Loss of Circadian Timing Disrupts Theta Episodes during Object Exploration

This study examined whether theta oscillations were compromised by the type of circadian disruption that impairs hippocampal-dependent memory processes. In prior studies on Siberian hamsters, we developed a one-time light treatment that eliminated circadian timing in the central pacemaker, the suprachiasmatic nucleus (SCN). These arrhythmic animals had impaired hippocampal-dependent memory whereas animals made arrhythmic with SCN lesions did not. The current study examined whether theta oscillations are compromised by the same light treatment that produced memory impairments in these animals. We found that both methods of inducing circadian-arrhythmia shortened theta episodes in the EEG by nearly 50%. SCN-lesioned animals, however, exhibited a 3-fold increase in the number of theta episodes and more than doubled the total time that theta dominated the EEG compared to SCN-intact circadian-arrhythmic animals. Video tracking showed that changes in theta were paralleled by similar changes in exploration behavior. These results suggest that the circadian-arrhythmic SCN interferes with hippocampal memory encoding by fragmenting theta oscillations. SCN-lesioned animals can, however, compensate for the shortened theta episodes by increasing their frequency. Implications for rhythm coherence and theta sequence models of memory formation are discussed

Fronto-striatal projections regulate innate avoidance behavior

The dorsomedial prefrontal cortex (dmPFC) has been linked to avoidance and decision-making under conflict, key neural computations altered in anxiety disorders. However, the heterogeneity of prefrontal projections has obscured identification of specific top-down projections involved. While the dmPFC-amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that dmPFC-dorsomedial striatum (DMS) projections may be more important for regulating avoidance. Using fiber photometry recordings in both male and female mice during the elevated zero maze task, we show heightened neural activity in frontostriatal but not frontoamygdalar projection neurons during exploration of the anxiogenic open arms. Additionally, using optogenetics, we demonstrate that this frontostriatal projection preferentially excites postsynaptic D1 receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. These results support a model for prefrontal control of defensive behavior in which the dmPFC-amygdala projection controls reflexive fear behavior and the dmPFC-striatum projection controls anxious avoidance behavior.SIGNIFICANCE STATEMENT The medial prefrontal cortex has been extensively linked to several behavioral symptom domains related to anxiety disorders, with much of the work centered around reflexive fear responses. Comparatively little is known at the mechanistic level about anxious avoidance behavior, a core feature across anxiety disorders. Recent work has suggested that the striatum may be an important hub for regulating avoidance behaviors. Our work uses optical circuit dissection techniques to identify a specific corticostriatal circuit involved in encoding and controlling avoidance behavior. Identifying neural circuits for avoidance will enable the development of more targeted symptom-specific treatments for anxiety disorders

Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections.

Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of dmPFC projections during active avoidance learning has never been recorded. Here we utilized fiber photometry to record from the dmPFC and its axonal projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in both male and female mice. We examined neural activity during conditioned stimulus (CS) presentations and during clinically relevant behaviors such as active avoidance or cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased and decreased patterns of activity during avoidance and cued freezing, respectively. Finally, dmPFC-DMS and dmPFC-BLA projections show divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA projection showing decreased activity during active avoidance. Our results demonstrate task-relevant encoding of active avoidance in projection-specific dmPFC subpopulations that play distinct but complementary roles in active avoidance learning

Micromirror-scanned dual-axis confocal microscope utilizing a gradient-index relay lens for image guidance during brain surgery

A fluorescence confocal microscope incorporating a 1.8-mm-diam gradient-index relay lens is developed for in vivo histological guidance during resection of brain tumors. The microscope utilizes a dual-axis confocal architecture to efficiently reject out-of-focus light for high-contrast optical sectioning. A biaxial microelectromechanical system (MEMS) scanning mirror is actuated at resonance along each axis to achieve a large field of view with low-voltage waveforms. The unstable Lissajous scan, which results from actuating the orthogonal axes of the MEMS mirror at highly disparate resonance frequencies, is optimized to fully sample 500×500 pixels at two frames per second. Optically sectioned fluorescence images of brain tissues are obtained in living mice to demonstrate the utility of this microscope for image-guided resections

A Real-Time Clinical Endoscopic System for Intraluminal, Multiplexed Imaging of Surface-Enhanced Raman Scattering Nanoparticles

<div><p>The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and <i>in vivo</i> demonstration of a miniature, non-contact, opto-electro-mechanical Raman device as an accessory to clinical endoscopes that can provide multiplexed molecular data via a panel of SERS NPs. This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy.</p></div

Imaging device and system.

<p>(a) Photographs of the components of the distal end of the device adjacent to a quarter (diameter = 24 mm) for scale. All the components shown, less the motor, were custom designed and fabricated for this device. (b) Close-up photograph of the distal end of the fully functional device. The fiber bundle was enclosed and sealed within a flexible extrusion sheath. The window was placed between the scan mirror and the tissue in order to seal the inner mechanisms of the device from fluids in the surrounding environment. The use of a toroidal mirror compensates for beam distortion from the curvature of the glass window in order to maintain a collimated beam. Utilization of a 50-degree inclination angle of the toroidal mirror effectively eliminates back reflections from the window into the fiber bundle detector. (c) System overview. A continuous wave (CW) laser at 785 nm was used and the Raman-scattered light is collected through the multi-mode fibers of the fiber bundle. At the proximal end of the fiber bundle, the multimode fibers are arranged into a vertical array for efficient coupling to the spectrometer. A long-pass filter at the entrance of the spectrometer filters out the illumination light. A function generator signal controls a motor control board to finely tune the rotational speed of the motor to the desired speed of 1 rev/s. (d) Photograph of the completed fully functional system.</p