Developmental exposure to pesticides that disrupt retinoic acid signaling causes persistent retinoid and behavioral dysfunction in zebrafish.

Early developmental exposure to environmental toxicants may play a role in the risk for developing autism. A variety of pesticides have direct effects on retinoic acid (RA) signaling and as RA signaling has important roles in neurodevelopment, such compounds may cause developmental neurotoxicity through an overlapping adverse outcome pathway. It is hypothesized that a pesticide's embryonic effects on retinoid function may correspond with neurobehavioral disruption later in development. In the current studies, we determined the effects of RA-acting pesticides on neurobehavioral development in zebrafish. Buprofezin and imazalil caused generalized hypoactivity in the larval motility test, whereas chlorothalonil and endosulfan I led to selective hypoactivity and hyperactivity, respectively. With buprofezin, chlorothalonil, and imazalil, hypoactivity and/or novel anxiety-like behaviors persisted in adulthood and buprofezin additionally decreased social attraction responses in adulthood. Endosulfan I did not produce significant adult behavioral effects. Using qPCR analyses of adult brain tissue, we observed treatment-induced alterations in RA synthesis or catabolic genes, indicating persistent changes in RA homeostasis. These changes were compound-specific, with respect to expression directionality, and potential patterns of homeostatic disruption. Results suggest the likely persistence of disruptions in RA signaling well into adulthood and may represent compensatory mechanisms following early life stage exposures. This study demonstrates that early developmental exposure to environmental toxicants that interfere with RA signaling causes short as well as long-term behavioral disruption in a well-established zebrafish behavioral model and expand upon the meaning of the RA adverse outcome pathway, indicating that observed effects likely correspond with the nature of underlying homeostatic effects.

Hemispheric Asymmetry on the Electroencephalogram during General Anesthesia Responsive to Blood Pressure Manipulations.

The electroencephalogram (EEG) has been extensively used to detect ischemia and the need for shunting during carotid endarterectomy. Limited literature exists using EEG data to detect ischemia in other surgeries. This case report depicts a 65-year-old man, with extensive vascular history including complete left carotid occlusion and severe right carotid stenosis, who presented for left first rib resection and left subclavian vein balloon angioplasty. Following induction of general anesthesia, frontal EEG (SedLine; Masimo Corporation, Irvine, CA, USA) demonstrated hemispheric asymmetry, which nearly resolved with vasoactive support. At three distinct periods, discordance reoccurred necessitating a higher mean arterial pressure threshold. This case demonstrates EEG patterns concerning for focal spectrographic ischemia and highlights the potential use of EEG signals to capture hypoperfusion and direct vasoactive therapy.

Regulation of l- and d-Aspartate Transport and Metabolism in Acinetobacter baylyi ADP1.

The regulated uptake and consumption of d-amino acids by bacteria remain largely unexplored, despite the physiological importance of these compounds. Unlike other characterized bacteria, such as Escherichia coli, which utilizes only l-Asp, Acinetobacter baylyi ADP1 can consume both d-Asp and l-Asp as the sole carbon or nitrogen source. As described here, two LysR-type transcriptional regulators (LTTRs), DarR and AalR, control d- and l-Asp metabolism in strain ADP1. Heterologous expression of A. baylyi proteins enabled E. coli to use d-Asp as the carbon source when either of two transporters (AspT or AspY) and a racemase (RacD) were coexpressed. A third transporter, designated AspS, was also discovered to transport Asp in ADP1. DarR and/or AalR controlled the transcription of aspT, aspY, racD, and aspA (which encodes aspartate ammonia lyase). Conserved residues in the N-terminal DNA-binding domains of both regulators likely enable them to recognize the same DNA consensus sequence (ATGC-N7-GCAT) in several operator-promoter regions. In strains lacking AalR, suppressor mutations revealed a role for the ClpAP protease in Asp metabolism. In the absence of the ClpA component of this protease, DarR can compensate for the loss of AalR. ADP1 consumed l- and d-Asn and l-Glu, but not d-Glu, as the sole carbon or nitrogen source using interrelated pathways. IMPORTANCE A regulatory scheme was revealed in which AalR responds to l-Asp and DarR responds to d-Asp, a molecule with critical signaling functions in many organisms. The RacD-mediated interconversion of these isomers causes overlap in transcriptional control in A. baylyi. Our studies improve understanding of transport and regulation and lay the foundation for determining how regulators distinguish l- and d-enantiomers. These studies are relevant for biotechnology applications, and they highlight the importance of d-amino acids as natural bacterial growth substrates.

Increases in sensory noise predict attentional disruptions to audiovisual speech perception.

We receive information about the world around us from multiple senses which combine in a process known as multisensory integration. Multisensory integration has been shown to be dependent on attention; however, the neural mechanisms underlying this effect are poorly understood. The current study investigates whether changes in sensory noise explain the effect of attention on multisensory integration and whether attentional modulations to multisensory integration occur via modality-specific mechanisms. A task based on the McGurk Illusion was used to measure multisensory integration while attention was manipulated via a concurrent auditory or visual task. Sensory noise was measured within modality based on variability in unisensory performance and was used to predict attentional changes to McGurk perception. Consistent with previous studies, reports of the McGurk illusion decreased when accompanied with a secondary task; however, this effect was stronger for the secondary visual (as opposed to auditory) task. While auditory noise was not influenced by either secondary task, visual noise increased with the addition of the secondary visual task specifically. Interestingly, visual noise accounted for significant variability in attentional disruptions to the McGurk illusion. Overall, these results strongly suggest that sensory noise may underlie attentional alterations to multisensory integration in a modality-specific manner. Future studies are needed to determine whether this finding generalizes to other types of multisensory integration and attentional manipulations. This line of research may inform future studies of attentional alterations to sensory processing in neurological disorders, such as Schizophrenia, Autism, and ADHD.

Neurobehavioral anomalies in zebrafish after sequential exposures to DDT and chlorpyrifos in adulthood: Do multiple exposures interact?

A sequence of different classes of synthetic insecticides have been used over the past 70 years. Over this period, the widely-used organochlorines were eventually replaced by organophosphates, with dichlorodiphenyltrichloroethane (DDT) and chlorpyrifos (CPF) as the principal prototypes. Considerable research has characterized the risks of DDT and CPF individually, but little is known about the toxicology of transitioning from one class of insecticides to another, as has been commonplace for agricultural and pest control workers. This study used adult zebrafish to investigate neurobehavioral toxicity following 5-week chronic exposure to either DDT or CPF, to or their sequential exposure (DDT for 5 weeks followed by CPF for 5 weeks). At the end of the exposure period, a subset of fish were analyzed for brain cholinesterase activity. Behavioral effects were initially assessed one week following the end of the CPF exposure and again at 14 months of age using a behavioral test battery covering sensorimotor responses, anxiety-like functions, predator avoidance and social attraction. Adult insecticide exposures, individually or sequentially, were found to modulate multiple behavioral features, including startle responsivity, social approach, predator avoidance, locomotor activity and novel location recognition and avoidance. Locomotor activity and startle responsivity were each impacted to a greater degree by the sequential exposures than by individual compounds, with the latter being pronounced at the early (1-week post exposure) time point, but not 3-4 months later in aging. Social approach responses were similarly impaired by the sequential exposure as by CPF-alone at the aging time point. Fleeing responses in the predator test showed flee-enhancing effects of both compounds individually versus controls, and no additive impact of the two following sequential exposure. Each compound was also associated with changes in recognition or avoidance patterns in a novel place recognition task in late adulthood, but sequential exposures did not enhance these phenotypes. The potential for chemical x chemical interactions did not appear related to changes in CPF metabolism to the active oxon, as prior DDT exposure did not affect the cholinesterase inhibition resulting from CPF. This study shows that the effects of chronic adult insecticide exposures may be relevant to behavioral health initially and much later in life, and that the effects of sequential exposures may be unpredictable based on their constituent exposures.

Adult exposure to insecticides causes persistent behavioral and neurochemical alterations in zebrafish.

Farmers are often chronically exposed to insecticides, which may present health risks including increased risk of neurobehavioral impairment during adulthood and across aging. Experimental animal studies complement epidemiological studies to help determine the cause-and-effect relationship between chronic adult insecticide exposure and behavioral dysfunction. With the zebrafish model, we examined short and long-term neurobehavioral effects of exposure to either an organochlorine insecticide, dichlorodiphenyltrichloroethane (DDT) or an organophosphate insecticide chlorpyrifos (CPF). Adult fish were exposed continuously for either two or 5 weeks (10-30 nM DDT, 0.3-3 µM CPF), with short- and long-term effects assessed at 1-week post-exposure and at 14 months of age respectively. The behavioral test battery included tests of locomotor activity, tap startle, social behavior, anxiety, predator avoidance and learning. Long-term effects on neurochemical indices of cholinergic function were also assessed. Two weeks of DDT exposure had only slight effects on locomotor activity, while a longer five-week exposure led to hypoactivity and increased anxiety-like diving responses and predator avoidance at 1-week post-exposure. When tested at 14 months of age, these fish showed hypoactivity and increased startle responses. Cholinergic function was not found to be significantly altered by DDT. The two-week CPF exposure led to reductions in anxiety-like diving and increases in shoaling responses at the 1-week time point, but these effects did not persist through 14 months of age. Nevertheless, there were persistent decrements in cholinergic presynaptic activity. A five-week CPF exposure led to long-term effects including locomotor hyperactivity and impaired predator avoidance at 14 months of age, although no effects were apparent at the 1-week time point. These studies documented neurobehavioral effects of adult exposure to chronic doses of either organochlorine or organophosphate pesticides that can be characterized in zebrafish. Zebrafish provide a low-cost model that has a variety of advantages for mechanistic studies and may be used to expand our understanding of neurobehavioral toxicity in adulthood, including the potential for such toxicity to influence behavior and development during aging.

Auditory and visual distractors disrupt multisensory temporal acuity in the crossmodal temporal order judgment task.

The ability to synthesize information across multiple senses is known as multisensory integration and is essential to our understanding of the world around us. Sensory stimuli that occur close in time are likely to be integrated, and the accuracy of this integration is dependent on our ability to precisely discriminate the relative timing of unisensory stimuli (crossmodal temporal acuity). Previous research has shown that multisensory integration is modulated by both bottom-up stimulus features, such as the temporal structure of unisensory stimuli, and top-down processes such as attention. However, it is currently uncertain how attention alters crossmodal temporal acuity. The present study investigated whether increasing attentional load would decrease crossmodal temporal acuity by utilizing a dual-task paradigm. In this study, participants were asked to judge the temporal order of a flash and beep presented at various temporal offsets (crossmodal temporal order judgment (CTOJ) task) while also directing their attention to a secondary distractor task in which they detected a target stimulus within a stream visual or auditory distractors. We found decreased performance on the CTOJ task as well as increases in both the positive and negative just noticeable difference with increasing load for both the auditory and visual distractor tasks. This strongly suggests that attention promotes greater crossmodal temporal acuity and that reducing the attentional capacity to process multisensory stimuli results in detriments to multisensory temporal processing. Our study is the first to demonstrate changes in multisensory temporal processing with decreased attentional capacity using a dual task paradigm and has strong implications for developmental disorders such as autism spectrum disorders and developmental dyslexia which are associated with alterations in both multisensory temporal processing and attention.

Visual Distractors Disrupt Audiovisual Integration Regardless of Stimulus Complexity.

The intricate relationship between multisensory integration and attention has been extensively researched in the multisensory field; however, the necessity of attention for the binding of multisensory stimuli remains contested. In the current study, we investigated whether diverting attention from well-known multisensory tasks would disrupt integration and whether the complexity of the stimulus and task modulated this interaction. A secondary objective of this study was to investigate individual differences in the interaction of attention and multisensory integration. Participants completed a simple audiovisual speeded detection task and McGurk task under various perceptual load conditions: no load (multisensory task while visual distractors present), low load (multisensory task while detecting the presence of a yellow letter in the visual distractors), and high load (multisensory task while detecting the presence of a number in the visual distractors). Consistent with prior studies, we found that increased perceptual load led to decreased reports of the McGurk illusion, thus confirming the necessity of attention for the integration of speech stimuli. Although increased perceptual load led to longer response times for all stimuli in the speeded detection task, participants responded faster on multisensory trials than unisensory trials. However, the increase in multisensory response times violated the race model for no and low perceptual load conditions only. Additionally, a geometric measure of Miller's inequality showed a decrease in multisensory integration for the speeded detection task with increasing perceptual load. Surprisingly, we found diverging changes in multisensory integration with increasing load for participants who did not show integration for the no load condition: no changes in integration for the McGurk task with increasing load but increases in integration for the detection task. The results of this study indicate that attention plays a crucial role in multisensory integration for both highly complex and simple multisensory tasks and that attention may interact differently with multisensory processing in individuals who do not strongly integrate multisensory information.