David M. Smith - US grants

DESCRIPTION (provided by applicant): Similar to other chronic viral infections, infection of an individual with a second viral strain (dual infection), also occurs in HIV infection. This proposal aims to determine: (1) novel methods of detecting intraclade dual infection, (2) the incidence and prevalence of dual infection (both coinfection and superinfection) among recently and chronically HIV infected individuals, and (3) the clinical and virologic correlates of dual infection. This proposal is based on a collaboration with the Acute Infection Early Disease Research Program (AIEDRP) network and the San Diego site of the Early Intervention Program (EIP). At UCSD we have available samples from 292 eligible participants from 7 AIEDRP sites for a total of 1224 well-characterized longitudinal samples. From EIP we conservatively estimate to enroll 140 participants over the two years of the study and ultimately have 320 timepoint samples available for dual infection screening. Using new methods for screening, we estimate to identify 55 instances of intraclade dual infection. Demographic and clinical data will also be available from the AIEDRP and EIP cohorts and will be used to determine the correlates associated with intraclade dual infection. We will also generate sequence data from blood samples available from participants identified with dual infection to characterize the virologic processes following dual infection, such as recombination. While not completely analogous to vaccination, the identification and characterization of intraclade dual infections represent a unique opportunity to learn how and why a sensitized immune system fails to protect its host from infection by a very closely related second HIV strain. We project that we will identify and characterize by far the largest cohort of intraclade dual infections reported to date. PUBLIC HEALTH RELEVANCE: Recently, it was discovered that individuals can be infected with HIV more than once. This is often called re-infection or dual infection. We aim to develop new methods for detecting when dual infection has occurred, how often dual infection occurs in a large clinical cohort of people with HIV infection, what are the clinical consequences of HIV dual infection, and evaluate how the two different viral strains interact with each other in the same person following dual infection.

DESCRIPTION (provided by applicant): This proposal is aimed at understanding the neural mechanisms of learning and memory. An extensive literature has documented the role of the hippocampus and the posterior cingulate cortex in memory functions. Damage to these brain regions has been linked to the memory impairments seen in Alzheimer's disease, age-related memory decline and various human amnesic syndromes and learning disabilities. Understanding how these systems work is crucial for the development of treatment strategies for patients with these conditions. The memory role of the hippocampus has been well documented and, although it has not been studied as extensively, the posterior cingulate cortex is also known to play a critical role in learning and memory. However, the precise contribution of each of these brain regions to the learning process remains unclear. Recent findings suggest that these two closely interconnected structures form a functional circuit which mediates contextual learning, but that each region makes a distinct contribution to the learning process. Findings of context-specific neuronal firing patterns suggest that the hippocampus generates a neural representation of the context. In contrast, neuronal responses to discrete cues suggest that the posterior cingulate cortex encodes behaviorally significant cues, including those cues that uniquely identify the context. These two regions function cooperatively to mediate contextual learning and memory. However, the relative contribution of each brain region should depend on the degree to which the task at hand requires the processing of contextual information or discrete cues. To examine this, rats will be trained on various contextual learning tasks which have differing cue- and context processing requirements. Neuronal activity will be recorded in both the hippocampus and posterior cingulate cortex throughout learning. Temporary neurochemical brain lesions will be used to disable each brain region, so that it will be possible to identify the specific contribution of each brain region to learning and to determine how the loss of one region disrupts processing in the other region. By monitoring the changes in neuronal responses as subjects learn and the effects of temporary damage to the circuit, it will be possible to determine what kinds of memory related information is processed in each brain region and how their interactions yield context-specific memories. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it investigates the learning and memory systems of the brain, particularly the hippocampus and posterior cingulate cortex. Damage to these brain regions has been linked to the memory impairments seen in Alzheimer's disease, age-related memory decline and various other amnesic syndromes and learning disabilities. Understanding how these systems work is crucial for the development of treatment strategies for patients with these conditions.

Project Summary/Abstract This project is aimed at understanding the neural mechanisms of learning and memory. An extensive literature has documented the role of the hippocampus, retrosplenial cingulate cortex and anterior thalamus in memory functions. Damage to these brain regions is a primary cause of the memory impairments seen in Alzheimer's disease, age-related memory decline, and various human amnesic syndromes and learning disabilities. Abnormalities in these structures have also been implicated in depression, anxiety and schizophrenia. Understanding the function of these systems is crucial for the development of treatment strategies for patients with these conditions. The memory role of the hippocampus has been well documented and, although they have not been studied as extensively, the retrosplenial cortex and anterior thalamus are also known to play a critical role in learning and memory. However, the precise contribution of each of these brain regions to the learning process remains unclear. Recent findings suggest that these closely interconnected structures form a functional circuit which mediates spatial and contextual memory. The proposed experiments are focused on understanding how memory-related information is represented by neurons in the retrosplenial cortex, and how interactions of the retrosplenial cortex, hippocampus and anterior thalamus support memory functions. In order to investigate this, neuronal activity will be recorded in these brain regions as rats perform various spatial and contextual memory tasks. Optogenetic, chemogenetic and neurochemical methods will be used to suppress neuronal activity in various components of this circuit in order to assess their contributions to functioning in the broader memory circuit. By monitoring neuronal responses as subjects learn and the effects of temporary inactivation within the circuit, it will be possible to determine how memory related information is processed and how memory may fail when damage occurs within the circuit.

Project Summary Sensory signals encountered under different circumstances may have quite different implications. In the early olfactory system, preliminary evidence suggests that this (non-olfactory) contextual information is integrated into odor representations at a very early stage, potentially even the main olfactory bulb. Recent evidence indicates that the anterior olfactory nucleus (AON), a structure directly adjoining the olfactory bulb, serves to integrate afferent odor information with contextual information from the ventral hippocampus (vHC) and is necessary to solve contextually-dependent olfactory decision-making tasks. The vHC is known to relay task-relevant spatial contextual information to other brain systems. We here hypothesize that direct projections from the vHC to the AON play a dominant role in the integration of contextual and olfactory information, and that the AON embeds this multisensory contextual information into early-stage odor representations. Our preliminary data show that rodents can learn to respond differently to odors based on the spatial context in which they are encountered, and that the expression of such a rule depends on both AON and vHC, whereas a similar but odor-independent task requires vHC but not AON. We propose a multipronged approach to understanding the integration of spatial context into olfactory representations, engaging electrophysiological ensemble recordings and interareal coherence measurements in awake, behaving rodents, the optogenetic manipulation of vHC and AON circuit activities, and a double-labeling strategy for the within-subjects comparison of immediate-early gene (Fos) responses across two experimental conditions separated in time.