Cortico-cortical connectivity behind acoustic information transfer to mouse orbitofrontal cortex is sensitive to neuromodulation and displays local sensory gating: relevance in disorders with auditory hallucinations?

Background: Auditory hallucinations (which occur when the distinction between thoughts and perceptions is blurred) are common in psychotic disorders. The orbitofrontal cortex (OFC) may be implicated, because it receives multiple inputs, including sound and affective value via the amygdala, orchestrating complex emotional responses. We aimed to elucidate the circuit and neuromodulatory mechanisms that underlie the processing of emotionally salient auditory stimuli in the OFC ­ mechanisms that may be involved in auditory hallucinations. Methods: We identified the cortico-cortical connectivity conveying auditory information to the mouse OFC; its sensitivity to neuromodulators involved in psychosis and postpartum depression, such as dopamine and neurosteroids; and its sensitivity to sensory gating (defective in dysexecutive syndromes). Results: Retrograde tracers in OFC revealed input cells in all auditory cortices. Acoustic responses were abolished by pharmacological and chemogenetic inactivation of the above-identified pathway. Acoustic responses in the OFC were reduced by local dopaminergic agonists and neurosteroids. Noticeably, apomorphine action lasted longer in the OFC than in auditory areas, and its effect was modality-specific (augmentation for visual responses), whereas neurosteroid action was sex-specific. Finally, acoustic responses in the OFC reverberated to the auditory association cortex via feedback connections and displayed sensory gating, a phenomenon of local origin, given that it was not detectable in input auditory cortices. Limitations: Although our findings were for mice, connectivity and sensitivity to neuromodulation are conserved across mammals. Conclusion: The corticocortical loop from the auditory association cortex to the OFC is dramatically sensitive to dopamine and neurosteroids. This suggests a clinically testable circuit behind auditory hallucinations. The function of OFC input­output circuits can be studied in mice with targeted and clinically relevant mutations related to their response to emotionally salient sounds.

Artificial Intelligence in Accelerating Drug Discovery and Development.

Drug discovery and development are critical processes that enable the treatment of wide variety of health-related problems. These are time-consuming, tedious, complicated, and costly processes. Numerous difficulties arise throughout the entire process of drug discovery, from design to testing. Corona Virus Disease 2019 (COVID-19) has recently posed a significant threat to global public health. SARS-Cov-2 and its variants are rapidly spreading in humans due to their high transmission rate. To effectively treat COVID-19, potential drugs and vaccines must be developed quickly. The advancement of artificial intelligence has shifted the focus of drug development away from traditional methods and toward bioinformatics tools. Computer-aided drug design techniques have demonstrated tremendous utility in dealing with massive amounts of biological data and developing efficient algorithms. Artificial intelligence enables more effective approaches to complex problems associated with drug discovery and development through the use of machine learning. Artificial intelligence-based technologies improve the pharmaceutical industry's ability to discover effective drugs. This review summarizes significant challenges encountered during the drug discovery and development processes, as well as the applications of artificial intelligence-based methods to overcome those obstacles in order to provide effective solutions to health problems. This may provide additional insight into the mechanism of action, resulting in the development of vaccines and potent substitutes for repurposed drugs that can be used to treat not only COVID-19 but also other ailments.

A Comprehensive Survey of Deep Learning Techniques in Protein Function Prediction.

Protein function prediction is a major challenge in the field of bioinformatics which aims at predicting the functions performed by a known protein. Many protein data forms like protein sequences, protein structures, protein-protein interaction networks, and micro-array data representations are being used to predict functions. During the past few decades, abundant protein sequence data has been generated using high throughput techniques making them a suitable candidate for predicting protein functions using deep learning techniques. Many such advanced techniques have been proposed so far. It becomes necessary to comprehend all these works in a survey to provide a systematic view of all the techniques along with the chronology in which the techniques have advanced. This survey provides comprehensive details of the latest methodologies, their pros and cons as well as predictive accuracy, and a new direction in terms of interpretability of the predictive models needed to be ventured by protein function prediction systems.

In vivo spontaneous activity and coital-evoked inhibition of mouse accessory olfactory bulb output neurons.

Little is known about estrous effects on brain microcircuits. We examined the accessory olfactory bulb (AOB) in vivo, in anesthetized naturally cycling females, as model microcircuit receiving coital somatosensory information. Whole-cell recordings demonstrate that output neurons are relatively hyperpolarized in estrus and unexpectedly fire high frequency bursts of action potentials. To mimic coitus, a calibrated artificial vagino-cervical stimulation (aVCS) protocol was devised. aVCS evoked stimulus-locked local field responses in the interneuron layer independent of estrous stage. The response is sensitive to α1-adrenergic receptor blockade, as expected since aVCS increases norepinephrine release in AOB. Intriguingly, only in estrus does aVCS inhibit AOB spike output. Estrus-specific output reduction coincides with prolonged aVCS activation of inhibitory interneurons. Accordingly, in estrus the AOB microcircuit sets the stage for coital stimulation to inhibit the output neurons, possibly via high frequency bursting-dependent enhancement of reciprocal synapse efficacy between inter- and output neurons.

A Semi-Supervised Autoencoder-Based Approach for Protein Function Prediction.

After the development of next-generation sequencing techniques, protein sequences are abundantly available. Determining the functional characteristics of these proteins is costly and time-consuming. The gap between the number of protein sequences and their corresponding functions is continuously increasing. Advanced machine-learning methods have stepped up to fill this gap. In this work, an advanced deep-learning-based approach is proposed for protein function prediction using protein sequences. A set of autoencoders is trained in a semi-supervised manner with protein sequences. Each autoencoder corresponds to a single protein function only. In particular, 932 autoencoders corresponding to 932 biological processes and 585 autoencoders corresponding to 585 molecular functions are trained separately. Reconstruction losses of each protein sample for every autoencoder are used as a feature to classify these sequences into their corresponding functions. The proposed model is tested on test protein samples and achieves promising results. This method can be easily extended to predict any number of functions having an ample amount of supporting protein sequences. All relevant codes, data and trained models are available at https://github.com/richadhanuka/PFP-Autoencoders.

Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress.

Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.

Expression of delta- and mu-opioid receptors in the ventricular and subventricular zones of the developing human neocortex.

Recent research has documented the involvement of the endogenous opioid system in neural development, including neurogenesis and neuronal differentiation. However, the expression of opioid receptors (ORs) in different cell types of the human ventricular and subventricular zones (VZ and SVZ) has not been studied during early gestation. In the present study, we have used immunohistochemistry and quantified the results to demonstrate that the levels of delta- and mu-OR subtypes were high in the VZ and SVZ between 11 and 16 gestation weeks (GW) and decreased by 20GW. These results have also been confirmed by studying OR mRNA expression in the VZ and SVZ. Both delta- and mu-OR subtypes were expressed by multipotential stem cells, newly differentiated neurons and developing glial cells to different extents. However, migrating neurons expressed negligible levels of both OR subtypes. Our results suggest that the opioid system may affect cellular proliferation and/or differentiation of stem cells into neurons and glia during the first and second trimesters of gestation in humans. Since layers II and III of the cerebral cortex are being formed during the second trimester, their development is most likely affected by the opioid system mediated through delta- and mu-ORs.

Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.

Inhibition of P-Glycoprotein Mediated Efflux of Paclitaxel by Coumarin Derivatives in Cancer Stem Cells: An In Silico Approach.

P-glycoprotein (P-gp) is well known to cause multidrug resistance (MDR) in cancer cells. This MDR leads to cancer recurrence which is a major obstacle in cancer treatment. High P-gp expression has been observed in the population of cancer stem cells (CSCs) having self-renewal potential. Early detection and inhibition of these CSCs is directly beneficial to cancer treatment. In this study coumarin derivatives are used to inhibit efflux process and thereby enhance bioavailability of various drugs like paclitaxel (PTX). This drug is most commonly used for the treatment of cancers of breast, ovary, head and neck. Coumarin derivatives can be used to reduce the growth of breast cancer stem cells through P-gp mediated efflux inhibition and paclitaxel bioavailability enhancement. With the use of computational approaches including molecular docking simulation and pharmacophore study, few coumarin derivatives have been found to be more potential inhibitors of P-gp mediated efflux. Based on high affinity inhibitors, new coumarin derivatives have been designed and docked at active site cavity of P-gps. Some newly designed coumarin derivatives were found to be more potent due to their higher binding affinity towards target protein. The finding that newly designed coumarins can be exploited for inhibition of P-gp mediated efflux in order to enhance paclitaxel bioavailability and can inhibit breast cancer stem cell growth is significant for designing potent anticancer drugs.

The hippocampal to prefrontal cortex circuit in mice: a promising electrophysiological signature in models for psychiatric disorders.

Interaction between the hippocampus and the medial prefrontal cortex (mPFC) has been identified as a key target in several neuropsychiatric disorders. However, the hippocampus-mPFC (H-PFC) pathway has not been outlined in mice, which are increasingly the leading choice for new animal models for neurological disorders. Our results, establish the existence of a topographical, monosynaptic pathway originating exclusively from the ventral CA1 and subiculum to the mPFC. Functional connectivity of the H-PFC pathway, examined in vivo through field potential recordings in the prelimbic mPFC after high-frequency stimulation of the hippocampal outflow, demonstrates an induction of a significant long lasting long-term potentiation, which is stable for at least one hour and strongly impaired by exposure to acute stress. Given that stress exposure is known to have serious detrimental effects on prefrontal cortical functioning and is considered a major risk factor for several neuropsychiatric disorders, the present study provides a crucial animal model of neural interaction and response to environmental stress which could lend itself to the study of disruption of brain circuits and test for potential drug candidates.

Axonal branching patterns of ventral pallidal neurons in the rat.

The ventral pallidum (VP) is a key component of the cortico-basal ganglia circuits that process motivational and emotional information, and also a crucial site for reward. Although the main targets of the two VP compartments, medial (VPm) and lateral (VPl) have already been established, the collateralization patterns of individual axons have not previously been investigated. Here we have fully traced eighty-four axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle (VPr), using the anterograde tracer biotinylated dextran amine in the rat. Thirty to fifty percent of axons originating from VPm and VPr collateralized in the mediodorsal thalamic nucleus and lateral habenula, indicating a close association between the ventral basal ganglia-thalamo-cortical loop and the reward network at the single axon level. Additional collateralization of these axons in diverse components of the extended amygdala and corticopetal system supports a multisystem integration that may take place at the basal forebrain. Remarkably, we did not find evidence for a sharp segregation in the targets of axons arising from the two VP compartments, as VPl axons frequently collateralized in the caudal lateral hypothalamus and ventral tegmental area, the well-known targets of VPm, while VPm axons, in turn, also collateralized in typical VPl targets such as the subthalamic nucleus, substantia nigra pars compacta and reticulata, and retrorubral field. Nevertheless, VPl and VPm displayed collateralization patterns that paralleled those of dorsal pallidal components, confirming at the single axon level the parallel organization of functionally different basal ganglia loops.

Axonal branching patterns of nucleus accumbens neurons in the rat.

The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons.