Biology subjects

Walsh, K.

Publications and source records attributed to Walsh, K..

26 records · Page 2Linked to original sources

bioRxiv2023

Neurophysiology of perceptual decision-making and its alterations in attention deficit hyperactivity disorder (ADHD)

Despite the prevalence of ADHD, efforts to develop a detailed understanding of the neuropsychology of this neurodevelopmental condition are complicated by the diversity of interindividual presentations and the inability of current clinical tests to distinguish between its sensory, attentional, arousal or motoric contributions. Identifying objective methods that can decompose the clinical heterogeneity of ADHD is a long-held goal that is hoped to advance our understanding of etiological processes and potentially aid the development of personalized treatment approaches. Here, we examine key neuropsychological components of ADHD within an electrophysiological (EEG) perceptual decision-making paradigm that is capable of isolating distinct neural signals of several key information processing stages necessary for sensory-guided actions from attentional selection to motor responses. We show that compared to typically developing children, children with ADHD displayed slower and less accurate performance, which was driven by the atypical dynamics of discrete electrophysiological signatures of attentional selection, the accumulation of sensory evidence, and strategic adjustments reflecting urgency of response. These findings offer an integrated account of decision-making in ADHD and establish discrete neural signals that can be used to understand the wide range of neuropsychological performance variations in individuals with ADHD. Significance StatementThe efficacy of diagnostic and therapeutic pathways in ADHD is limited by our incomplete understanding of its neurological basis. One promising avenue of research is the search for basic neural mechanisms that may contribute to the variety of cognitive challenges associated with ADHD. We developed a mechanistic account of differences in a fundamental cognitive process by integrating across neurocognitive, neurophysiological (i.e., EEG), and computational levels of analysis. We detected distinct neural changes in ADHD that explained altered performance (e.g., slowed and less accurate responses). These included changes in neural patterns of attentional selection, sensory information processing, and response preparation. These findings enhance our understanding of the neurophysiological profile of ADHD and may offer potential targets for more effective, personalized interventions.

neuroscience↗

bioRxiv2023

Mouse Model of Heart Attack and Stroke Shows Improved Survival with MPO Inhibition

Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide1. Unfortunately, the lack of a mouse model that develops advanced coronary atherosclerosis and that exhibits a high incidence of spontaneous plaque rupture with MI or stroke has greatly stymied development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Herein, we describe a novel mouse model that develops widespread advanced atherosclerosis including in coronary, brachiocephalic, and carotid arteries. These mice show high mortality following Western Diet feeding with clear evidence of plaque rupture, MI, and stroke. To validate the utility of this model, mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme primarily produced by activated neutrophils and predictive of rupture of human atherosclerotic lesions2-7. AZM198 treatment resulted in marked improvements in survival with a greater than 60% decrease in the incidence of plaque rupture, MI, and stroke. In summary, our work describes a novel mouse model that closely replicates late-stage clinical events of advanced human atherosclerotic disease and evidence that this model can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.

physiology↗

bioRxiv2023

Prior probability cues bias sensory encoding with increasing task exposure

When observers have prior knowledge about the likely outcome of their perceptual decisions, they exhibit robust behavioural biases in reaction time and choice accuracy. Computational modelling typically attributes these effects to strategic adjustments in the criterion amount of evidence required to commit to a choice alternative - usually implemented by a starting point shift - but recent work suggests that expectations may also fundamentally bias the encoding of the sensory evidence itself. Here, we recorded neural activity with EEG while participants performed a contrast discrimination task with valid, invalid, or neutral probabilistic cues across multiple testing sessions. We measured sensory evidence encoding via contrast-dependent steady-state visual-evoked potentials (SSVEP), while a read-out of criterion adjustments was provided by effector-selective mu-beta band activity over motor cortex. In keeping with prior modelling and neural recording studies, cues evoked substantial biases in motor preparation consistent with criterion adjustments, but we additionally found that the cues produced a significant modulation of the SSVEP during evidence presentation. While motor preparation adjustments were observed in the earliest trials, the sensory-level effects only emerged with extended task exposure. Our results suggest that, in addition to strategic adjustments to the decision process, probabilistic information can also induce subtle biases in the encoding of the evidence itself.

neuroscience↗

bioRxiv2021

The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

BackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage. ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

cell biology↗

bioRxiv2020

Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues1-3. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression4,5, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations6. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying retinal vascular development in Fucci2aR reporter mice7, we found that venous and arterial endothelial cells are in distinct cell cycle states during development and in adulthood. That is, venous endothelial cells reside in early G1 state, while arterial endothelial cells reside in late G1 state. Endothelial cells in early vs. late G1 exhibited significant differences in gene expression and activity, especially among BMP/TGF-{beta} signaling components. The early G1 state was found to be essential for BMP4-induced venous specification, whereas late G1 state is essential for TGF-{beta}1-induced arterial specification. In a mouse model of endothelial cell hyperproliferation and disrupted vascular remodeling, pharmacological inhibition of endothelial cell cycle rescues the arterial-venous specification defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

developmental biology↗

bioRxiv2020

Read counts from environmental DNA (eDNA) metabarcoding reflect fish abundance and biomass in drained ponds

The sampling of environmental DNA (eDNA) coupled with cost-efficient and ever-advancing sequencing technology is propelling changes in biodiversity monitoring within aquatic ecosystems. Despite the growth of DNA metabarcoding approaches, the ability to quantify species biomass and abundance in natural systems remains a major challenge. Few studies have examined the association between eDNA metabarcoding data and biomass inferred by whole-organism sampling, mesocosms or mock communities, and the interpretation of sequencing reads as a measure of biomass or number of organisms is largely disputed. Here we tested whether read counts from eDNA metabarcoding provide accurate quantitative estimates of fish abundance in holding ponds with known fish biomass and number of individuals. eDNA samples were collected from two fishery ponds with high fish density and broad species diversity. In one pond, two different DNA capture strategies (on-site filtration with enclosed filters and three different preservation buffers versus lab filtration using open filters) were used to evaluate their performance in relation to fish community composition and biomass/abundance estimates. Fish species read counts were significantly correlated with both biomass and abundance, and this result, together with information on fish diversity, was repeatable when open or enclosed filters with different preservation buffers were used. This research demonstrates that eDNA metabarcoding provides accurate qualitative and quantitative information on fish communities in small ponds, and results are consistent between different methods of DNA capture. This method flexibility will be beneficial for future eDNA-based fish monitoring and their integration into fisheries management.

molecular biology↗

bioRxiv2020

Long-term Behavioural Rewriting of Maladaptive Drinking Memories via Reconsolidation-Update Mechanisms

BackgroundAlcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are a key therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. MethodsHazardous/harmful beer-drinking volunteers (N=120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels assessed up to 9 months. ResultsGreater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning were noted. Responsiveness to counterconditioning predicted subsequent responses to acute alcohol in RET+PE only, consistent with reconsolidation-update mechanisms. ConclusionsThe longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions.

neuroscience↗

bioRxiv2019

Contralateral Delay Activity is not sensitive to cognitive decline in older adults at risk of Mild Cognitive Impairment.

Contralateral delay activity (CDA) has been proposed as a pre-clinical marker for Mild Cognitive Impairment (MCI). However, existing evidence is limited to one study with a small sample size (n=12 per group). Our aim was to compare CDA amplitudes in a larger sample of low- and high-risk older adult groups (n=35 per group). As expected, behavioural performance decreased as the number of memory items increased, and the low-risk group out-performed the high-risk group. However, we found no differences in CDA amplitudes across groups, indicating that WM capacity increased irrespective of risk-level. These findings suggest that the CDA is not a sensitive marker of MCI risk. More broadly, our results highlight the difficulty in identifying at-risk individuals, particularly as MCI is a heterogeneous, unstable condition. Future research should prioritise longitudinal approaches in order to track the progression of the CDA and its association with cognitive decline in later life.

neuroscience↗