Environmental disturbance confounds prenatal glucocorticoid programming experiments in Wistar rats

Abstract Low birth weight in humans is predictive of hypertension in adult life, and while the mechanisms underlying this link remain unknown, fetal overexposure to glucocorticoids has been implicated. We have previously shown that prenatal dexamethasone (DEX) exposure in the rat lowers birth weight and programmes adult hypertension. This current study aimed to unravel the molecular nature of this hypertension. However, unknowingly, post hoc investigations revealed that our animals had been subjected to environmental noise stresses from an adjacent construction site, which were sufficient to confound our prenatal DEX-programming experiments. This perinatal stress successfully established low birth weight, hypercorticosteronaemia, insulin resistance, hypertension and hypothalamic-pituitary -adrenal axis dysfunction in vehicle (VEH)-treated offspring, such that the typical distinctions between both treatment groups were ameliorated. The lack of an additional effect on DEX-treated offspring is suggestive of a maximal effect of perinatal stress and glucocorticoids, serving to prevent against the potentially detrimental effects of sustained glucocorticoid hyper-exposure. Finally, this paper serves to inform researchers of the potential detrimental effects of neighbouring construction sites to their experiments. As research institutions expand and respond to everchanging building and animal welfare regulations, they are required to undergo either new construction and/or renovation. However, such structural changes are associated with a plethora of nuisances, such as noise and vibration, with each disturbance being capable of powerfully stimulating the hypothalamic -pituitary -adrenal (HPA) axis. 1 The auditory system is permanently open -even during sleep. Its rapid and overshooting excitations in response to noise signals are subcortically connected, via the amygdala, to the HPA axis, resulting in corticotrophin releasing hormone and adrenocorticotrophic hormone release. 2 Animal experiments show noise-induced changes in the sensitivity of glucocorticoid receptor (GR) by increase of heat-shock proteins 3 and ultrastructural changes of the adrenal gland. 4 Increased cortisol levels have been found in humans when exposed to aircraft 5 or road traffic noise, 6 even during sleep, 7 implying these effects are mainly without mental control. Of course, increased glucocorticoid and sympathetic neural secretion is a perfect short-term stress response, coordinating appropriate metabolic and vascular changes, and thereby assisting the individual to negotiate the stressor. However, over prolonged time periods, such as persistent noise-induced stress responses, can be gravely damaging to health. 2,8 Numerous animal studies have documented the programming effects of pre-and postnatal stress on offspring physiology and behaviour, which are remarkably analogous to those induced by fetal glucocorticoid overexposure. Exposing pregnant dams to stressful stimuli results in both maternal and fetal HPA activation. 9,10 Moreover, these offspring display an activated HPA axis till weaning, as adults are more anxious and stress-responsive

A Clinical Trial to Validate Event-Related Potential Markers of Alzheimer\u27s Disease in Outpatient Settings

INTRODUCTION: We investigated whether event-related potentials (ERP) collected in outpatient settings and analyzed with standardized methods can provide a sensitive and reliable measure of the cognitive deficits associated with early Alzheimer\u27s disease (AD). METHODS: A total of 103 subjects with probable mild AD and 101 healthy controls were recruited at seven clinical study sites. Subjects were tested using an auditory oddball ERP paradigm. RESULTS: Subjects with mild AD showed lower amplitude and increased latency for ERP features associated with attention, working memory, and executive function. These subjects also had decreased accuracy and longer reaction time in the target detection task associated with the ERP test. DISCUSSION: Analysis of ERP data showed significant changes in subjects with mild AD that are consistent with the cognitive deficits found in this population. The use of an integrated hardware/software system for data acquisition and automated data analysis methods make administration of ERP tests practical in outpatient settings

Spontaneous and deliberate future thinking: A dual process account

© 2019 Springer Nature.This is the final published version of an article published in Psychological Research, licensed under a Creative Commons Attri-bution 4.0 International License. Available online at: https://doi.org/10.1007/s00426-019-01262-7.In this article, we address an apparent paradox in the literature on mental time travel and mind-wandering: How is it possible that future thinking is both constructive, yet often experienced as occurring spontaneously? We identify and describe two ‘routes’ whereby episodic future thoughts are brought to consciousness, with each of the ‘routes’ being associated with separable cognitive processes and functions. Voluntary future thinking relies on controlled, deliberate and slow cognitive processing. The other, termed involuntary or spontaneous future thinking, relies on automatic processes that allows ‘fully-fledged’ episodic future thoughts to freely come to mind, often triggered by internal or external cues. To unravel the paradox, we propose that the majority of spontaneous future thoughts are ‘pre-made’ (i.e., each spontaneous future thought is a re-iteration of a previously constructed future event), and therefore based on simple, well-understood, memory processes. We also propose that the pre-made hypothesis explains why spontaneous future thoughts occur rapidly, are similar to involuntary memories, and predominantly about upcoming tasks and goals. We also raise the possibility that spontaneous future thinking is the default mode of imagining the future. This dual process approach complements and extends standard theoretical approaches that emphasise constructive simulation, and outlines novel opportunities for researchers examining voluntary and spontaneous forms of future thinking.Peer reviewe

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

Probing the screening of the Casimir interaction with optical tweezers

We measure the colloidal interaction between two silica microspheres in aqueous solution in the distance range from $0.2\,\mu$m to $0.5\,\mu$m with the help of optical tweezers. When employing a sample with a low salt concentration, the resulting interaction is dominated by the repulsive double-layer interaction which is fully characterized. The double-layer interaction is suppressed when adding $0.22\,$M of salt to our sample, thus leading to a purely attractive Casimir signal. When analyzing the experimental data for the potential energy and force, we find good agreement with theoretical results based on the scattering approach. At the distance range probed experimentally, the interaction arises mainly from the unscreened transverse magnetic contribution in the zero-frequency limit, with nonzero Matsubara frequencies providing a negligible contribution. In contrast, such unscreened contribution is not included by the standard theoretical model of the Casimir interaction in electrolyte solutions, in which the zero-frequency term is treated separately as an electrostatic fluctuational effect. As a consequence, the resulting attraction is too weak in this standard model, by approximately one order of magnitude, to explain the experimental data. Overall, our experimental results shed light on the nature of the thermal zero-frequency contribution and indicate that the Casimir attraction across polar liquids has a longer range than previously predicted.Comment: 19 pages, 9 figures; updated references; added a detailed discussion of the subtraction procedure leading to the interaction potentia

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses

Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and the SARS-CoV-2 pandemic1–4. Vaccines that elicit protective immunity against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that macaque immunization with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052/Alum elicited cross-neutralizing antibody (cross-nAb) responses against batCoVs, SARS-CoV-1, SARS-CoV-2, and SARS-CoV-2 variants B.1.1.7, P.1, and B.1.351. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization ID50 titer of 47,216, and protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD also induced SARS-CoV-1 and batCoV cross-nAbs, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV vaccines

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap‐prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude‐intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2‐weeks following noise‐exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20–60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus‐specific changes were particularly prominent in hippocampal synapse‐rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus‐specific changes occurred in synapse‐rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150542/1/hipo23058.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150542/2/hipo23058_am.pd