Key pointsr The main cause of death from opioid overdose is respiratory depression due to the activation of µ-opioid receptors (MORs).r We conditionally deleted MORs from neurons in two key areas of the brainstem respiratory circuitry (the Kölliker-Fuse nucleus (KF) and pre-Bötzinger complex (preBötC)) to determine their role in opioid-induced respiratory disturbances in adult, awake mice.r Deletion of MORs from KF neurons attenuated respiratory rate depression at all doses of morphine.r Deletion of MORs from preBötC neurons attenuated rate depression at the low dose, but had no effect on rate following high doses of morphine. Instead, high doses of morphine increased the occurrence of apnoeas.r The results indicate that opioids affect distributed key areas of the respiratory network in a dose-dependent manner and countering the respiratory effects of high dose opioids via the KF may be an effective approach to combat overdose.Abstract The primary cause of death from opioid overdose is respiratory failure. High doses of opioids cause severe rate depression and increased risk of fatal apnoea, which correlate with increasing irregularities in breathing pattern. µ-Opioid receptors (MORs) are widely distributed throughout the brainstem respiratory network, but the mechanisms underlying respiratory depression are poorly understood. The medullary pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) are considered critical for inducing opioid-related respiratory disturbances. We used a conditional knockout approach to investigate the roles and relative contribution of MORs in KF and preBötC neurons in opioid-induced respiratory depression in Adrienn Varga received her Ph.D. from Case Western Reserve University, where she studied the neural processes underlying navigation in an insect model. This work provided her with an appreciation for how the central nervous system integrates sensory information to shape motor commands. For her postdoctoral work at the University of Florida, she has continued to build on this previous training by moving into the rodent respiratory system, which provides a powerful model for relating sensory cues to the coordination of rhythmic behaviours. An important component of this research is seeking to define the neural mechanisms underlying opioid-induced respiratory depression.A. G. Varga and others J Physiol 598.1 awake adult mice. The results revealed dose-dependent and region-specific opioid effects on the control of both respiratory rate and pattern. Respiratory depression induced by an anti-nociceptive dose of morphine was significantly attenuated following deletion of MORs from either the KF or the preBötC, suggesting cumulative network effects on respiratory rate control at low opioid doses. Deletion of MORs from KF neurons also relieved rate depression at near-maximal respiratory depressant doses of morphine. Meanwhile, deletion of MORs from the preBötC had no effect on rate following administration of high doses of morphine. Instead, a severe ataxic breathing pa...

Animals rely upon integrated sensory information for spatial navigation. A question of wide importance in navigation is how sensory cues get transformed into neural codes that represent the animal's orientation within its proximal environment. Here, we investigated the possibility of head-direction coding in the central complex of the cockroach, Blaberus discoidalis. We used extracellular recordings in restrained animals that were rotated on a platform relative to a fixed landmark. The passive rotations allowed us to test for head-direction coding in the absence of self-generated motion cues. Our results indicate that individual cells in the central complex encode the animal's heading relative to a landmark's position in several ways. In some cells, directional tuning was established even in the absence of visual cues, suggesting that the directional code can be maintained solely based on the internal motion cues derived from the passive rotations. Additionally, some cells in the central complex encoded rotation-direction history, a navigational context cue, by increasing or decreasing the firing rate during the stationary periods following clockwise or counterclockwise rotations. Together, these results unveil head-direction cell-like activity in the insect central complex, which highly resemble similarly functioning cells in the mammalian brain that encode head direction. We predict that the observed head-orientation coding and directionally sensitive cells are essential components of the brain circuitry mediating insect navigation.

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Cockroaches are scavengers that forage through dark, maze-like environments. Like other foraging animals, for instance rats, they must continually asses their situation to keep track of targets and negotiate barriers. While navigating a complex environment, all animals need to integrate sensory information in order to produce appropriate motor commands. The integrated sensory cues can be used to provide the animal with an environmental and contextual reference frame for the behavior. To successfully reach a goal location, navigational cues continuously derived from sensory inputs have to be utilized in the spatial guidance of motor commands. The sensory processes, contextual and spatial mechanisms, and motor outputs contributing to navigation have been heavily studied in rats. In contrast, many insect studies focused on the sensory and/or motor components of navigation, and our knowledge of the abstract representation of environmental context and spatial information in the insect brain is relatively limited. Recent reports from several laboratories have explored the role of the central complex (CX), a sensorimotor region of the insect brain, in navigational processes by recording the activity of CX neurons in freely-moving insects and in more constrained, experimenter-controlled situations. The results of these studies indicate that the CX participates in processing the temporal and spatial components of sensory cues, and utilizes these cues in creating an internal representation of orientation and context, while also directing motor control. Although these studies led to a better understanding of the CX's role in insect navigation, there are still major voids in the literature regarding the underlying mechanisms and brain regions involved in spatial navigation. The main goal of this review is to place the above listed findings in the wider context of animal navigation by providing an overview of the neural mechanisms of navigation in rats and summarizing and comparing our current knowledge on the CX's role in insect navigation to these processes. By doing so, we aimed to highlight some of the missing puzzle pieces in insect navigation and provide a different perspective for future directions.

PACAP is a neuropeptide with diverse functions in various organs, including reproductive system. It is present in the testis in high concentrations, and in addition to the stage-specific expression within the seminiferous tubules, PACAP affects spermatogenesis and the functions of Leydig and Sertoli cells. Mice lacking endogenous PACAP show reduced fertility, but the possibility of abnormalities in spermatogenic signaling has not yet been investigated. Therefore, we performed a detailed morphological analysis of spermatozoa, sperm motility and investigated signaling pathways that play a role during spermatogenesis in knockout mice. No significant alterations were found in testicular morphology or motility of sperm in homozygous and heterozygous PACAP-deficient mice in spite of the moderately increased number of severely damaged sperms. However, we found robust changes in mRNA and/or protein expression of several factors that play an important role in spermatogenesis. Protein kinase A expression was markedly reduced, while downstream phospho-ERK and p38 were elevated in knockout animals. Expression of major transcription factors, such as Sox9 and phospho-Sox9, was decreased, while that of Sox10, as a redundant factor, was increased in PACAP-deficient mice. The reduced phospho-Sox9 expression was partly due to increased expression and activity of phosphatase PP2A in knockout mice. Targets of Sox transcription factors, such as collagen type IV, were reduced in knockout mice. In summary, our results show that lack of PACAP leads to disturbed signaling in spermatogenesis, which could be a factor responsible for reduced fertility in PACAP knockout mice, and further support the role of PACAP in reproduction.