Investigating Resistance to Antidepressants in Animal Models.

Major depressive disorder is one of the most prevalent psychiatric diseases, and up to 30-40% of patients remain symptomatic despite treatment. Novel therapies are sorely needed, and animal models may be used to elucidate fundamental neurobiological processes that contribute to human disease states. We conducted a systematic review of current preclinical approaches to investigating treatment resistance with the goal of describing a path forward for improving our understanding of treatment resistant depression. We conducted a broad literature search to identify studies relevant to the preclinical investigation of treatment resistant depression. We followed PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) guidelines and included all relevant studies. We identified 467 studies in our initial search. Of these studies, we included 69 in our systematic review after applying our inclusion/exclusion criteria. We identified 10 broad strategies for investigating treatment resistance in animal models. Stress hormone administration was the most commonly used model, and the most common behavioral test was the forced swim test. We systematically identified and reviewed current approaches for gaining insight into the neurobiology underlying treatment resistant depression using animal models. Each approach has its advantages and disadvantages, but all require careful consideration of their potential limitations regarding therapeutic translation. An enhanced understanding of treatment resistant depression is sorely needed given the burden of disease and lack of effective therapies.

An optoelectronic implantable neurostimulation platform allowing full MRI safety and optical sensing and communication.

A novel programmable implantable neurostimulation platform based on photonic power transfer has been developed for various clinical applications with the main focus of being safe to use with MRI scanners. The wires usually conveying electrical current from the neurostimulator to the electrodes are replaced by optical fibers. Photovoltaic cells at the tip of the fibers convert laser light to biphasic electrical impulses together with feedback signals with 54% efficiency. Furthermore, a biocompatible, implantable and ultra-flexible optical lead was developed including custom optical fibers. The neurostimulator platform incorporates advanced signal processing and optical physiological sensing capabilities thanks to a hermetically sealed transparent nonmetallic casing. Skin transparency also allowed the development of a high-speed optical transcutaneous communication channel. This implantable neurostimulation platform was first adapted to a vagus nerve stimulator for the treatment of epilepsy. This neurostimulator has been designed to fulfill the requirements of a class III long-term implantable medical device. It has been proven compliant with standard ISO/TS10974 for 1.5 T and 3 T MRI scanners. The device poses no related threat and patients can safely undergo MRI without specific or additional precautions. Especially, the RF induced heating near the implant remains below 2 °C whatever the MRI settings used. The main features of this unique advanced neurostimulator and its architecture are presented. Its functional performance is evaluated, and results are described with a focus on optoelectronics aspects and MRI safety.

Integration of High-Performance InGaAs/GaN Photodetectors by Direct Bonding via Micro-transfer Printing.

The integration of dissimilar semiconductor materials holds immense potential for harnessing their complementary properties in novel applications. However, achieving such combinations through conventional heteroepitaxy or wafer bonding techniques presents significant challenges. In this research, we present a novel approach involving the direct bonding of InGaAs-based p-i-n membranes with GaN, facilitated by van der Waals forces and microtransfer printing technology. The resulting n-InP/n-GaN heterojunction was rigorously characterized through electrical measurements, with a comprehensive investigation into the impact of various surface treatments on device performance. The obtained InGaAs/GaN photodetector demonstrates remarkable electrical properties and exhibits a high optical responsivity of 0.5 A/W at the critical wavelength of 1550 nm wavelength. This pioneering work underscores the viability of microtransfer printing technology in realizing large lattice-mismatched heterojunction devices, thus expanding the horizons of semiconductor device applications.

Highly Efficient Inverted Light-Emitting Diodes Based on Vertically Aligned CdSe/CdS Nanorod Layers Fabricated by Electrophoretic Deposition.

Inverted colloidal-nanocrystal-based LEDs (NC-LEDs) are highly interesting and invaluable for large-scale display technology and flexible electronics. Semiconductor nanorods (NRs), in addition to the tunable wavelengths of the emitted light (achieved, for example, by the variation of the NR diameter or the diameter of core in a core-shell configuration), also exhibit linearly polarized emission, a larger Stokes shift, faster radiative decay, and slower bleaching kinetics than quantum dots (QDs). Despite these advantages, it is difficult to achieve void-free active NR layers using simple spin-coating techniques. Herein, we employ electrophoretic deposition (EPD) to make closely packed, vertically aligned CdSe/CdS core/shell nanorods (NRs) as the emissive layer. Following an inverted architecture, the device fabricated yields an external quantum efficiency (EQE) of 6.3% and a maximum luminance of 4320 cd/m2 at 11 V. This good performance can be attributed to the vertically aligned NR layer, enhancing the charge transport by reducing the resistance of carrier passage, which is supported by our finite element simulations. To the best of our knowledge, this is the first time vertically aligned NR layers made by EPD have been reported for the fabrication of NC-LEDs and the device performance is one of the best for inverted red NR-LEDs. The findings presented in this work bring forth a simple and effective technique for making vertically aligned NRs, and the mechanism behind the NR-LED device with enhanced performance using these NRs is illustrated. This technique may prove useful to the development of a vast class of nanocrystal-based optoelectronics, including solar cells and laser devices.

100 Gbps PAM4 ultra-thin photodetectors integrated on SOI platform by micro transfer printing.

The integration of compact high-bandwidth III-V active devices in a scalable manner is highly significant for Silicon-on-insulator (SOI) photonic integrated circuits. To address this, we demonstrate the integration of pre-fabricated 21 × 57 µm2 InGaAs photodetector (PD) coupons with a thickness of 675 nm to a 500 nm SOI platform using a direct bonding micro-transfer printing process. The common devices are coupled to the Si waveguides via butt, grating and evanescent coupling schemes with responsivities of 0.13, 0.3 and 0.6 A/W respectively, in line with simulations. The thin device facilitates simplified high-speed connections without the need for an interlayer dielectric. A back-to-back data communication rate of 50 Gb/s is achieved with on-off keying and with post processing of four-level pulse-amplitude modulation (PAM4) 100 Gb/s is realized. Potentially, around 1 million devices per 75 mm InP wafer can be attained. The integration of compact PDs exhibited in this work can be extended to modulators and lasers in the future.

Stress circuitry: mechanisms behind nervous and immune system communication that influence behavior.

Inflammatory processes are increased by stress and contribute to the pathology of mood disorders. Stress is thought to primarily induce inflammation through peripheral and central noradrenergic neurotransmission. In healthy individuals, these pro-inflammatory effects are countered by glucocorticoid signaling, which is also activated by stress. In chronically stressed individuals, the anti-inflammatory effects of glucocorticoids are impaired, allowing pro-inflammatory effects to go unchecked. Mechanisms underlying this glucocorticoid resistance are well understood, but the precise circuits and molecular mechanisms by which stress increases inflammation are not as well known. In this narrative review, we summarize the mechanisms by which chronic stress increases inflammation and contributes to the onset and development of stress-related mood disorders. We focus on the neural substrates and molecular mechanisms, especially those regulated by noradrenergic signaling, that increase inflammatory processes in stressed individuals. We also discuss key knowledge gaps in our understanding of the communication between nervous and immune systems during stress and considerations for future therapeutic strategies. Here we highlight the mechanisms by which noradrenergic signaling contributes to inflammatory processes during stress and how this inflammation can contribute to the pathology of stress-related mood disorders. Understanding the mechanisms underlying crosstalk between the nervous and immune systems may lead to novel therapeutic strategies for mood disorders and/or provide important considerations for treating immune-related diseases in individuals suffering from stress-related disorders.

Robust single frequency index-patterned laser design using a Fourier design method.

We use a Fourier-transform based method to investigate the magnitude and robustness of mode selectivity in as-cleaved discrete-mode semiconductor lasers, where a small number of refractive index perturbations are introduced into a Fabry-Pérot laser cavity. Three exemplar index perturbation patterns are considered. Our results demonstrate the capability to significantly improve modal selectivity by choosing a perturbation distribution function that avoids placing perturbations near to the cavity centre. Our analysis also highlights the ability to select functions that can increase the yield despite facet phase errors introduced during device fabrication.

Sex differences in electrophysiological properties and voltage-gated ion channel expression in the paraventricular thalamic nucleus following repeated stress.

BACKGROUND: Habituation to repeated stress refers to a progressive reduction in the stress response following multiple exposures to the same, predictable stressor. We previously demonstrated that the posterior division of the paraventricular thalamic nucleus (pPVT) nucleus regulates habituation to 5 days of repeated restraint stress in male rats. Compared to males, female rats display impaired habituation to 5 days of restraint. To better understand how activity of pPVT neurons is differentially impacted in stressed males and females, we examined the electrophysiological properties of pPVT neurons under baseline conditions or following restraint. METHODS: Adult male and female rats were exposed to no stress (handling only), a single period of 30 min restraint or 5 daily exposures to 30 min restraint. 24 h later, pPVT tissue was prepared for recordings. RESULTS: We report here that spontaneous excitatory post-synaptic current (sEPSC) amplitude was increased in males, but not females, following restraint. Furthermore, resting membrane potential of pPVT neurons was more depolarized in males. This may be partially due to reduced potassium leakage in restrained males as input resistance was increased in male, but not female, rats 24 h following 1 or 5 days of 30-min restraint. Reduced potassium efflux during action potential firing also occurred in males following a single restraint as action potential half-width was increased following a single restraint. Restraint had limited effects on electrophysiological properties in females, although the mRNA for 10 voltage-gated ion channel subunits was altered in the pPVT of female rats. CONCLUSIONS: The results suggest that restraint-induced changes in pPVT activation promote habituation in males. These findings are the first to describe a sexual dimorphism in stress-induced electrophysiological properties and voltage-gated ion channel expression in the pPVT. These results may explain, at least in part, why habituation to 5 days of restraint is disrupted in female rats.

Arc-Mediated Plasticity in the Paraventricular Thalamic Nucleus Promotes Habituation to Stress.

BACKGROUND: Habituation is defined as a progressive decline in response to repeated exposure to a familiar and predictable stimulus and is highly conserved across species. Disrupted habituation is a signature of posttraumatic stress disorder. In rodents, habituation is observed in neural, neuroendocrine, and behavioral responses to repeated exposure to predictable and moderately intense stress or restraint. We previously demonstrated that lesioning the posterior paraventricular thalamic nucleus (pPVT) impairs habituation. However, the underlying molecular mechanisms and specific neural connections among the pPVT and other brain regions that underlie habituation are unknown. METHODS: Behavioral and neuroendocrine habituation was assessed in adult male Sprague Dawley rats using the repeated restraint paradigm. Pan-neuronal and Cre-dependent DREADDs (designer receptors exclusively activated by designer drugs) were used to chemogenetically inhibit the pPVT and the subpopulation of pPVT neurons that project to the medial prefrontal cortex (mPFC), respectively. Activity-regulated cytoskeleton-associated protein (Arc) expression was knocked down in the pPVT using small interfering RNA. Structural plasticity of pPVT neurons was assessed using Golgi staining. Local field potential recordings were used to assess coherent neural activity between the pPVT and mPFC. The attentional set shifting task was used to assess mPFC-dependent behavior. RESULTS: Here, we show that Arc promotes habituation by increasing stress-induced spinogenesis in the pPVT, increasing coherent neural activity with the mPFC, and improving mPFC-mediated cognitive flexibility. CONCLUSIONS: Our results demonstrate that Arc induction in the pPVT regulates habituation and mPFC function. Therapies that improve synaptic plasticity during posttraumatic stress disorder therapy may enhance habituation and the efficacy of posttraumatic stress disorder treatment.

Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aß accumulation in mice.

Sleep disruptions promote increases of amyloid ß (Aß) and tau in the brain and increase Alzheimer's disease (AD) risk, but the precise mechanisms that give rise to sleep disturbances have yet to be defined. The thalamic reticular nucleus (TRN) is essential for sleep maintenance and for the regulation of slow-wave sleep (SWS). We examined the TRN in transgenic mice that express mutant human amyloid precursor protein (APP) and found reduced neuronal activity, increased sleep fragmentation, and decreased SWS time as compared to nontransgenic littermates. Selective activation of the TRN using excitatory DREADDs restored sleep maintenance, increased time in SWS, and reduced amyloid plaque load in both hippocampus and cortex. Our findings suggest that the TRN may play a major role in symptoms associated with AD. Enhancing TRN activity might be a promising therapeutic strategy for AD.

FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety.

FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and vascular remodeling. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen, TgfB2, Pdgfa, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced vascular remodeling. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced vascular remodeling as increased stress-induced blood vessel density in the brain contributes to behavior associated with vulnerability in rats. Together, these results demonstrate that FTY720 regulates baseline HPA axis activity but reduces social anxiety and despair, providing further evidence that S1PRs are important and novel regulators of stress-related functions.

Laser to laser power conversion with remote signaling.

We demonstrate laser power conversion using an edge-coupled waveguide configuration. A laser with an emission energy of 0.87 eV (1427 nm) optically pumps a second with an emission energy of 0.80 eV (1540 nm), achieving the maximum possible open circuit voltage of 0.83 V due to optically pumped lasing. A fiber to device power conversion efficiency of 33% is achieved with internal power conversion efficiency ranging from 57% to 51%. The voltage at maximum power is 0.6 V, which is a record for the wavelength range. The same optically pumped device is used for effectively power-free 500 Mbps upstream data transmission, enabling compact powering and signaling for emerging applications in minimally invasive medical interventions and remote photonics.

S-MRUT: Sectored-Multiring Ultrasonic Transducer for Selective Powering of Brain Implants.

One of the main challenges of the current ultrasonic transducers for powering brain implants is the complexity of focusing ultrasonic waves in various axial and lateral directions. The available transducers usually use electrically controlled phased array for beamforming the ultrasonic waves, which increases the complexity of the system even further. In this article, we propose a straightforward solution for selective powering of brain implants to remove the complexity of conventional phased arrays. Our approach features a Sectored-Multiring Ultrasonic Transducer (S-MRUT) on a single piezoelectric sheet, specifically designed for powering implantable devices for optogenetics in freely moving animals. The proposed unidirectional S-MRUT is capable of focusing the ultrasonic waves on brain implants located at different depths and regions of the brain. The S-MRUT is designed based on Fresnel Zone Plate (FZP) theory, simulated in COMSOL, and fabricated with the microfabrication process. The acoustic profile of the seven different configurations of the S-MRUT was measured using a hydrophone with the total number of 7436 grid points. The measurements show the ability of the proposed S-MRUT to sweep the focus point of the acoustic waves in the axial direction in depths of 1 - 3 mm, which is suitable for powering implants in the striatum of the mouse. Furthermore, the proposed S-MRUT demonstrates a steering area with an average radius of 0.862 mm and 0.678 mm in experiments and simulations, respectively. The S-MRUT is designed with the size of 3.8×3.8×0.5 mm3 and the weight of 0.054gr , showing that it is compact and light enough to be worn by a mouse. Finally, the S-MRUT was tested in our measurement setup, where it successfully transfers sufficient power to a 2.8-mm3 optogentic stimulator to turn on a micro-LED on the stimulator.

Micro-transfer-printed III-V-on-silicon C-band distributed feedback lasers.

We report on single-mode C-band distributed feedback lasers fabricated through micro-transfer-printing of semiconductor optical amplifier coupons fabricated on a InP source wafer onto a silicon-on-insulator photonic circuit. The coupons are micro-transfer printed on quarter-wave shifted gratings defined in SiN deposited on the silicon waveguide. Alignment-tolerant adiabatic tapers are used to efficiently couple light from the hybrid III-V/Si waveguide to the Si waveguide circuit. 80 mA threshold current and a maximum single-sided waveguide-coupled output power above 6.9 mW is obtained at 20 °C. Single mode operation around 1558 nm with > 33 dB side mode suppression ratio is demonstrated. Micro-transfer printing-based heterogeneous integration is promising for the wafer-level integration of advanced laser sources on complex silicon photonic integrated circuit platforms without changing the foundry process flow.

Direct visualization of phase-matched efficient second harmonic and broadband sum frequency generation in hybrid plasmonic nanostructures.

Second harmonic generation and sum frequency generation (SHG and SFG) provide effective means to realize coherent light at desired frequencies when lasing is not easily achievable. They have found applications from sensing to quantum optics and are of particular interest for integrated photonics at communication wavelengths. Decreasing the footprints of nonlinear components while maintaining their high up-conversion efficiency remains a challenge in the miniaturization of integrated photonics. Here we explore lithographically defined AlGaInP nano(micro)structures/Al2O3/Ag as a versatile platform to achieve efficient SHG/SFG in both waveguide and resonant cavity configurations in both narrow- and broadband infrared (IR) wavelength regimes (1300-1600 nm). The effective excitation of highly confined hybrid plasmonic modes at fundamental wavelengths allows efficient SHG/SFG to be achieved in a waveguide of a cross-section of 113 nm × 250 nm, with a mode area on the deep subwavelength scale (λ 2/135) at fundamental wavelengths. Remarkably, we demonstrate direct visualization of SHG/SFG phase-matching evolution in the waveguides. This together with mode analysis highlights the origin of the improved SHG/SFG efficiency. We also demonstrate strongly enhanced SFG with a broadband IR source by exploiting multiple coherent SFG processes on 1 µm diameter AlGaInP disks/Al2O3/Ag with a conversion efficiency of 14.8% MW-1 which is five times the SHG value using the narrowband IR source. In both configurations, the hybrid plasmonic structures exhibit >1000 enhancement in the nonlinear conversion efficiency compared to their photonic counterparts. Our results manifest the potential of developing such nanoscale hybrid plasmonic devices for state-of-the-art on-chip nonlinear optics applications.

Transfer-print integration of GaAs p-i-n photodiodes onto silicon nitride waveguides for near-infrared applications.

We demonstrate waveguide-detector coupling through the integration of GaAs p-i-n photodiodes (PDs) on top of silicon nitride grating couplers (GCs) by means of transfer-printing. Both single device and arrayed printing is demonstrated. The photodiodes exhibit dark currents below 20 pA and waveguide-referred responsivities of up to 0.30 A/W at 2V reverse bias, corresponding to an external quantum efficiency of 47% at 860 nm. We have integrated the detectors on top of a 10-channel on-chip arrayed waveguide grating (AWG) spectrometer, made in the commercially available imec BioPIX-300 nm platform.

Ultrasonically Powered Compact Implantable Dust for Optogenetics.

This paper presents an ultrasonically powered microsystem for deep tissue optogenetic stimulation. All the phases in developing the prototype starting from modelling the piezoelectric crystal used for energy harvesting, design, simulation and measurement of the chip, and finally testing the whole system in a mimicking setup are explained. The developed system is composed of a piezoelectric harvesting cube, a rectifier chip, and a micro-scale custom-designed light-emitting-diode (LED), and envisioned to be used for freely moving animal studies. The proposed rectifier chip with a silicon area of [Formula: see text] is implemented in standard TSMC [Formula: see text] CMOS technology, for interfacing the piezoelectric cube and the microLED. Experimental results show that the proposed microsystem produces an available electrical power of  [Formula: see text] while loaded by a microLED, out of an acoustic intensity of [Formula: see text] using a [Formula: see text] crystal as the receiver. The whole system including the tested rectifier chip, a piezoelectric cube with the dimensions of [Formula: see text], and a µLED of [Formula: see text] have been integrated on a [Formula: see text] glass substrate, encapsulated inside a bio-compatible PDMS layer and tested successfully for final prototyping. The total volume of the fully-packaged device is estimated around [Formula: see text].

CMOS-Compatible Titanium Nitride for On-Chip Plasmonic Schottky Photodetectors.

Here, we propose a waveguide-integrated plasmonic Schottky photodetector (PD) operating based on an internal photoemission process with a titanium nitride plasmonic material. The theoretically examined structure employs an asymmetric metal-semiconductor-metal waveguide configuration with one of the electrodes being gold and the second being either gold, titanium, or titanium nitride. For the first time, we measured a Schottky barrier height of 0.67 eV for titanium nitride on p-doped silicon, which is very close to the optimal value of 0.697 eV. This barrier height will enable photodetection with a high signal-to-noise ratio when operating at a wavelength of 1550 nm. In addition to the measured optical properties of high absorption losses and reasonably large real part of the permittivity that are desired for this type of PD, titanium nitride is also compatible with easy integration on existing complementary metal-oxide-semiconductor technology. The use of titanium nitride results in a shorter penetration depth of the optical mode into the metal when compared to Ti, which in turn enhances the probability for transmission of hot electrons to the adjacent semiconductor, giving rise to an enhancement in responsivity.

Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons.

We recently found that non-stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared to non-stressed males, which lead to impaired habituation to repeated restraint stress at the behavioral, neural, and endocrine level. Here, we extended our study of sex differences in the orexin system by examining spine densities and dendritic morphology in putative orexin neurons in adult male and female rats that were exposed to 5 consecutive days of 30-min restraint. Analysis of spine distribution and density indicated that putative orexinergic neurons in control non-stressed females had significantly more dendritic spines than those in control males, and the majority of these were mushroom spines. This morphological finding may suggest more excitatory input onto orexin neurons in female rats. As orexin neurons are known to promote the hypothalamic-pituitary-adrenal response, this morphological change in orexin neurons could underlie the impaired habituation to repeated stress in female rats. Dendritic complexity did not differ between non-stressed males and females, however repeated restraint stress decreased total dendritic length, nodes, and branching primarily in males. Thus, reduced dendritic complexity of putative orexinergic neurons is observed in males but not in females after 5days of repeated restraint stress. This morphological change might be reflective of decreased orexin system function, which may allow males to habituate more fully to repeated restraint than females. These results extend our understanding of the role of orexin neurons in regulating habituation and demonstrate changes in putative orexin cell morphology and spines that may underlie sex differences in habituation.