Faculty Bibliography

A substantial portion of our sensory experience happens during active behaviors such as walking around or paying attention. How do sensory systems work during such behaviors? Neural processing in sensory systems can be shaped by behavior in multiple ways ranging from a modulation of responsiveness or sharpening of tuning to a dynamic change of response properties or functional connectivity. Here, we review recent findings on the modulation of sensory processing during active behaviors in different systems: insect vision, rodent thalamus, and rodent sensory cortices. We discuss the circuit-level mechanisms that might lead to these modulations and their potential role in sensory function. Finally, we highlight the open questions and future perspectives of this exciting new field.

Cerebral lateralization is expressed at both the structural and functional levels, and can exist as either a stable characteristic or as a dynamic feature during behavior and development. The anatomically relatively simple olfactory system demonstrates lateralization in both human and non-human animals. Here, we explored functional lateralization in both primary olfactory cortex - a region critical for odor memory and perception- and orbitofrontal cortex (OFC) - a region involved in reversal learning- in rats performing an odor learning and reversal task. We find significant asymmetry in both olfactory and orbitofrontal cortical odor-evoked activity, which is expressed in a performance- and task-dependent manner. The emergence of learning-dependent asymmetry during reversal learning was associated with decreased functional connectivity both between the bilateral OFC and between the OFC-olfactory cortex. The results suggest an inter-hemispheric asymmetry and olfactory cortical functional separation that may allow multiple, specialized processing circuits to emerge during a reversal task requiring behavioral flexibility.

Pain is a complex experience. The aversive component of pain has been assessed through conditioned place aversion in rodents. However, this behavioral test does not allow the evaluation of the aversion of an acute pain stimulus. In Zhang et al. (2017), we provide an updated version of a Conditioned Place Aversion paradigm to address this challenge. In this protocol, a detailed version of this method is described.

Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain.

The proper function of synapses relies on efficient recycling of synaptic vesicles. The small size of synaptic boutons has hampered efforts to define the dynamical states of vesicles during recycling. Moreover, whether vesicle motion during recycling is regulated by neural activity remains largely unknown. We combined nanoscale-resolution tracking of individual synaptic vesicles in cultured hippocampal neurons from rats of both sexes with advanced motion analyses to demonstrate that the majority of recently endocytosed vesicles undergo sequences of transient dynamical states including epochs of directed, diffusional, and stalled motion. We observed that vesicle motion is modulated in an activity-dependent manner, with dynamical changes apparent in ∼20% of observed boutons. Within this subpopulation of boutons, 35% of observed vesicles exhibited acceleration and 65% exhibited deceleration, accompanied by corresponding changes in directed motion. Individual vesicles observed in the remaining ∼80% of boutons did not exhibit apparent dynamical changes in response to stimulation. More quantitative transient motion analyses revealed that the overall reduction of vesicle mobility, and specifically of the directed motion component, is the predominant activity-evoked change across the entire bouton population. Activity-dependent modulation of vesicle mobility may represent an important mechanism controlling vesicle availability and neurotransmitter release.SIGNIFICANCE STATEMENT Mechanisms governing synaptic vesicle dynamics during recycling remain poorly understood. Using nanoscale resolution tracking of individual synaptic vesicles in hippocampal synapses and advanced motion analysis tools we demonstrate that synaptic vesicles undergo complex sets of dynamical states that include epochs of directed, diffusive, and stalled motion. Most importantly, our analyses revealed that vesicle motion is modulated in an activity-dependent manner apparent as the reduction in overall vesicle mobility in response to stimulation. These results define the vesicle dynamical states during recycling and reveal their activity-dependent modulation. Our study thus provides fundamental new insights into the principles governing synaptic function.

Fatty acids activate GPR40 and K⁺channels to modulate β-cell function. Herein, we describe the design and synthesis ofFAAzo-10, a light-controllable GPR40 agonist based on Gw-9508.FAAzo-10is a potent GPR40 agonist in thetrans-configuration and can be inactivated on isomerization tociswith UV-A light. Irradiation with blue light reverses this effect, allowingFAAzo-10activity to be cycled ON and OFF with a high degree of spatiotemporal precision. In dissociated primary mouse β-cells,FAAzo-10also inactivates voltage-activated and ATP-sensitive K⁺channels, and allows us to control glucose-stimulated Ca²⁺oscillations in whole islets with light. As such,FAAzo-10is a useful tool to study the complex effects, with high specificity, which FA-derivatives such as Gw-9508 exert at multiple targets in mouse β-cells.

Blind source separation-the extraction of independent sources from a mixture-is an important problem for both artificial and natural signal processing. Here, we address a special case of this problem when sources (but not the mixing matrix) are known to be nonnegative-for example, due to the physical nature of the sources. We search for the solution to this problem that can be implemented using biologically plausible neural networks. Specifically, we consider the online setting where the data set is streamed to a neural network. The novelty of our approach is that we formulate blind nonnegative source separation as a similarity matching problem and derive neural networks from the similarity matching objective. Importantly, synaptic weights in our networks are updated according to biologically plausible local learning rules.

Contraction of the heart is central to its purpose of pumping blood around the body. While simple global function measures (such as the ejection fraction) are most commonly used in the clinical assessment of cardiac function, MRI also provides a range of approaches for quantitatively characterizing regional cardiac function, including the local deformation (or strain) within the heart wall. While they have been around for some years, these methods are still undergoing further technical development, and they have had relatively little clinical evaluation. However, they can provide potentially useful new ways to assess cardiac function, which may be able to contribute to better classification and treatment of heart disease. This article provides some basic background on the physical and physiological factors that determine the motion of the heart, in health and disease and then reviews some of the ways that MRI methods are being developed to image and quantify strain within the myocardium. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia.