functional changes

Borrelia burgdorferi genotypic diversity, pathogenesis, and host cellular responses

PROJECT SUMMARY Lyme disease is the most common tick-borne illness in the United States, with an estimated 476,000 cases annually, and Pennsylvania (PA) consistently reports one of the highest case numbers nationwide. Borrelia burgdorferi sensu stricto (Bb) is a causative agent of Lyme disease in the US and is transmitted by Ixodes spp. ticks. Bb produces various outer surface proteins (Osp) and other mechanisms to survive in vectors, evade host immune systems, and to propagate infection within a host. Over 35 OspC genotypes have been characterized, which fluctuate in abundance in natural vector and host populations, suggesting host adaptation. While many Lyme-infected patients recover following antibiotic treatment, some may experience neurological symptoms, Lyme neuroborreliosis (LNB), which may be associated with specific genotypes. While previous studies focused on clinical manifestations, pathogenicity, genetic variations, and host immune responses using mouse models or patient samples, the genotype-specific immune responses that contribute to disease progression in humans remain poorly understood. Our central hypothesis is that certain Bb OspC genotypes, maintained in natural populations, are associated with distinct host immune responses that influence disease severity, progression, and persistence. Aim 1 will define the dynamics of OspC genotypes in tick and small mammal populations over time in Western PA to establish a 16-year longitudinal tick study and an 8-year longitudinal small mammal study. Using deep amplicon sequencing, we will quantify genotype diversity, detect low-abundance genotypes, and identify potential host-adapted genotypes. These empirical data will inform a compartmental mathematical model to evaluate OspC genotype prevalence, distribution, and public health risks, including LNB, across space and time. Aim 2 will assess how distinct Bb OspC genotypes affect the host immune landscape and cellular responses using human samples. To determine how Bb genotype contributes to disease phenotype, we will perform immune profiling studies which will include microscopy-based assessment of infected cell cultures, flow cytometric analysis of immune cell phenotypes, and measurement of genotype-specific cytokine, chemokine, and antigen production (sub-Aim2a). We will also employ multi-omics approaches that integrate single cell RNA sequencing with antibody-based protein profiling (scRNA-seq/Ab-seq) to characterize transcriptional and functional changes in immune cell populations exposed to different Bb genotypes (sub-Aim2b). This work is innovative in its integration of long-term ecological data with advanced immune profiling and single cell multi- omics to uncover genotype-specific mechanisms of Bb pathogenicity and human immune response—an approach not previously applied in Lyme disease research. These studies will clarify how specific genotypes influence immune responses and disease severity. Together, the proposed aims will identify critical genetic and immunological mechanisms that drive Bb pathogenicity and human susceptibility, informing the development of improved diagnostics, targeted therapies, and public health interventions to reduce the burden of Lyme disease.

Microbiome and behaviour: Exploring underlying mechanisms

Environmental insults alter brain function and behaviour inboth rodents and people. One putative underlying mechanism that has receivedsubstantial attention recently is the gut microbiota, the ecosystem ofsymbiotic microorganisms that populate the intestinal tract, which is known toplay a role in brain health and function via the gut-brain axis. Two keyenvironmental insults known to affect both brain function and behaviour, andthe gut microbiome, are poor diet and psychological stress. While there isstrong evidence for interactions between the microbiome and host physiology inthe context of chronic stress, little is known about the role of the microbiomein the host response to acute stress. Determining the underlying mechanisms bywhich stress may provoke functional changes in the gut and brain is criticalfor developing therapeutics to alleviate adverse consequences of traumaticstress.

Understanding how photoreceptor degeneration alters retinal signaling, and how to intervene to rescue vision

Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) are vision disorders caused by loss of rod and cone photoreceptors, but downstream retinal neurons also show physiological and morphological changes, resulting in the emergence of hyperactivity and rhythmic firing in many retinal ganglion cells (RGC). We recently discovered that retinoic acid (RA) is a key signal that triggers hyperactivity and that blockers of RA unmask light responses in RGCs that would otherwise be obscured. Recent work is revealing where in the retina circuit RA initiates functional changes. Moreover, interfering with the RA signaling pathway with drug or gene therapy can improve spatial vision in a mouse model of RP, providing a new strategy for enhancing low vision in human RP and AMD.

Neuronal encoding of drug choices and preference in the orbitofrontal cortex

Human neuroimaging research has consistently shown that drug addiction is associated with structural and functional changes within the orbitofrontal cortex (OFC). In view of the important role of the OFC in value-based decision-making, these changes have been hypothesised to bias choice towards drug use despite and at the expense of other competing pursuits, thereby explaining drug addiction. Here I will present in vivo recording data in the OFC supporting this hypothesis in a choice-based model of addiction where rats could choose between two actions, one rewarded by a drug (cocaine or heroin), the other by a nondrug alternative (saccharin).

Drosophila circuit model of Alzheimer’s Disease reveals neuron type-specific functional changes that are linked to altered behavior

Morphological and functional changes of nigral dopamine neurons in an α-synuclein overexpressing rat model of Parkinson’s disease

Prenatal glucocorticoid exposure alters effort decision making and triggers nucleus accumbens and anterior cingulate cortex functional changes

Shotgun metagenomics reveals taxonomic and functional changes in the salivary microbiome in young adults with depression

Depressive and anxious phenotype correlates with functional changes in the ventromedial prefrontal cortex - dorsal raphe nucleus circuit in female mice with alpha-synucleinopathy

FENS Forum 2024

Functional changes in the basal ganglia-thalamus-cortex loop in L-DOPA-induced dyskinesia in a mouse model of unilateral Parkinson's disease

FENS Forum 2024