Anxiety disorders

Anxiety is a normal phenomenon that represents an ‘alarm system’, which allows preparation of physical and psychological responses to a perceived threat or danger (the ‘fight-or-flight’ response). Anxiety is usually appropriate, short-lived and controllable. When anxiety is present inappropriately, and its symptoms are abnormally severe, persistent and impair physical, social or occupational functioning, an ‘anxiety disorder’ can be diagnosed. In this section, we summarise what is known about the aetiology and neurobiology of the anxiety disorders included in the International Classification of Diseases, 11th edition (ICD-11) classification of mental disorders: generalised anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social anxiety disorder and separation anxiety disorder [1]. As there is significant overlap in the neurobiology of these disorders, we discuss the anxiety disorders as a whole, highlighting specific aspects where relevant. Characteristic features of the anxiety disorders are shown in Table 9.4.1

Understanding the relationship between the perineuronal net and glia within the auditory pathway in a mouse model of age-related hearing loss

Age-related hearing loss (ARHL) affects over 11 million people in the UK and ~50% of over 75yr olds. Although hearing loss is often perceived as an inconsequential part of aging, there is evidence it is important in general brain health. Adults with ARHL develop significant impairments in their cognitive abilities 3 years sooner and 30-40% more severely than those with normal hearing. The severity of ARHL is associated with a greater risk (2-5 fold) of developing dementia. Hearing aids and cochlear implants improve quality of life for many individuals however there are no approved therapies to prevent or slow ARHL. This is likely due to inadequate understanding of the neurobiological changes underling the progression of this chronic debilitating condition. In a murine model of ARHL, we have observed changes within the auditory pathway in both the perineuronal net (PNN) and glia.We hypothesise that the loss of sensory input to the auditory nerve in ARHL may induce compensatory changes to the PNN to alter neuronal activity and synaptic plasticity. Such changes may contribute to a pathological glial response making the auditory pathway more vulnerable to inflammation and progression of hearing loss.The auditory circuit is modulated by synaptic inhibition to maintain temporal precision and process sound localization cues. The majority of fast-spiking interneurons associated with this inhibition are surrounded by a specialized extracellular matrix, the PNN. The PNN is important for synaptic stabilization, protects against glial activation and pathological insults and has restrictive effects on plasticity in the mature CNS.Here we exploit the well-characterized C57BL/6J mouse model of ARHL, to assess changes in expression and localization of the PNN and glial cells across the life-course and in disease progression. We have found changes in expression of the PNN during progression of hearing loss. We also observe changes in the organization and phenotype of microglia and astrocytes in the auditory pathway.Gaining a better understanding of the pathological processes involved in progression of ARHL may identify cellular or molecular compartments amenable to modulation. For example tempering the glial response and associated changes in the PNN may slow disease progression and help retain auditory function for longer. ARHL is associated with increased risk of developing dementia and exacerbating cognitive decline. Therapies that modulate ARHL could therefore be significant in the treatment of dementia and related neurodegenerative conditions

Investigating immune priming in the auditory system as a cause of variable outcomes after cochlear implantation

AimDespite the huge success of cochlear implants (CIs), our evidence shows some individuals have less favorable outcomes with their CI either immediately after implantation or in the subsequent years following surgery. We hypothesise that one source of variability arises from the priming of innate immune cells, in response to inflammatory insults. Priming describes a change whereby these cells exhibit an exaggerated inflammatory response to a second stimulus having previously been exposed to an initial ‘trigger’ stimulus. Using mouse models, we aim to investigate whether a primary insult likely experienced by CI patients such as noise-exposure or surgical insertion of the implant itself, causes priming of the innate immune cells; macrophages and microglia. Additionally, we will investigate whether the combination of pre-exposure to a primary insult and then cochlear implantation leads to a heightened inflammatory response upon this secondary insult; which could lead to the less favourable outcomes seen in CI users. Method Mice will be exposed to varying primary insults such a noise-exposure (octave band noise 8-16 kHz 100 dB SPL for 2 hours) and cochlear implantation (with CIs supplied by Oticon medical). Electrodes designed of different materials including pure silicon and platinum (+PEDOT and +PEDOT and dexamethasone) will be implanted into CBA mice to determine variation in the overall inflammation in the tissue surrounding the electrode. Any evidence of metal shedding from the electrode will also be investigated using immunostaining.Tissue will be collected, processed and sectioned to enable immunohistochemical analysis after each primary insult, with the aim to measure and characterise the presence and phenotype of the innate immune cells in close proximity to the electrode and along the auditory pathway. Biomedical imaging will be used to support this. We will then measure whether the addition of a secondary insult leads to an exaggerated inflammatory response by measuring cytokine production. Results In the noise-exposed mouse model, ABR recordings have shown an increase in threshold post-exposure compared to control, indicating functional damage to hearing function. Immunohistochemical staining has confirmed the presence and identified the morphology of microglia/macrophages in key regions of the cochlea and auditory pathway, suggesting these cells may experience a change in phenotype in response to an immune challenge such as implantation. The expression of genes involved in the activation and signalling of the cells will be measured by RNAscope to further characterise their phenotype In the CI model, surgical technique and implant design are being continually optimised to ensure correct insertion and successful recovery of the mice. This will ensure sufficient time for the inflammatory response to occur before obtaining the tissue for analysis. CT scanning has provided detailed, structural 3D information about the cochlea pre-implantation and will be used as a method to validate our surgical technique post-implantation. Conclusion For CI users, life-long success with their implant is pivotal to enable the connection and communication with the world around them. Our group believes that the lifestyle choices we make and the impact this has on our immune system, could play a role in how individuals succeed with their CIs. Gaining a better understanding of the immune response to cochlear implantation in the auditory system through the use of mouse models, presents an opportunity to develop clinical biomarkers which could allow early identification of individuals with an increased inflammatory status. This would initiate the appropriate anti-inflammatory interventions to optimise CI performance. Additionally, it would support the optimisation of electrode design to ultimately improve long-term hearing performance and ensure positive patient outcomes for life.<br/