Combining Sensory Information in the Mammalian Temporal Lobe: Approaching realism in audiovisual integration, spatial perception, and comparative neurophysiology

The temporal lobe of the mammalian brain receives and processes information from the visual and auditory system. In primates, the inferior temporal lobe is particularly important for the processing of high-level visual form information including regions, which respond specifically to faces, termed face patches. However, some of these face patches sit in the superior temporal sulcus (STS), which is a zone of convergence for different kinds of visual and auditory afferent connections. Similarly, visual regions near the auditory cortex in ferrets also contain widespread connections to different kinds of auditory and visual regions. This thesis aims to investigate and further understand the convergence of these sensory inputs and how single neurons in the temporal lobe can combine auditory, visual, social, and spatial information. Following a table of contents in chapter 1, chapter 2 reviews the literature exploring functions that the temporal cortex subserves across both primates and carnivores including form-based vision, 3D vision, audiovisual integration, and the potential combination of these functions. Chapter 3 describes experiments, which discovered, for the first time, that neurons in an STS face patch showed acoustic modulation of visual signals and even responses to auditory stimulus alone. Chapter 4 focuses on visual processing, which revealed that neurons in the same face patch were tuned not to retinal angle but the physical size of a face, indicating that spatial information combines with form visual information in this region. Chapter 5 combines these two approaches to examine how spatial manipulations influence the audiovisual responses in this region. Chapter 6 then takes a comparative approach detailing experiments that uncovered face and body selective neurons in ferret visual regions. Finally, chapter 7 synthesize these results and details future experiments that further explore the relationship of audiovisual integration and space as well the comparative functions of the temporal lobe

Age-related macular degeneration: a disease of systemic or local complement dysregulation?

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement activation in association with AMD. It is unclear which one is the primary driver of disease. This has important implications for designing novel complement-based AMD therapies. We present a summary of the current literature and suggest that intraocular rather than systemic modulation of complement may prove more effective

Audiovisual integration in macaque face patch neurons

Primate social communication depends on the perceptual integration of visual and auditory cues, reflected in the multimodal mixing of sensory signals in certain cortical areas. The macaque cortical face patch network, identified through visual, face-selective responses measured with fMRI, is assumed to contribute to visual social interactions. However, whether face patch neurons are also influenced by acoustic information, such as the auditory component of a natural vocalization, remains unknown. Here, we recorded single-unit activity in the anterior fundus (AF) face patch, in the superior temporal sulcus, and anterior medial (AM) face patch, on the undersurface of the temporal lobe, in macaques presented with audiovisual, visual-only, and auditory-only renditions of natural movies of macaques vocalizing. The results revealed that 76% of neurons in face patch AF were significantly influenced by the auditory component of the movie, most often through enhancement of visual responses but sometimes in response to the auditory stimulus alone. By contrast, few neurons in face patch AM exhibited significant auditory responses or modulation. Control experiments in AF used an animated macaque avatar to demonstrate, first, that the structural elements of the face were often essential for audiovisual modulation and, second, that the temporal modulation of the acoustic stimulus was more important than its frequency spectrum. Together, these results identify a striking contrast between two face patches and specifically identify AF as playing a potential role in the integration of audiovisual cues during natural modes of social communication

Chlamydia infection status, genotype, and age-related macular degeneration

PURPOSE: To evaluate whether Chlamydia (C.) infections are associated with age-related macular degeneration (AMD) and to assess if this association is influenced by the complement factor H (CFH) Y402H or the high temperature requirement A serine peptidase 1 (HTRA1) rs11200638 risk genotypes.METHODS: One hundred ninety-nine AMD patients with early and late forms of the disease and 100 unaffected controls, at least 50 years old were included in the study. Patients in the AMD and control groups were selected based on known CFH Y402H variant genotype status (one third homozygous CC, one third heterozygous CT, and one third wild-type TT). Plasma from all patients and controls was tested for C. pneumoniae, C. trachomatis, and C. psittaci IgG seropositivity using a micro-immunofluorescent assay to establish previous infection status. Assays were conducted blind to risk genotypes and the results analyzed using univariate and multivariate (logistic regression) analysis.RESULTS:IgG seropositivity to C. pneumoniae was most prevalent (69.2%, n=207), followed by C. trachomatis (7.4%, n=22) and C. psittaci (3.3%, n=10). No association was found between each of the three Chlamydia species IgG seropositivity and AMD status or severity (early/late). There was also no significant association between Chlamydia species IgG seropositivity and AMD status or severity, in patients carrying at least one CFH Y402H risk allele (C) or HTRA1 rs11200638 risk allele (A), with univariate or logistic regression analysis. CONCLUSIONS:Chlamydia infection status does not appear to be associated with AMD status or severity. The presence of CFH Y402H and HTRA1 rs11200638 risk genotypes does not alter this negative association

Transcriptome changes in age-related macular degeneration

Age-related macular degeneration (AMD) is a debilitating, common cause of visual impairment. While the last decade has seen great progress in understanding the pathophysiology of AMD, the molecular changes that occur in eyes with AMD are still poorly understood. In the current issue of Genome Medicine, Newman and colleagues present the first systematic transcriptional profile analysis of AMD-affected tissues, providing a comprehensive set of expression data for different regions (macula versus periphery), tissues (retina versus retinal pigment epithelium (RPE)/choroid), and disease state (control versus early or advanced AMD). Their findings will serve as a foundation for additional systems-level research into the pathogenesis of this blinding disease

Modulation of the rod outer segment aerobic metabolism diminishes the production of radicals due to light absorption

Oxidative stress is a primary risk factor for both inflammatory and degenerative retinopathies. Our previous data on blue light-irradiated retinas demonstrated an oxidative stress higher in the rod outer segment (OS) than in the inner limb, leading to impairment of the rod OS extra-mitochondrial aerobic metabolism. Here the oxidative metabolism and Reactive Oxygen Intermediates (ROI) production was evaluated in purified bovine rod OS in function of exposure to different illumination conditions. A dose response was observed to varying light intensities and duration in terms of both ROI production and ATP synthesis. Pretreatment with resveratrol, inhibitor of F1Fo-ATP synthase, or metformin, inhibitor of the respiratory complex I, significantly diminished the ROI production. Metformin also diminished the rod OS Complex I activity and reduced the maximal OS response to light in ATP production. Data show for the first time the relationship existing in the rod OS between its -aerobic- metabolism, light absorption, and ROI production. A beneficial effect was exerted by metformin and resveratrol, in modulating the ROI production in the illuminated rod OS, suggestive of their beneficial action also in vivo. Data shed new light on preventative interventions for cone loss secondary to rod damage due to oxidative stress

Analysis of copy number variation at DMBT1 and age-related macular degeneration

BACKGROUND: DMBT1 is a gene that shows extensive copy number variation (CNV) that alters the number of bacteria-binding domains in the protein and has been shown to activate the complement pathway. It lies next to the ARMS2/HTRA1 genes in a region of chromosome 10q26, where single nucleotide variants have been strongly associated with age-related macular degeneration (AMD), the commonest cause of blindness in Western populations. Complement activation is thought to be a key factor in the pathogenesis of this condition. We sought to investigate whether DMBT1 CNV plays any role in the susceptibility to AMD. METHODS: We analysed long-range linkage disequilibrium of DMBT1 CNV1 and CNV2 with flanking single nucleotide polymorphisms (SNPs) using our previously published CNV and HapMap Phase 3 SNP data in the CEPH Europeans from Utah (CEU). We then typed a large cohort of 860 AMD patients and 419 examined age-matched controls for copy number at DMBT1 CNV1 and CNV2 and combined these data with copy numbers from a further 480 unexamined controls. RESULTS: We found weak linkage disequilibrium between DMBT1 CNV1 and CNV2 with the SNPs rs1474526 and rs714816 in the HTRA1/ARMS2 region. By directly analysing copy number variation, we found no evidence of association of CNV1 or CNV2 with AMD. CONCLUSIONS: We have shown that copy number variation at DMBT1 does not affect risk of developing age-related macular degeneration and can therefore be ruled out from future studies investigating the association of structural variation at 10q26 with AMD

Genetic polymorphism of the iron-regulatory protein-1 and -2 genes in age-related macular degeneration

Iron can be involved in the pathogenesis of AMD through the oxidative stress because it may catalyze the Haber–Weiss and Fenton reactions converting hydrogen peroxide to free radicals, which can induce cellular damage. We hypothesized that genetic polymorphism in genes related to iron metabolism may predispose individuals to the development of AMD and therefore we checked for an association between the g.32373708 G>A polymorphism (rs867469) of the IRP1 gene and the g.49520870 G>A (rs17483548) polymorphism of the IRP2 gene and AMD risk as well as the modulation of this association by some environmental and life-style factors. Genotypes were determined in DNA from blood of 269 AMD patients and 116 controls by the allele-specific oligonucleotide-restriction fragment length polymorphism and the polymerase chain reaction-restriction fragment length polymorphism. An association between AMD, dry and wet forms of AMD and the G/G genotype of the g.32373708 G>A-IRP1 polymorphism was found (OR 3.40, 4.15, and 2.75). On the other hand, the G/A genotype reduced the risk of AMD as well as its dry or wet form (OR 0.23, 0.21, 0.26). Moreover, the G allele of the g.49520870 G>A-IRP2 polymorphism increased the risk of the dry form of the disease (OR 1.51) and the A/A genotype and the A allele decreased such risk (OR 0.43 and 0.66). Our data suggest that the g.32373708 G>A-IRP1 and g.49520870 G>A-IRP2 polymorphisms may be associated with increased risk for AMD

Genetic variation in complement regulators and susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H. We therefore investigated other complement regulators for association with AMD