Biology subjects

Husain, M.

Publications and source records attributed to Husain, M..

30 records · Page 2Linked to original sources

bioRxiv2020

5-HT2c receptors regulate the balance between instrumental vigour and restraint

The serotonin (5-HT) system, particularly the 5-HT2C receptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2C receptors plays in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2C receptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2C receptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to administration of d-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2C receptors - but crucially not intra-NAcC infusions - consistently boosted rats performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC with d-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2C receptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward.

neuroscience↗

bioRxiv2020

Ageing disrupts reinforcement learning whilst learning to help others is preserved

Reinforcement learning is a fundamental mechanism displayed by many species. However, adaptive behaviour depends not only on learning about actions and outcomes that affect ourselves, but also those that affect others. Here, using computational reinforcement learning models, we tested whether young (age 18-36) and older (age 60-80, total n=152) adults can learn to gain rewards for themselves, another person (prosocial), or neither individual (control). Detailed model comparison showed that a model with separate learning rates for each recipient best explained behaviour. Young adults were faster to learn when their actions benefitted themselves, compared to helping others. Strikingly, compared to younger adults, older adults showed preserved prosocial learning rates but reduced self-relevant learning rates. Moreover, psychopathic traits were lower in older adults and negatively correlated with prosocial learning. These findings suggest learning how to benefit others is preserved across the lifespan with implications for reinforcement learning and theories of healthy ageing.

neuroscience↗

bioRxiv2020

Neural signatures of pathological hyperdirect pathway activity in Parkinson's disease

Parkinsons disease (PD) is characterised by the emergence of pathological patterns of oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between anatomical connectivity and oscillatory synchronisation within this system remains poorly understood. We address this by integrating evidence from invasive electrophysiology, magnetoencephalography, tractography and computational modelling in patients. Coupling between supplementary motor area (SMA) and subthalamic nucleus (STN) within the high beta frequency (21-30 Hz) range correlated with fibre tract densities between these two structures. Additionally within the STN, non-linear waveform features suggestive of cortical synchronisation correlated with cortico-STN fibre densities. Finally, computational modelling revealed that exaggerated hyperdirect cortical inputs to the STN in the upper beta frequency range can provoke the generation of widespread pathological synchrony at lower beta (13-20 Hz) frequencies. These observations reveal a spectral signature of the hyperdirect pathway at high beta frequencies and provide evidence for its pathophysiological role in oscillatory network dysfunction in PD. One sentence summarySignatures of the hyperdirect pathway and its likely role in pathological network disruption in Parkinsons disease are identified.

neuroscience↗

bioRxiv2020

Spatial distribution and cognitive impact of cerebrovascular risk-related white matter hyperintensities

ObjectivesWhite matter hyperintensities (WMHs) are considered macroscale markers of cerebrovascular burden and are associated with increased risk of vascular cognitive impairment and dementia. However, the spatial location of WMHs has typically been considered in broad categories of periventricular versus deep white matter. The spatial distribution of WHMs associated with individual cerebrovascular risk factors (CVR), controlling for frequently comorbid risk factors, has not been systematically investigated at the population level in a healthy ageing cohort. Furthermore, there is an inconsistent relationship between total white matter hyperintensity load and cognition, which may be due to the confounding of several simultaneous risk factors in models based on smaller cohorts. MethodsWe examined trends in individual CVR factors on total WMH burden in 13,680 individuals (aged 45-80) using data from the UK Biobank. We estimated the spatial distribution of white matter hyperintensities associated with each risk factor and their contribution to explaining total WMH load using voxel-wise probit regression and univariate linear regression. Finally, we explored the impact of CVR-related WMHs on speed of processing using regression and mediation analysis. ResultsContrary to the assumed dominance of hypertension as the biggest predictor of WMH burden, we show associations with a number of risk factors including diabetes, heavy smoking, APOE{varepsilon} 4/{varepsilon}4 status and high waist-to-hip ratio of similar, or greater magnitude to hypertension. The spatial distribution of WMHs varied considerably with individual cerebrovascular risk factors. There were independent effects of visceral adiposity, as measured by waist-to-hip ratio, and carriage of the APOE{varepsilon} 4 allele in terms of the unique spatial distribution of CVR-related WMHs. Importantly, the relationship between total WMH load and speed of processing was mediated by waist-to-hip ratio suggesting cognitive consequences to WMHs associated with excessive visceral fat deposition. ConclusionWaist-to-hip ratio, diabetes, heavy smoking, hypercholesterolemia and homozygous APOE{varepsilon} 4 status are important risk factors, beyond hypertension, associated with WMH total burden and warrant careful control across ageing. The spatial distribution associated with different risk factors may provide important clues as to the pathogenesis and cognitive consequences of WMHs. High waist-to-hip ratio is a key risk factor associated with slowing in speed of processing. With global obesity levels rising, focused management of visceral adiposity may present a useful strategy for the mitigation of cognitive decline in ageing.

neuroscience↗

bioRxiv2019

Long-term functional culture and in vitro manipulation of adult mouse cardiomyocytes

Primary adult cardiomyocyte (aCM) culture is challenged by poor survival and loss of phenotype, rendering extended in vitro experiments unfeasible. Here, we establish murine aCM culture methods that enhance survival and maintain sarcomeric structure and Ca2+ cycling to enable physiologically-relevant contractile force measurements. We also demonstrate genetic and small-molecule manipulations that probe mechanisms underlying myocyte functional performance.

cell biology↗

bioRxiv2019

Dopamine and motivational state drive dynamics of human decision making

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by travelling elsewhere (background reward rate), in order to determine the opportunity cost of staying versus leaving. We hypothesised that dopamine specifically modulates the influence of background - but not foreground - reward information when making a dynamic comparison of these variables for optimal behaviour. On a novel foraging task based on an ecological account of animal behaviour (marginal value theorem), human participants were required to decide when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background rates. In line with theoretical accounts, peoples decisions to move from current locations were independently modulated by both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background but not foreground rewards rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signalling the opportunity cost of rewards, not value per se. Using this ecologically derived framework we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared. Significance statementMany decisions, across economic, political and social spheres, involve choices to "leave". Such decisions depend on a continuous comparison of a current locations value, with that of other locations you could move on to. However, how the brain makes such decisions is poorly understood. Here, we developed a computerized task, based around theories of how animals make decisions to move on when foraging for food. Healthy human participants had to decide when to leave collecting financial rewards in a location, and travel to collect rewards elsewhere. Using a pharmacological manipulation, we show that the activity of dopamine in the brain modulates decisions to move on, with people valuing other locations differently depending on their dopaminergic state.

neuroscience↗

bioRxiv2019

Type I interferons are important co-stimulatory signals during T cell receptor mediated MAIT cell activation

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stimulated either via their T cell receptor (TCR) or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as Toll-like receptor agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-D-ribitylaminouracil/methylglyoxal (5-A-RU/MG). We found that T1-IFNs were able to boost interferon-{gamma} and granzyme B production in 5-A-RU/MG-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was confirmed using liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.

immunology↗

bioRxiv2019

Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank

Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimers disease (AD). For example, an objective evaluation of a patients hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patients hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individuals hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.

neuroscience↗

bioRxiv2019

Transcranial photobiomodulation with infrared laser increases power of brain oscillations

Non-invasive transcranial photobiomodulation with a 1064-nm laser (tPBML1064) has been reported to improve human performance on cognitive tasks as well as locally upregulate cerebral oxygen metabolism and hemodynamics. However, it is unknown whether tPBML1064 also modulates electrophysiology, and specifically neural oscillations, in the human brain. The hypothesis guiding this study was that tPBML1064 of the right prefrontal cortex enhances neurophysiological rhythms at specific frequency bands in the human brain under resting conditions. To test this hypothesis, we recorded the 64-channel scalp electroencephalogram (EEG) before, during, and after the application of 11 minutes of 4-cm-diameter tPBML1064 to the right forehead of human subjects (n=20) using a within-subject, sham-controlled design. Time-resolved scalp topographies of EEG power at five frequency bands were computed to examine tPBML1064-induced EEG power changes across the scalp. The results showed time-dependent, significant increases of EEG spectral powers at the alpha (8-13 Hz) and beta (13-30 Hz) bands at broad scalp regions, exhibiting a front-to-back pattern. The findings provide the first sham-controlled topographic mapping that tPBML1064 increases the strength of electrophysiological oscillations (alpha and beta bands), while also shedding light on the mechanisms of tPBM in the human brain.

bioengineering↗

bioRxiv2018

Automated lesion segmentation with BIANCA: impact of population-level features, classification algorithm and locally adaptive thresholding

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurode-generative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions.\n\nIn this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature, with respect to K-nearest neighbour algorithm currently used for lesion probability map estimation in BIANCA. Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort and a vascular cohort.\n\nWe observed that including population-level parametric lesion probabilities with re-spect to age and using alternative machine learning techniques provided negligible im-provement. However, LOCATE provided a substantial improvement in the lesion segmentation performance when compared to the global thresholding currently used in BIANCA. We further validated LOCATE on a cohort of CADASIL (Cerebral autoso-mal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease characterised by extensive WMH burden, and healthy controls showing that LOCATE adapts well to wide variations in lesion load and spatial distribution.

neuroscience↗

bioRxiv2018

Parallel encoding of information into visual short-term memory

Humans can temporarily retain information in their highly limited short-term memory. Traditionally, objects are thought to be attentionally selected and committed to short-term memory one-by-one. However, few studies directly test this serial encoding assumption. Here, we demonstrate that information from separate objects can be encoded into short-term memory in parallel. We developed models of serial and parallel encoding that describe probabilities of items being present in short-term memory throughout the encoding process, and tested them in a whole-report design. Empirical data from four experiments in healthy individuals were fitted best by the parallel encoding model, even when items were presented unilaterally (processed within one hemisphere). Our results demonstrate that information from several items can be attentionally selected and consequently encoded into short-term memory simultaneously. This suggests the popular feature integration theory needs to be reformulated to account for parallel encoding, and provides important boundaries for computational models of short-term memory.

neuroscience↗

bioRxiv2017

A neural model of working memory

Working memory, the ability to keep recently encountered information available for immediate processing, has been proposed to rely on two mechanisms that appear difficult to reconcile: selfsustained neural firing, or the opposite--activity-silent synaptic traces. Here we show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or \"focused\" state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diverse range of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework.

neuroscience↗