Regulation of auditory plasticity during critical periods and following hearing loss

Sensory input has profound effects on neuronal organization and sensory maps in the brain. The mechanisms regulating plasticity of the auditory pathway have been revealed by examining the consequences of altered auditory input during both developmental critical periods—when plasticity facilitates the optimization of neural circuits in concert with the external environment—and in adulthood—when hearing loss is linked to the generation of tinnitus. In this review, we summarize research identifying the molecular, cellular, and circuit-level mechanisms regulating neuronal organization and tonotopic map plasticity during developmental critical periods and in adulthood. These mechanisms are shared in both the juvenile and adult brain and along the length of the auditory pathway and serve to regulate disinhibitory networks, synaptic structure and function, as well as structural barriers to plasticity. Regulation of plasticity also involves both neuromodulatory circuits, which link plasticity with learning and attention, as well as ascending and descending auditory circuits, which link the auditory cortex and lower structures. Further work identifying the interplay of molecular and cellular mechanisms associating hearing loss induced plasticity with brain changes observed as part of tinnitus should advance strategies to treat tinnitus by molecularly modulating plasticity

Sensory sensitivity as a link between concussive traumatic brain injury and PTSD.

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity

Diffusion tensor imaging reveals changes in the adult rat brain following long-term and passive moderate acoustic exposure

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Dissecting the neuronal basis of threat responding in mice

Environmental threats demand adaptive defensive responses of an organism that ensure its survival. Extreme stressors, however, can unbalance stress homeostasis and lead to long-term changes that impair appropriate defensive behaviors and emotional responses. In my thesis, I assessed (1) the interaction of two stress-related neuromodulatory systems, (2) the effects of a traumatic incident on brain volume and hyperarousal, and (3) sonic vocalization as a defensive behavior in mice, and discussed the topics in three independent studies.In the first study, I evaluated the interaction of two regulatory systems with respect to fear, anxiety, and trauma-related behaviors. Although the endocannabinoid and the corticotropin-releasing factor (CRF) systems are well described in modulating stressrelatedresponses, the direct interaction of both systems remained poorly understood. The generation of a new conditional knockout mouse line that selectively lacked the expression of the cannabinoid type 1 (CB1) receptor in CRF-positive neurons presented no differences in various tests of fear and anxiety-related behaviors under basal conditions or after a traumatic event. Also stress hormone levels were unaffected. However, male knockout animals exhibited a significantly increased acoustic startle response thus suggesting a specific involvement of CB1-CRF interactions in controlling arousal.In the second study, I assessed the consequences of a traumatic experience on behavior and grey matter volume in mice. Whole-brain deformation-based morphometry (DBM) by means of magnetic resonance imaging (MRI) after incubation of a traumatic incident showed changes in the dorsal hippocampus and the reticular nucleus. Using the severity of hyperarousal as regressor for cross-sectional volumetric differences between traumatized mice and controls revealed a negative correlation with the dorsal hippocampus. Further, longitudinal analysis including volumetric measurements before and after the traumatic incident showed that volume reductions in the globus pallidus reflect trauma-related changes in hyperarousal severity.In the third study, I characterized sonic vocalization as a defensive behavior in mice. Mice bred for high anxiety-related behavior (HAB) were found to have a high disposition to emit audible squeaks when taken by the tail which was not the case for any of the other five mouse lines tested. The calls emitted had a fundamental frequency of 3.8 kHz and were shown to be sensitive to anxiolytic but not panicolytic compounds. Manganese-enhanced MRI (MEMRI) scans pointed towards an increased tonic activity, among others, in the periaqueductal grey (PAG). Inhibition of the dorsal PAG by muscimol not only completely abolished sonic vocalization, but also reduced anxiety-like behavior. This suggests that sonic vocalization of mice is related to anxiety and controlled by the PAG. To explore the ecological relevance of defensive vocalization, I performed playback experiments with conspecifics and putative predators. Squeaks turned out to be aversive to HAB mice but became appetitive to both mice and rats when a stimulus mouse was present during playback.Collectively, the results of this thesis provide novel insights into fear and anxiety-related behaviors and shine light onto their mechanistic basis and ecological relevance

Auditory Cues in Social Transmission of Fear

When an animal faces a threat, both behavioral and physiological changes occur that promote the avoidance of the menace. Individuals in the surroundings of the fearful animal (both con and heterospecifics) may detect some of these changes, that become cues that signal an impending danger. The detection of such cues can therefore trigger defense behaviors in observers, in a phenomenon called Social Transmission of Fear.(...)Fundação ChampalimaudFundação BialInstituto Gulbenkian de Ciênci

MULTIMODAL ASSESSMENT OF CETACEAN CENTRAL NERVOUS AUDITORY PATHWAYS WITH EMPHASIS ON FORENSIC DIAGNOSTICS OF ACOUSTIC TRAUMA

Cetaceans encompass some of the world’s most enigmatic species, with one of their greatest adaptations to the marine environment being the ability to “see” by hearing. Their anatomy and behavior are fine-tuned to emit and respond to underwater sounds, which is why anthropogenic noise pollution is likely to affect them negatively. There are many effects of noise on living organisms, and while knowledge on their entire palette and interplay remain incomplete, evidence for insults ranging from acoustic trauma over behavioral changes, to masking and stress, is accumulating. Humans are subject to peak interest in terms of medical research on noise-induced hearing loss. As major health concerns can be expected across species, addressing this problem in free-ranging cetacean populations will lead to a more sustainable management of marine ecosystems, more effective and balanced policies, and successes in conservation. While progress has been made in behavioral monitoring, electrophysiological hearing assessments and post-mortem examination of the inner ear of cetaceans, but very little is known about the neurochemical baseline and neuropathology of their central auditory pathways. In the present work, we reviewed the known effects of sound on cetaceans in both wild and managed settings and explored the value of animal models of neurodegenerative disease. We began by evaluating a row of antibodies associated with neurodegeneration in a more readily available species, the dog, where acute neurological insult could be derived from clinical history. We then set out to systematically validate a key panel of protein biomarkers for the assessment of similar neurodegenerative processes of the cetacean central nervous system. For this, we developed protocols to adequately sample cetacean auditory nuclei, optimized the immunohistochemical workflow, and used Western blot and alignment of protein sequences between the antigen targeted by our antibodies and the dolphin proteome. A Histoscore was used to semi-quantitively categorize immunoreactivity patterns and dolphins by age and presence of pathology. First results indicated significant differences both between sick and healthy, and young and old animals. We then expanded our list of validated antibodies for use in the bottlenose dolphin and the techniques used to assess them in a multimodal, quantitative way. 7T-MRI and stereology were implemented to assess the neuronal, axonal, glial and fiber tract counts in the inferior colliculus and ventral cochlear nucleus of a healthy bottlenose dolphin, which created a baseline understanding of protein expression in these structures, and the influence of tissue processing. This will make a valuable comparison for when positive controls of acoustic trauma would become available. Furthermore, we explored the connectome and neuronal morphology of auditory nuclei and experimented with probe designs and machine learning algorithms to quantify structures of interest. Comparisons with pathological human brains revealed similarities in the configuration of extracellular matrix components to those of a healthy dolphin, in line with existing knowledge on the tolerance to hypoxia in these diving animals. This could have interesting implications in future investigation of the evolutionary development of marine mammal brains, as well as help diversify out-of-the-box approaches to researching human neurodegenerative disease, as is being done with hibernating species. The data and methodologies described herein contribute to the knowledge on neurochemical signature of the cetacean central nervous system. They are intended to facilitate understanding of auditory and non-auditory pathology and build an evidence-based backbone to future policies regarding noise and other form of anthropogenic threats to the marine environment.Cetaceans encompass some of the world’s most enigmatic species, with one of their greatest adaptations to the marine environment being the ability to “see” by hearing. Their anatomy and behavior are fine-tuned to emit and respond to underwater sounds, which is why anthropogenic noise pollution is likely to affect them negatively. There are many effects of noise on living organisms, and while knowledge on their entire palette and interplay remain incomplete, evidence for insults ranging from acoustic trauma over behavioral changes, to masking and stress, is accumulating. Humans are subject to peak interest in terms of medical research on noise-induced hearing loss. As major health concerns can be expected across species, addressing this problem in free-ranging cetacean populations will lead to a more sustainable management of marine ecosystems, more effective and balanced policies, and successes in conservation. While progress has been made in behavioral monitoring, electrophysiological hearing assessments and post-mortem examination of the inner ear of cetaceans, but very little is known about the neurochemical baseline and neuropathology of their central auditory pathways. In the present work, we reviewed the known effects of sound on cetaceans in both wild and managed settings and explored the value of animal models of neurodegenerative disease. We began by evaluating a row of antibodies associated with neurodegeneration in a more readily available species, the dog, where acute neurological insult could be derived from clinical history. We then set out to systematically validate a key panel of protein biomarkers for the assessment of similar neurodegenerative processes of the cetacean central nervous system. For this, we developed protocols to adequately sample cetacean auditory nuclei, optimized the immunohistochemical workflow, and used Western blot and alignment of protein sequences between the antigen targeted by our antibodies and the dolphin proteome. A Histoscore was used to semi-quantitively categorize immunoreactivity patterns and dolphins by age and presence of pathology. First results indicated significant differences both between sick and healthy, and young and old animals. We then expanded our list of validated antibodies for use in the bottlenose dolphin and the techniques used to assess them in a multimodal, quantitative way. 7T-MRI and stereology were implemented to assess the neuronal, axonal, glial and fiber tract counts in the inferior colliculus and ventral cochlear nucleus of a healthy bottlenose dolphin, which created a baseline understanding of protein expression in these structures, and the influence of tissue processing. This will make a valuable comparison for when positive controls of acoustic trauma would become available. Furthermore, we explored the connectome and neuronal morphology of auditory nuclei and experimented with probe designs and machine learning algorithms to quantify structures of interest. Comparisons with pathological human brains revealed similarities in the configuration of extracellular matrix components to those of a healthy dolphin, in line with existing knowledge on the tolerance to hypoxia in these diving animals. This could have interesting implications in future investigation of the evolutionary development of marine mammal brains, as well as help diversify out-of-the-box approaches to researching human neurodegenerative disease, as is being done with hibernating species. The data and methodologies described herein contribute to the knowledge on neurochemical signature of the cetacean central nervous system. They are intended to facilitate understanding of auditory and non-auditory pathology and build an evidence-based backbone to future policies regarding noise and other form of anthropogenic threats to the marine environment

The hearing hippocampus

The hippocampus has a well-established role in spatial and episodic memory but a broader function has been proposed including aspects of perception and relational processing. Neural bases of sound analysis have been described in the pathway to auditory cortex, but wider networks supporting auditory cognition are still being established. We review what is known about the role of the hippocampus in processing auditory information, and how the hippocampus itself is shaped by sound. In examining imaging, recording, and lesion studies in species from rodents to humans, we uncover a hierarchy of hippocampal responses to sound including during passive exposure, active listening, and the learning of associations between sounds and other stimuli. We describe how the hippocampus' connectivity and computational architecture allow it to track and manipulate auditory information – whether in the form of speech, music, or environmental, emotional, or phantom sounds. Functional and structural correlates of auditory experience are also identified. The extent of auditory-hippocampal interactions is consistent with the view that the hippocampus makes broad contributions to perception and cognition, beyond spatial and episodic memory. More deeply understanding these interactions may unlock applications including entraining hippocampal rhythms to support cognition, and intervening in links between hearing loss and dementia

Development and Plasticity of Intrinsic Connectivity in the Central Nucleus of the Mouse Inferior Colliculus

Proper brain function depends upon the precise organization of neural circuits. In the central auditory system, accurate acoustic processing depends upon the assembly and preservation of tonotopically-organized networks of excitatory and inhibitory synaptic connections. In this thesis, we investigated the development and plasticity of intrinsic synaptic circuitry in the central nucleus of the mouse inferior colliculus (CNIC), a tonotopically-organized midbrain nucleus that serves as the major subcortical center for auditory integration. In the CNIC, intrinsic connections comprise the majority of synapses, yet the functional organization of these local networks has remained largely obscure. In Chapter 2, we mapped the functional organization of intrinsic connections in the CNIC during the first three weeks of postnatal development. We found evidence of robust excitatory and inhibitory intrinsic connections already at postnatal day 2 (P2). Excitatory and inhibitory intrinsic connections underwent a period of dramatic refinement after hearing onset, resulting in a predominance of intrinsic inhibition. In Chapter 3, we examined the role of hearing experience in directing the maturation of intrinsic CNIC circuits by rearing mice in pulsed white noise. We found that pulsed noise delivered from P12-25, but not P19-25, led to a profound reorganization of excitatory and inhibitory intrinsic connections received by both glutamatergic and GABAergic neurons, suggesting that intrinsic CNIC circuits are sculpted by acoustic experience during an early critical period. In Chapter 4, we investigated the effects of hearing-loss on the organization of CNIC circuits in a mouse model of tinnitus. We found that hearing loss led to reorganizations of excitatory and inhibitory local CNIC circuits, the nature of which correlated with the presence or absence of behavioral evidence of tinnitus. Acoustic enrichment with pulsed white noise delivered immediately after acoustic trauma prevented circuit reorganization and the emergence of behavioral signs of tinnitus. In addition to providing the first characterization of functional intrinsic connectivity in the auditory midbrain, our findings may also have broader implications for the principles that govern the organization and balance of excitatory and inhibitory networks in subcortical circuits. Our findings also have potentially important clinical implications for the prevention and treatment of tinnitus

Early Stage Alterations in White Matter and Decreased Functional Interhemispheric Hippocampal Connectivity in the 3xTg Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD