the primary auditory cortex was developed, as the frequency-specific tuning of dendritic spines in this cortical area forms a compelling environment in which to study the relationship between spine form and function. </p>

Tinnitus is a common and often severely disabling symptom that is characterized by the perceived sensation of sound in the absence of an external stimulus. Traditional treatment approaches have limited efficacy. It is assumed, that tinnitus is connected with dysfunctional activation of neuronal plasticity induced by altered sensory and somatosensory input. Adaptive neuroplastic processes alter the balance between excitatory and inhibitory function of the auditory system at several levels. Functional imaging studies in tinnitus patients have revealed increased neronal activity of primary auditory cortex (PAC). Repetitive transcranial magnetic stimulation (rTMS) induces changes of neuronal activity that outlast the stimulation period. Low-frequency rTMS over the PAC region results in a decrease of cortical activity by inducing long term depression (LTD) and leads to reduced tinnitus perception. The aim of this study was to assess in prospective randomized placebo- controlled study the ability of active low-frequency rTMS guided by frameless stereotaxy to affect symptoms of chronic tinnitus compared to placebo stimulation. Treatment outcome was assessed by subjective specific questionnaires; Tinnitus Handicap Inventory (THI), Tinnitus Questionnaire (TQ) and Visual analogue scales (VAS1, VAS2)...

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Cette thèse concerne l’anatomie macroscopique des gyri de Heschl (GH) en relation avec la Préférence Manuelle (PM) et la Spécialisation Hémisphérique (SH) pour le langage étudiée dans une base de données multimodale dédiée à l’étude de la SH (la BIL&GIN), équilibrée pour le sexe et la PM. Le GH, situé à la surface du lobe temporal, abrite l’aire auditive primaire. Des études ont montré que le volume du GH est asymétrique gauche, et que le GH gauche (GHG) covarie avec les performances phonologiques et avec la quantité de cortex dévolu au traitement temporel des sons, suggérant une relation entre GHG et SH pour le langage. Pourtant l’anatomie des GH, très variable en terme de gyrification, est mal connue. Nous avons : 1- Décrit la distribution inter-hémisphérique de la gyrification des GH sur les images IRM anatomiques de 430 sujets. 2- Etudié les variations de surface et d’asymétrie du premier gyrus ou GH antérieur (GHa), montré sa diminution en présence de duplication et l’existence d’une asymétrie gauche pour les configurations les plus fréquentes avec GHG unique. Les gauchers présentaient moins de duplications droites et une perte de l’asymétrie gauche de GHa. 3- Testé si la variance de l’anatomie du GH expliquait la variabilité interindividuelle des asymétries mesurées en IRM fonctionnel pendant une tâche d’écoute de mots chez 281 sujets, et si les différences anatomiques liées à la PM étaient en relation avec une diminution de la SH pour le langage des gauchers. La distribution du nombre de GH expliquait 11% de la variance de l’asymétrie fonctionnelle du GH, les configurations à GHG unique étant les plus asymétriques gauches, sans effet de la PM sur la latéralisation fonctionnelle du GH. / This thesis concerns the macroscopical anatomy of Heschl’s gyri (HG) in relation with Manual Preference (MP) and the Hemispheric Specialization (HS) for language studied in a multimodal database dedicated to the investigation of HS and balanced for sex and MP (BIL&GIN). HG, located on the surface of the temporal lobe, hosts the primary auditory cortex. Previous studies have shown that HG volume is leftward asymmetrical and that the left HG (LHG) covaries with phonological performance and with the amount of cortex dedicated to the processing of the temporal aspects of sounds, suggesting a relationship between LHG and HSL. However HG anatomy is highly variable and little known. In this thesis we have: 1- Described HG inter-hemispheric gyrification pattern on the anatomical MRI images of 430 healthy participants. 2- Studied the variation of the first or anterior HG (aHG) surface area and its asymmetry and shown its reduction in the presence of duplication and that its leftward asymmetry was present only in the case of a single LHG. Left-handers exhibited a lower incidence of right duplication and a loss of aHG leftward asymmetry. 3- Tested whether the variance of HG anatomy explained the interindividual variability of asymmetries measured with fMRI during the listening of a list of words in 281 participants, and whether differences in HG anatomy with MP were related to decreased HS for language in left-handers. HG inter-hemispheric gyrification pattern explained 11% of the variance of HG functional asymmetry, the patterns including a unique LHG being those with the strongest leftward asymmetry. There was no incidence of MP on HG functional lateralization.