The auditory temporal processing deficits associated with age-dependent hearing decline have been increasingly attributed to issues beyond peripheral hearing loss. Age-related hearing loss (ARHL), also known as presbycusis, is linked with changes in the expression of both excitatory and inhibitory neurotransmitters in the central auditory system. There are also age-related changes in the expression and function of the ion channels which mediate action potential firing. The slow, Ca2+ activated, K+ channels of the BK-type are essential in controlling both neurotransmitter release and neural communication via alteration of action potential durations, firing frequency, and neural adaptation. There are many subsets of this type of ion channel located throughout the body, and though it is evident that these channels are involved in cellular activation within the peripheral auditory system, little is known about their contribution to auditory processing in the brain. There is a need for further understanding of the functional involvement and mechanisms of neurotransmitter loss and how this relates to the BK channel and auditory disorders such as presbycusis and tinnitus (the perception of a phantom sound). My research focused on investigating how the downregulation of neurotransmitter production and the reductions in BK channel expression affect ARHL. I also evaluated a custom BK-channel modulating peptide as a path towards a possible therapeutic intervention for age-related hearing loss. This custom peptide is especially useful because it reduces the potential for serious side effects, due to mechanisms which best mimic natural occurring peptide systems. The initial investigation described in this dissertation measured auditory system changes in aged mice that occurred following a drug-induced increase in the availability of the inhibitory neurotransmitter GABA. This increase in GABA decreased minimum response thresholds in the auditory midbrain of aged mice, bringing them to levels seen in young adult animals. The other changes that occurred following increased GABA availability were increased acoustically driven neuronal firing rates, frequency-dependent decreases in spontaneous rates, and increases in the symmetry of the receptive fields. The return of clear and fine-tuned acoustically-evoked responses in aged mice was a major finding of this experiment. The second phase of the dissertation built on this demonstration that modulation of the aged auditory system was possible by changing neurotransmitter levels. This second portion of the study focused on how a novel potent neuropeptide (LS3), which increases the probability of the BK channel remaining in the closed conformational state, might invoke alterations in auditory-evoked responses. First, the LS3 neuropeptide was used to modify addictive behavior in the C. Elegans; followed by evaluation of in vitro changes to a human cell line. This study then confirmed that LS3 is a potent BK channel modulator with a greater affinity than those known toxins classified as high-affinity toxins. In vivo testing demonstrated that LS3 could rapidly cross the blood-brain barrier (BBB) following systemic injections, where it altered auditory evoked activity in a manner similar to that of the direct application to the dura over the midbrain. This work demonstrates that the BK channel is highly responsible for the control of auditory-evoked neurological processes, and that a potent BK channel modulator may be useful for the treatment of certain neurological disorders. The third study was designed to confirm that the BK channel plays an important role in sound-evoked activity generated in the auditory midbrain, by testing the effects of a general BK channel pore blocker, PAX. The results established that the BK channel is vital for sound processing in the midbrain of young adult mice, and is responsible for the maintenance of receptive field properties. I also evaluated the role it plays in temporal processing, which is an underlying mechanism for the processing of neurologically-relevant complex acoustic signals such as speech. Here, blocking of the channel increased (worsened) the threshold for the detection of a silent gap-in-noise and the neural recovery functions that occurred following the stimuli. The fourth study significantly expanded the in vivo testing of the custom peptide channel blocker, LS3, and added a behavioral measure of changes to auditory perception in addition to the electrophysiology recordings. The auditory-evoked receptive fields from midbrain neurons were modulated in a dose-dependent manner following the application of LS3. The neural recordings took place in the inferior colliculus, where the dorsal region responds to low-frequency sounds and ventral areas to high frequencies. The LS3-induced suppression or enhancement of evoked responses was different for the various tonotopic regions of the auditory midbrain. The improvements shown in receptive fields and improvement in auditory perception indicates a plausible route for direct translational treatment of auditory disorders through small custom peptide therapeutics. These studies provide supportive information about how auditory evoked responses in the midbrain, including the coding of different sound features, are affected by the down-regulation of a key inhibitory neurotransmitter (GABA), and how GABA-dependent neural evoked responses are altered in older mice through the modulation of BK channel activity.

The purpose of this thesis was to determine the neuronal circuitry mediating U50,488-induced locomotion in preweanling rats. To this end, preweanling rats received bilateral electrolytic lesions of the ventromedial thalamus or superior colliculus and, two days later, the same rats received a challenge injection of U50,488. It was predicted that bilateral lesions of the ventromedial thalamus or superior colliculus would attenuate the U50,488-induced locomotor activity of 18-day-old rats.

No description available.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23340号 / 生博第458号 / 新制||生||61(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 松田 道行, 教授 見学 美根子, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Ziel dieser Arbeit ist es, die funktionellen Eigenschaften von sechs Zellen des Colliculus superior zu analysieren. Diese Zellen wurden morphologisch rekonstruiert, und die Werte des Eingangswiderstandes und der Membranzeitkonstanten gemessen. Aus diesen beiden Werten und der Morphologie der Zelle wurden die elektrischen Parameter der Zellen bestimmt. Für die dabei erhaltenen Parameterkombinationen wurden Abschwächungnen und Verzögerungen von Signalen innerhalb der Zelle berechnet. Die dabei ermittelten Werte wurden itteinander verglichen, um festzustellen ob die Zellen in Gruppen entsprechend ihrer Morphologie und anatomischen Lage eingeteilt werden können. Aufgrund der erhaltenen Ergebnisse wurde weiterhin untersucht welche Art der Informationsverarbeitung diese Zellen durchführen können.

<div> <p>Half of people over 75 in the United States suffer from age related hearing loss and have trouble understanding speech in a noisy background. Even older adults who have normal pure tone audiograms can have trouble understanding speech in a noisy background. Speech is a complex sound and therefore sounds more complex than pure tones are required to understand the differences in processing noisy speech in young and aged individuals. Band passed noise is easily controlled and is more complex than pure tones making it better stimulus for testing. The first place in the ascending auditory pathway that does complex processing is the inferior colliculus. Single unit recordings from the inferior colliculus of young and aged F344 rats were preformed using half octave band passed noise and pure tones. Firing rates, first spike latencies, the number of tuning peaks, normalized peak slope, bandwidth, and Q factors were all evaluated for each unit in response to band passed noise. For 54 of the units their responses to pure tones were also collected. Out of 286 units recorded from young animals, 218 were responsive and 178 of them had a band passed response. Out of 193 aged units, 145 were responsive and 134 had a band passed response. Young units had a significantly higher total firing rate (p = 0.008) and bandwidth (p = 0.004). The normalized peak slopes and Q factors were significantly lower in young units indicating sharper tuning in the aged units. Pure tones elicited a stronger response than band passed noise however, for many units the best frequency was similar for both stimuli. These results show that aged units are less responsive to stimuli containing multiple frequencies which may help explain why older adults have trouble understanding noisy speech. </p> </div> <br>

Hearing loss of various types is increasingly plaguing our modern world (Geneva: World Health Organization 2018). As the life expectancy increased in the industrialized world, age-related hearing loss (ARHL) has become more prevalent. The wars and terrorism of the modern world also created a significant body of blast-induced hearing loss (BIHL) patients. Both types of hearing loss present significant challenges for listeners even at suprathreshold sound levels. However, increasing bodies of clinical and laboratory evidence have suggested that the difficulties in the processing of time-varying auditory features in speech and other natural sounds may not be sufficiently diagnosed by threshold changes and simple auditory electrophysiological measures (Snell and Frisina 2000; Saunders et al. 2015; Bressler et al. 2017; Guest et al. 2018).<br>Studies have emphasized that excitatory/inhibitory neurotransmission imbalance plays important roles in ARHL (Caspary et al. 2008) and may also be key in BIHL, as hinted by the strong presence of GABA regulation in non-blast TBI (O’Dell et al. 2000; Cantu et al. 2015; Guerriero et al. 2015). The current studies focus on age-related and blast-induced hearing deficits by examining changes in the processing of simple, brief stimuli and complex, sustained, temporally modulated sounds.<br>Through post hoc circular analysis of single-unit, in vivo recording of young and aged inferior colliculus (IC) neurons responding to amplitude modulation (AM) stimuli and modulation depth changes, we observed evidence of central compensation in the IC manifesting as increased sensitivity to presynaptic input, which was measured via local field potentials (LFPs). We also found decreased sensitivity to decreasing modulation depth. Age-related central gain in the IC single units, while preserving and even overcompensating for temporal phase coding in the form of vector strength, was unable to make up for the loss of envelope shape coding.<br>Through careful, longitudinal measurements of auditory evoked potential (AEP) responses towards simple sounds, AM and speech-like iterated rippled noise (IRN), we documented the development and recovery of BIHL induced by a single mild blast in a previously established (Song et al. 2015; Walls et al. 2016; Race et al. 2017) rat blast model over the course of two months. We identified crucial acute (day 1-4 post-exposure) and early recovery (day 7-14) time windows in which drastic changes in electrophysiology take place. Challenging conditions and broadband, speech-like stimuli can better elucidate mild bTBI-induced auditory deficits during the sub-acute period. The anatomical significance of the aforementioned time windows was demonstrated with immunohistochemistry methods, showing two distinct waves of GABA inhibitory transmission changes taking place in the auditory brainstem, the IC, and the auditory thalamus. These changes were in addition to axonal and oxidative damage evident in the acute phase. We examined the roles and patterns of excitatory/inhibitory imbalance in BIHL, its distinction compared to that of ARHL, and demonstrated the complexity of its electrophysiological consequences. Blast traumatizes the peripheral auditory system and auditory brainstem, evident through membrane damage and acrolein-mediated oxidative stress. These initial traumas kickstart a unique, interlocking cascade of excitatory/inhibitory imbalances along the auditory neuraxis that is more complex and individually varied than the gradual, non-traumatic degradations in ARHL. Systemic treatment with the FDA-approved acrolein scavenger Hydralazine (HZ) was attempted with limited effects.<br>Taken together, the current study provided insights into the similarities and distinctions between the mechanisms of ARHL and BIHL and called for innovative and individual diagnostic and therapeutic measures.<br>

No description available.

本研究では、聴覚神経系で入力の統合を担う下丘におけるシナプス伝達特性の生後発達段階における変化について、シナプス電流をパッチクランプ法で計測した。NMDA-EPSCにおいて、聴覚入力開始後に減衰時間が短縮していた。上行性経路からのシナプス伝達では、発達段階に応じて短期シナプス可塑性が変化した。一方で、交連性経路からのシナプス伝達では、発達段階に伴う短期シナプス可塑性の傾向には有意な変化はなかった。 / The inferior colliculus (IC) is the primal center of convergence and integration in the auditory pathway. I have measured excitatory synaptic currents (EPSCs) of the neurons in the central nucleus of the IC in response to stimulation of the lateral lemniscus and the commissure of the IC. Before hearing onset, the lemniscus inputs exhibited short-term depression, whereas commissural inputs showed facilitation. After hearing onset, the NMDA-EPSCs exhibited faster decay for both pathways. Furthermore, the EPSCs showed less short-term plasticity in both pathways. These developmental changes may ensure faster and more reliable signal transmission to the IC after onset of hearing. / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

As theoretical neuroscience has grown as a field, machine learning techniques have played an increasingly important role in the development and evaluation of theories of neural computation. Today, machine learning is used in a variety of neuroscientific contexts from statistical inference to neural network training to normative modeling. This dissertation introduces machine learning techniques for use across the various domains of theoretical neuroscience, and the application of these techniques to build theories of neural circuits. First, we introduce a variety of optimization techniques for normative modeling of neural activity, which were used to evaluate theories of primary motor cortex (M1) and supplementary motor area (SMA). Specifically, neural responses during a cycling task performed by monkeys displayed distinctive dynamical geometries, which motivated hypotheses of how these geometries conferred computational properties necessary for the robust production of cyclic movements. By using normative optimization techniques to predict neural responses encoding muscle activity while ascribing to an “untangled” geometry, we found that minimal tangling was an accurate model of M1. Analyses with trajectory constrained RNNs showed that such an organization of M1 neural activity confers noise robustness, and that minimally “divergent” trajectories in SMA enable the tracking of contextual factors. In the remainder of the dissertation, we focus on the introduction and application of deep generative modeling techniques for theoretical neuroscience. Specifically, both techniques employ recent advancements in approaches to deep generative modeling -- normalizing flows -- to capture complex parametric structure in neural models. The first technique, which is designed for statistical generative models, enables look-up inference in intractable exponential family models. The efficiency of this technique is demonstrated by inferring neural firing rates in a log-gaussian poisson model of spiking responses to drift gratings in primary visual cortex. The second technique is designed for statistical inference in mechanistic models, where the inferred parameter distribution is constrained to produce emergent properties of computation. Once fit, the deep generative model confers analytic tools for quantifying the parametric structure giving rise to emergent properties. This technique was used for novel scientific insight into the nature of neuron-type variability in primary visual cortex and of distinct connectivity regimes of rapid task switching in superior colliculus.