Biology subjects

Wong, F. S.

Publications and source records attributed to Wong, F. S..

6 recordsLinked to original sources

bioRxiv2026

Number, order and time influence how the brain integrates distinct experiences

How does the brain integrate experiences that are separated in time? The present study addressed this question using sensory preconditioning protocols in rats. In these protocols, rats integrate an A-B association (e.g., tone-light) formed in stage 1 with a B-shock association (e.g., light-shock) formed in stage 2 to generate fear responses (freezing) when tested with A alone in stage 3. Here we show that the mechanism of integration depends on the number, order and timing of events across the two stages of training. When the events are novel (low number of exposures) and the interval between stages 1 and 2 is short (24 hours), the A-B and B-shock associations are integrated through formation of a mediated A-shock association during stage 2. By contrast, when the events are more familiar (greater number of exposures), ordered in a particular way, and the interval between stages 1 and 2 is long (14-days), the A-B and B-shock associations are integrated through their chaining at the time of testing with A alone. Thus, number, order and time determine how distinct experiences are integrated in the brain. These findings are discussed with respect to theories of integration and information processing in the medial temporal lobe.

neuroscience↗

bioRxiv2025

Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge

Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of GAD-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In draining LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing [~]0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge, coupled with scRNAseq, enables direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific specific T cells to monitor disease activity and evaluate immune interventions in T1D.

immunology↗

bioRxiv2025

The basolateral amygdala complex and perirhinal cortex represent focal and peripheral states of information processing in rats

This study used variations of a sensory preconditioning protocol in male and female rats to test a theory that the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) represent focal and peripheral states of attention, respectively. It specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required activation of NMDAR in the BLA and not the PRh (Experiments 2A and 2B) regardless of whether the stimulus-shock pairings were contiguous or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required activation of NMDAR in the BLA and not the PRh (Experiments 1A, 1B, 3A and 3B). However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required activation of NMDAR in the PRh and not the BLA (Experiments 1A, 1B, 3A and 3B). These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.

neuroscience↗

bioRxiv2024

Integration of sensory and fear memories in the rat medial temporal lobe

Wong et al. (2019) used a sensory preconditioning protocol to examine how sensory and fear memories are integrated in the rat medial temporal lobe. In this protocol, rats integrate a sound-light (sensory) memory that forms in stage 1 with a light-shock (fear) memory that forms in stage 2 to generate fear responses (freezing) across test presentations of the sound in stage 3. Here, we advance this research by showing that: 1) how/when rats integrate the sound-light and light-shock memories (online in stage 2 or at test in stage 3) changes with the number of sound-light pairings in stage 1; and 2) regardless of how/when it occurs, the integration requires communication between two regions of the medial temporal lobe: the perirhinal cortex and basolateral amygdala complex. Thus, "event familiarity" determines how/when sensory and fear memories are integrated but not the circuitry by which the integration occurs: this remains the same.

neuroscience↗

bioRxiv2024

Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer cells and late-stage differentiated T cells. There is accumulating evidence that iKIRs regulate T cell-mediated immunity. Recently, we reported that T cell-mediated control was enhanced by iKIRs in chronic viral infections. We hypothesized that in the context of autoimmunity, where an enhanced T cell response might be considered detrimental, iKIRs would have an opposite effect. We studied Type 1 diabetes (T1D) as a paradigmatic example of autoimmunity. In T1D, variation in the Human Leucocyte Antigen (HLA) genes explains up to 50% of the genetic risk, indicating that T cells have a major role in T1D etiopathogenesis. To investigate if iKIRs affect this T cell response we asked whether HLA associations were modified by iKIR genes. We conducted an immunogenetic analysis of a case-control T1D dataset (N= 11,961) and found that iKIR genes, in the presence of genes encoding their ligands, have a consistent and significant effect on protective HLA class II genetic associations. Our results were validated in an independent data set. We conclude that iKIRs significantly decrease HLA class II protective associations and suggest that iKIRs regulate CD4+ T cell responses in T1D.

immunology↗

bioRxiv2022

Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes

B cells play an important role in driving the development of type 1 diabetes, however, it remains unclear how they contribute to local beta-cell destruction during disease progression. Using gene expression profiling of B cell subsets in the pancreas and pancreatic lymph nodes, we reveal that B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph node. We identified both a discrete and a core shared gene expression profile in islet CD19+CD138- and CD19+CD138+ B cell subsets, the latter known to have enriched autoreactivity during diabetes development. Upon localisation to pancreatic islets, CD138+ B cells overexpressed genes associated with adhesion molecules and growth factors compared to CD138- B cells. Their shared signature displayed gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with interferon signalling pathways, pro-inflammatory cytokines and toll-like receptor activation. Finally, abundant TLR7 expression was detected in islet B cells, and was enhanced specifically in CD138+ B cells. Our study, therefore, provides a detailed transcriptional analysis of islet B cells identifying specific gene signatures and interaction networks that point towards a functional role for B cells in driving autoimmune diabetes.

immunology↗