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Cell type specific tracing of the subcortical input to primary visual cortex from the basal forebrain

UC Irvine Previously Published Works (2019)

The basal forebrain provides cholinergic inputs to primary visual cortex (V1) that play a key modulatory role on visual function. While basal forebrain afferents terminate in the infragranular layers of V1, acetylcholine is delivered to more superficial layers through volume transmission. Nevertheless, direct synaptic contact in deep layers 5 and 6 may provide a more immediate effect on V1 modulation. Using helper viruses with cell type specific promoters to target retrograde infection of pseudotyped and genetically modified rabies virus evidence was found for direct synaptic input onto V1 inhibitory neurons. These inputs were similar in number to geniculocortical inputs and, therefore, considered robust. In contrast, while clear evidence for dorsal lateral geniculate nucleus input to V1 excitatory neurons was found, there was no evidence of direct synaptic input from the basal forebrain. These results suggest a direct and more immediate influence of the basal forebrain on local V1 inhibition.

Cover page: Cell type specific tracing of the subcortical input to primary visual cortex from the basal forebrain

Article
Peer Reviewed

Differences in orientation tuning between pinwheel and domain neurons in primary visual cortex depend on contrast and size

UC Irvine Previously Published Works (2017)

Intrinsic signal optical imaging reveals a highly modular map of orientation preference in the primary visual cortex (V1) of several species. This orientation map is characterized by domains and pinwheels where local circuitry is either more or less orientation selective, respectively. It has now been repeatedly demonstrated that neurons in pinwheels tend to be more broadly tuned to orientation, likely due to the broad range of orientation preference of the neighboring neurons forming pinwheels. However, certain stimulus conditions, such as a decrease in contrast or an increase in size, significantly sharpen tuning widths of V1 neurons. Here, we find that pinwheel neuron tuning widths are broader than domain neurons only for high contrast, optimally sized stimuli, conditions that maximize excitation through feedforward, and local cortical processing. When contrast was lowered or size increased, orientation tuning width sharpened and became equal. These latter conditions are conducive to less local excitation either through lower feedforward drive or by surround suppression arising from long-range cortical circuits. Tuning width differences between pinwheel and domain neurons likely arise through more local circuitry and are overcome through recruitment of longer-range cortical circuits.

Cover page: Differences in orientation tuning between pinwheel and domain neurons in primary visual cortex depend on contrast and size

Creative Commons 'BY' version 4.0 license

Article
Peer Reviewed

Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex.

UC Irvine Previously Published Works (2021)

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.

Cover page: Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex.

Article
Peer Reviewed

Very-long-range disynaptic V1 connections through layer 6 pyramidal neurons revealed by transneuronal tracing with rabies virus

UC Irvine Previously Published Works (2014)

Neurons in primary visual cortex (V1) integrate across the representation of the visual field through networks of long-range projecting pyramidal neurons. These projections, which originate from within V1 and through feedback from higher visual areas, are likely to play a key role in such visual processes as low contrast facilitation and extraclassical surround suppression. The extent of the visual field representation covered by feedback is generally much larger than that covered through monosynaptic horizontal connections within V1, and, although it may be possible that multisynaptic horizontal connections across V1 could also lead to more widespread spatial integration, nothing is known regarding such circuits. In this study, we used injections of the CVS-11 strain of rabies virus to examine disynaptic long-range horizontal connections within macaque monkey V1. Injections were made around the representation of 5° eccentricity in the lower visual field. Along the opercular surface of V1, we found that the majority of connected neurons extended up to 8 mm in most layers, consistent with twice the typically reported distances of monosynaptic connections. In addition, mainly in layer 6, a steady presence of connected neurons within V1 was observed up to 16 mm away. A relatively high percentage of these connected neurons had large-diameter somata characteristic of Meynert cells, which are known to project as far as 8 mm individually. Several neurons, predominantly in layer 6, were also found deep within the calcarine sulcus, reaching as far as 20° of eccentricity, based on estimates, and extending well into the upper visual field representation. Thus, our anatomical results provide evidence for a wide-ranging disynaptic circuit within V1, mediated largely through layer 6, that accounts for integration across a large region of the visual field.

Cover page: Very-long-range disynaptic V1 connections through layer 6 pyramidal neurons revealed by transneuronal tracing with rabies virus

Creative Commons 'BY-NC' version 4.0 license

Article
Peer Reviewed

Commentary: How Do Microglia Regulate Neural Circuit Connectivity and Activity in the Adult Brain?

UC Irvine Previously Published Works (2022)

Microglia are the primary immune cells in CNS. Recent work shows that microglia are also essential for proper brain development through synaptic pruning and remodeling during early life development. But the question of whether and how microglia regulate synaptic connectivity in the adult brain remains open. Our recently published study provides new insights into the functional roles of microglia in the adult mouse brain. We find that chronic depletion of microglia via CSF1R inhibitors in the visual cortex in adult mice induces a dramatic increase in perineuronal nets, and enhances neural activities of both excitatory neurons and parvalbumin interneurons. These findings highlight new potential therapeutic avenues to enhance adult neural plasticity by manipulating microglia.

Cover page: Commentary: How Do Microglia Regulate Neural Circuit Connectivity and Activity in the Adult Brain?

Article
Peer Reviewed

Tracing Inputs to Inhibitory or Excitatory Neurons of Mouse and Cat Visual Cortex with a Targeted Rabies Virus

UC Irvine Previously Published Works (2013)

Background

Cortical inhibition plays a critical role in controlling and modulating cortical excitation, and a more detailed understanding of the neuronal circuits contributing to each will provide more insight into their roles in complex cortical computations. Traditional neuronal tracers lack a means for easily distinguishing between circuits of inhibitory and excitatory neurons. To overcome this limitation, we have developed a technique for retrogradely labeling inputs to local clusters of inhibitory or excitatory neurons, but not both, using neurotropic adenoassociated and lentiviral vectors, cell-type-specific promoters, and a modified rabies virus.

Results

Applied to primary visual cortex (V1) in mouse, the cell-type-specific tracing technique labeled thousands of presynaptically connected neurons and revealed that the dominant source of input to inhibitory and excitatory neurons is local in origin. Neurons in other visual areas are also labeled; the percentage of these intercortical inputs to excitatory neurons is somewhat higher (~20%) than to inhibitory neurons (<10%), suggesting that intercortical connections have less direct control over inhibition. The inputs to inhibitory neurons were also traced in cat V1, and when aligned with the orientation preference map revealed for the first time that long-range inputs to inhibitory neurons are well tuned to orientation.

Conclusions

These novel findings for inhibitory and excitatory circuits in the visual cortex demonstrate the efficacy of our new technique and its ability to work across species, including larger-brained mammals such as the cat. This paves the way for a better understanding of the roles of specific cell types in higher-order perceptual and cognitive processes.

Article
Peer Reviewed

Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

UC San Francisco Previously Published Works (2001)

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1-mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4-dependent manner. Thus, it is important to understand how the development of IL-4- versus interferon (IFN)-gamma-producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500-70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-gamma, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4(+)IFN-gamma(-) NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4(-)IFN-gamma(+) NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4(+)IFN-gamma(-) NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-gamma.

Cover page: Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

Creative Commons 'BY-NC-SA' version 4.0 license

Article
Peer Reviewed

Nano-La₂O₃ Induces Honeybee (Apis mellifera) Death and Enriches for Pathogens in Honeybee Gut Bacterial Communities.

UC Santa Barbara Previously Published Works (2021)

Honeybees (Apis mellifera) can be exposed via numerous potential pathways to ambient nanoparticles (NPs), including rare earth oxide (REO) NPs that are increasingly used and released into the environment. Gut microorganisms are pivotal in mediating honeybee health, but how REO NPs may affect honeybee health and gut microbiota remains poorly understood. To address this knowledge gap, honeybees were fed pollen and sucrose syrup containing 0, 1, 10, 100, and 1000mgkg^-1 of nano-La₂O₃ for 12days. Nano-La₂O₃ exerted detrimental effects on honeybee physiology, as reflected by dose-dependent adverse effects of nano-La₂O₃ on survival, pollen consumption, and body weight (p<0.05). Nano-La₂O₃ caused the dysbiosis of honeybee gut bacterial communities, as evidenced by the change of gut bacterial community composition, the enrichment of pathogenic Serratia and Frischella, and the alteration of digestion-related taxa Bombella (p<0.05). There were significant correlations between honeybee physiological parameters and the relative abundances of pathogenic Serratia and Frischella (p<0.05), underscoring linkages between honeybee health and gut bacterial communities. Taken together, this study demonstrates that nano-La₂O₃ can cause detrimental effects on honeybee health, potentially by disordering gut bacterial communities. This study thus reveals a previously overlooked effect of nano-La₂O₃ on the ecologically and economically important honeybee species Apis mellifera.

Cover page: Nano-La<sub>2</sub>O<sub>3</sub> Induces Honeybee (<i>Apis mellifera</i>) Death and Enriches for Pathogens in Honeybee Gut Bacterial Communities.

Article
Peer Reviewed

Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production.

UC San Francisco Previously Published Works (2006)

Immunoglobulin-like transcripts are a family of inhibitory and stimulatory cell surface immune receptors. Transcripts for one member of this family, ILT7, are selectively expressed in human plasmacytoid dendritic cells (pDCs). We demonstrate here that ILT7 protein associates with the signal adapter protein Fc epsilonRI gamma to form a receptor complex. Using an anti-ILT7 monoclonal antibody, we show that ILT7 is expressed specifically on human pDCs, but not on myeloid dendritic cells or other peripheral blood leukocytes. Cross-linking of ILT7 resulted in phosphorylation of Src family kinases and Syk kinase and induced a calcium influx in freshly isolated pDCs, which was blocked by Src family and Syk kinases inhibitors, thus indicating the activation of an immunoreceptor-based tyrosine activation motif-mediated signaling pathway. ILT7 cross-linking on CpG or influenza virus-stimulated primary pDCs inhibited the transcription and secretion of type I interferon and other cytokines. Therefore, the ILT7-Fc epsilonRI gamma receptor complex negatively regulates the innate immune functions of human pDCs.

Cover page: Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production.

Article
Peer Reviewed

Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilon RI gamma inhibits Toll-like receptor-induced interferon production

UC San Francisco Previously Published Works (2006)

Immunoglobulin-like transcripts are a family of inhibitory and stimulatory cell surface immune receptors. Transcripts for one member of this family, ILT7, are selectively expressed in human plasmacytoid dendritic cells ( pDCs). We demonstrate here that ILT7 protein associates with the signal adapter protein Fc epsilon RI gamma to form a receptor complex. Using an anti-ILT7 monoclonal antibody, we show that ILT7 is expressed specifically on human pDCs, but not on myeloid dendritic cells or other peripheral blood leukocytes. Cross-linking of ILT7 resulted in phosphorylation of Src family kinases and Syk kinase and induced a calcium influx in freshly isolated pDCs, which was blocked by Src family and Syk kinases inhibitors, thus indicating the activation of an immunoreceptor-based tyrosine activation motif mediated signaling pathway. ILT7 cross-linking on CpG or influenza virus-stimulated primary pDCs inhibited the transcription and secretion of type I interferon and other cytokines. Therefore, the ILT7-Fc epsilon RI gamma receptor complex negatively regulates the innate immune functions of human pDCs.