What Role Does Striatal Dopamine Play in Goal-directed Action?

Evidence suggests that dopamine activity provides a US-related prediction error for Pavlovian conditioning and the reinforcement signal supporting the acquisition of habits. However, its role in goal-directed action is less clear. There are currently few studies that have assessed dopamine release as animals acquire and perform self-paced instrumental actions. Here we briefly review the literature documenting the psychological, behavioral and neural bases of goal-directed actions in rats and mice, before turning to describe recent studies investigating the role of dopamine in instrumental learning and performance. Plasticity in dorsomedial striatum, a central node in the network supporting goal-directed action, clearly requires dopamine release, the timing of which, relative to cortical and thalamic inputs, determines the degree and form of that plasticity. Beyond this, bilateral release appears to reflect reward prediction errors as animals experience the consequences of an action. Such signals feedforward to update the value of the specific action associated with that outcome during subsequent performance, with dopamine release at the time of action reflecting the updated predicted action value. More recently, evidence has also emerged for a hemispherically lateralised signal associated with the action; dopamine release is greater in the hemisphere contralateral to the spatial target of the action. This effect emerges over the course of acquisition and appears to reflect the strength of the action-outcome association. Thus, during goal-directed action, dopamine release signals the action, the outcome and their association to shape the learning and performance processes necessary to support this form of behavioral control.

Stimulus-outcome associations are required for the expression of specific Pavlovian-instrumental transfer.

A series of experiments employed a specific Pavlovian-instrumental transfer (PIT) task in rats to determine the capacity of various treatments to undermine two outcome-specific stimulus-outcome (S-O) associations. Experiment 1 tested a random treatment, which involved uncorrelated presentations of the two stimuli and their predicted outcomes. This treatment disrupted the capacity of the outcome-specific S-O associations to drive specific PIT. Experiment 2 used a negative-contingency treatment during which the predicted outcomes were exclusively delivered in the absence of their associated stimulus. This treatment spared specific PIT, suggesting that it left the outcome-specific S-O associations relatively intact. The same outcome was obtained in Experiment 3, which implemented a zero-contingency treatment consisting of delivering the predicted outcomes in the presence and absence of their associated stimulus. Experiment 4 tested a mixed treatment, which distributed the predicted outcomes at an equal rate during each stimulus. This treatment disrupted the capacity of the outcome-specific S-O associations to drive specific PIT. We suggest that the mixed treatment disrupted specific PIT by generating new and competing outcome-specific S-O associations. By contrast, we propose that the random treatment disrupted specific PIT by undermining the original outcome-specific S-O associations, indicating that these associations must be retrieved to express specific PIT. We discuss how these findings inform our theoretical understanding of the mechanisms underlying this phenomenon. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

What does dopamine release reveal about latent inhibition?

A recent paper by Kutlu et al. (2022) argues that changes in dopamine release during stimulus pre-exposure reflect non-associative changes in attention to the conditioned stimulus that are causally related to latent inhibition effects. Associative accounts of pre-exposure-induced changes in associability suggest, however, that such conclusions may be premature.

Fatal sepsis from appendicitis caused by an impacted tooth.

Acute appendicitis is one of the most common causes of acute abdominal pain globally. The pathophysiology of acute appendicitis is due to occlusion of the appendiceal lumen commonly from a faecolith. Obstruction of the appendiceal lumen by ingested foreign bodies is possible albeit rare. Here, we present an extremely rare case of acute appendicitis caused by impaction of the patients tooth within the lumen of the appendix. There have been only seven reported cases of impacted teeth causing appendicitis in the literature. There are no evidence-based guidelines for the management of appendicitis caused by tooth impaction. The authors suggest operative management with appendicectomy should be considered in the first instance.

The positive valence system, adaptive behaviour and the origins of reward.

Although the hey-day of motivation as an area of study is long past, the issues with which motivational theorists grappled have not grown less important: i.e. the development of deterministic explanations for the particular tuning of the nervous system to specific changes in the internal and external environment and the organisation of adaptive behavioural responses to those changes. Here, we briefly elaborate these issues in describing the structure and function of the 'positive valence system'. We describe the origins of adaptive behaviour in an ascending arousal system, sensitive to peripheral regulatory changes, that modulates and activates various central motivational states. Associations between these motivational states and sensory inputs underlie evaluative conditioning and generate the representation of the 'unconditioned' stimuli fundamental to Pavlovian conditioning. As a consequence, associations with these stimuli can generate Pavlovian conditioned responses through the motivational control of stimulus event associations with sensory and affective components of the valence system to elicit conditioned orienting, consummatory and preparatory responses, particularly the affective responses reflecting Pavlovian excitation and inhibition, arousal and reinforcement, the latter used to control the formation of habits. These affective processes also provoke emotional responses, allowing the externalisation of positive valence in hedonic experience to generate the goal or reward values that mediate goal-directed action. Together these processes form the positive valence system, ensure the maintenance of adaptive behaviour and, through the association of sensory events and emotional responses through consummatory experience, provide the origins of reward.

Charge Transport Across Dynamic Covalent Chemical Bridges.

Relationships between chemical structure and conductivity in ordered polymers (OPs) are difficult to probe using bulk samples. We propose that conductance measurements of appropriate molecular-scale models can reveal trends in electronic coupling(s) between repeat units that may help inform OP design. Here, we apply the scanning tunneling microscope-based break-junction (STM-BJ) method to study transport through single-molecules comprising OP-relevant imine, imidazole, diazaborole, and boronate ester dynamic covalent chemical bridges. Notably, solution-stable boron-based compounds dissociate in situ unless measured under a rigorously inert glovebox atmosphere. We find that junction conductance negatively correlates with the electronegativity difference between bridge atoms, and corroborative first-principles calculations further reveal a different nodal structure in the transmission eigenchannels of boronate ester junctions. This work reaffirms expectations that highly polarized bridge motifs represent poor choices for the construction of OPs with high through-bond conductivity and underscores the utility of glovebox STM-BJ instrumentation for studies of air-sensitive materials.

Response-independent outcome presentations weaken the instrumental response-outcome association.

The present article explored the fate of previously formed response-outcome associations when the relation between R and O was disrupted by arranging for O to occur independently of R. In each of three experiments response independent outcome delivery selectively reduced the R earning that O. Nevertheless, in Experiments 1 and 2, the R continued to show sensitivity to outcome devaluation, suggesting that the strength of the R-O association was undiminished by this treatment. These experiments used a two-lever, two-outcome design introducing the possibility that devaluation reflected the influence of specific Pavlovian lever-outcome associations. In an attempt to nullify the influence of these incidental Pavlovian cues Experiment 3 used a single bidirectional vertical lever that rats could press left or right for different outcomes. Again, response-independent outcome presentations selectively depressed the performance of the R that delivered the response-independent O. However, in this situation, the response independent O also reduced the sensitivity of R to outcome devaluation; whereas the nondegraded R was sensitive to devaluation, the degraded R was not. We conclude that selective degradation of the instrumental contingency can weaken a specific R-O association while leaving other R-O associations intact. Furthermore, the use of a bidirectional vertical lever in Experiment 3 revealed that unidirectional and spatially separated instrumental manipulanda, such as levers or chains, may produce Pavlovian cues capable of forming incidental associations with the instrumental outcome that can obscure the relative influence of R-O associations after various manipulations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Beware the pancreatic incidentaloma in colorectal tumours: pancreatic adenocarcinoma with metastases to the colon and rectum.

Colorectal cancer (CRC) is the third most diagnosed malignancy in the Western world. Routine staging of CRC often identifies incidental lesions on cross-sectional imaging. Appropriate treatment is dependent on a correct histological diagnosis. Pancreatic Ductal Adenocarcinoma (PDAC) is a rarer and often devastating diagnosis for which the treatment pathway differs significantly to CRC. We report two rare cases: the first recorded case of PDAC with synchronous rectal metastasis and a case of an acute presentation with large bowel obstruction from synchronous colonic metastasis. Both cases presented a significant diagnostic challenge. The management of both cases would have been altered had the histological diagnosis been known prior to surgery. Clinicians treating CRC should be wary of incidental lesions on staging investigations as they rarely represent an occult extra-intestinal primary malignancy. Immunohistochemistry plays an important role in ascertaining the origin of gastrointestinal malignancy.

Skill decay following Basic Life Support training: a systematic review protocol.

INTRODUCTION: Survival from out of hospital cardiac arrest (OHCA) is lower in the UK than in several developed nations. Bystander cardiopulmonary resuscitation (CPR) is associated with increased rates of survival to hospital discharge following OHCA, prompting the introduction of several initiatives by the UK government to increase rates of bystander CPR, including the inclusion of Basic Life Support (BLS) teaching within the English national curriculum. While there is clear benefit in this, increasing evidence suggests poor retention of skills following BLS teaching. The aim of this systematic review is to summarise the literature regarding skill decay following BLS training, reporting particularly the time period over which this occurs, and which components of would-be rescuers' performance of the BLS algorithm are most affected. METHODS AND ANALYSIS: A search will be conducted to identify studies in which individuals have received BLS training and received subsequent assessment of their skills at a later date. A search strategy comprising relevant Medical Subject Headings (MeSH) terms and keywords has been devised with assistance from an experienced librarian. Relevant databases will be searched with titles, abstract and full-text review conducted independently by two reviewers. Data will be extracted from included studies by two reviewers, with meta-analysis conducted if the appropriate preconditions (such as limited heterogeneity) are met. ETHIC AND DISSEMINATION: No formal ethical approval is required for this systematic review. Results will be disseminated in the form of manuscript submission to a relevant journal and presentation at relevant meetings. To maximise the public's access to this review's findings, any scientific report will be accompanied by a lay summary posted via social media channels, and a press release disseminated to national and international news agencies. PROSPERO REGISTRATION NUMBER: CRD42021237233.

Applications of Deep Mutational Scanning in Virology.

Several recently developed high-throughput techniques have changed the field of molecular virology. For example, proteomics studies reveal complete interactomes of a viral protein, genome-wide CRISPR knockout and activation screens probe the importance of every single human gene in aiding or fighting a virus, and ChIP-seq experiments reveal genome-wide epigenetic changes in response to infection. Deep mutational scanning is a relatively novel form of protein science which allows the in-depth functional analysis of every nucleotide within a viral gene or genome, revealing regions of importance, flexibility, and mutational potential. In this review, we discuss the application of this technique to RNA viruses including members of the Flaviviridae family, Influenza A Virus and Severe Acute Respiratory Syndrome Coronavirus 2. We also briefly discuss the reverse genetics systems which allow for analysis of viral replication cycles, next-generation sequencing technologies and the bioinformatics tools that facilitate this research.

Privacy preserving data visualizations.

Data visualizations are a valuable tool used during both statistical analysis and the interpretation of results as they graphically reveal useful information about the structure, properties and relationships between variables, which may otherwise be concealed in tabulated data. In disciplines like medicine and the social sciences, where collected data include sensitive information about study participants, the sharing and publication of individual-level records is controlled by data protection laws and ethico-legal norms. Thus, as data visualizations - such as graphs and plots - may be linked to other released information and used to identify study participants and their personal attributes, their creation is often prohibited by the terms of data use. These restrictions are enforced to reduce the risk of breaching data subject confidentiality, however they limit analysts from displaying useful descriptive plots for their research features and findings. Here we propose the use of anonymization techniques to generate privacy-preserving visualizations that retain the statistical properties of the underlying data while still adhering to strict data disclosure rules. We demonstrate the use of (i) the well-known k-anonymization process which preserves privacy by reducing the granularity of the data using suppression and generalization, (ii) a novel deterministic approach that replaces individual-level observations with the centroids of each k nearest neighbours, and (iii) a probabilistic procedure that perturbs individual attributes with the addition of random stochastic noise. We apply the proposed methods to generate privacy-preserving data visualizations for exploratory data analysis and inferential regression plot diagnostics, and we discuss their strengths and limitations.

The role of sodium thiocyanate supplementation during dextran sodium sulphate-stimulated experimental colitis.

Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl-) and thiocyanous (SCN-) anions, respectively. While HOCl indiscriminately oxidises biomolecules, HOSCN primarily targets low-molecular weight protein thiols. Oxidative damage mediated by HOSCN may be reversible, potentially decreasing MPO-associated host tissue destruction. This study investigated the effect of SCN- supplementation in a model of acute colitis. Female mice were supplemented dextran sodium sulphate (DSS, 3% w/v) in the presence of 10 mM Cl- or SCN- in drinking water ad libitum, or with salts (NaCl and NaSCN only) or water only (controls). Behavioural studies showed mice tolerated NaSCN and NaCl-treated water with water-seeking frequency. Ion-exchange chromatography showed increased fecal and plasma SCN- levels in thiocyanate supplemented mice; plasma SCN- reached similar fold-increase for smokers. Overall there was no difference in weight loss and clinical score, mucin levels, crypt integrity and extent of cellular infiltration between DSS/SCN- and DSS/Cl- groups. Neutrophil recruitment remained unchanged in DSS-treated mice, as assessed by fecal calprotectin levels. Total thiol and tyrosine phosphatase activity remained unchanged between DSS/Cl- and DSS/SCN- groups, however, colonic tissue showed a trend in decreased 3-chlorotyrosine (1.5-fold reduction, p < 0.051) and marked increase in colonic GCLC, the rate-limiting enzyme in glutathione synthesis. These data suggest that SCN- administration can modulate MPO activity towards a HOSCN-specific pathway, however, this does not alter the development of colitis within a DSS murine model.

The gene for the lysosomal protein LAMP3 is a direct target of the transcription factor ATF4.

Autophagy and lysosomal activities play a key role in the cell by initiating and carrying out the degradation of misfolded proteins. Transcription factor EB (TFEB) functions as a master controller of lysosomal biogenesis and function during lysosomal stress, controlling most but, importantly, not all lysosomal genes. Here, we sought to better understand the regulation of lysosomal genes whose expression does not appear to be controlled by TFEB. Sixteen of these genes were screened for transactivation in response to diverse cellular insults. mRNA levels for lysosomal-associated membrane protein 3 (LAMP3), a gene that is highly up-regulated in many forms of cancer, including breast and cervical cancers, were significantly increased during the integrated stress response, which occurs in eukaryotic cells in response to accumulation of unfolded and misfolded proteins. Of note, results from siRNA-mediated knockdown of activating transcription factor 4 (ATF4) and overexpression of exogenous ATF4 cDNA indicated that ATF4 up-regulates LAMP3 mRNA levels. Finally, ChIP assays verified an ATF4-binding site in the LAMP3 gene promoter, and a dual-luciferase assay confirmed that this ATF4-binding site is indeed required for transcriptional up-regulation of LAMP3 These results reveal that ATF4 directly regulates LAMP3, representing the first identification of a gene for a lysosomal component whose expression is directly controlled by ATF4. This finding may provide a key link between stresses such as accumulation of unfolded proteins and modulation of autophagy, which removes them.

PUblications Metadata Augmentation (PUMA) pipeline.

Cohort studies collect, generate and distribute data over long periods of time - often over the lifecourse of their participants. It is common for these studies to host a list of publications (which can number many thousands) on their website to demonstrate the impact of the study and facilitate the search of existing research to which the study data has contributed. The ability to search and explore these publication lists varies greatly between studies. We believe a lack of rich search and exploration functionality of study publications is a barrier to entry for new or prospective users of a study's data, since it may be difficult to find and evaluate previous work in a given area. These lists of publications are also typically manually curated, resulting in a lack of rich metadata to analyse, making bibliometric analysis difficult. We present here a software pipeline that aggregates metadata from a variety of third-party providers to power a web based search and exploration tool for lists of publications. Alongside core publication metadata (i.e. author lists, keywords etc.), we include geocoding of first authors and citation counts in our pipeline. This allows a characterisation of a study as a whole based on common locations of authors, frequency of keywords, citation profile etc. This enriched publications metadata can be useful for generating study impact metrics and web-based graphics for public dissemination. In addition, the pipeline produces a research data set for bibliometric analysis or social studies of science. We use a previously published list of publications from a cohort study as an exemplar input data set to show the output and utility of the pipeline here.

Direct access surgery for cholecystectomy - can we speed up the process?

BACKGROUND: In appropriate patients, direct referral from general practitioners to surgery without pre-operative clinic assessment can streamlining the process and allow more efficient use of clinical time. This study aimed to look at the feasibility of a direct access cholecystectomy pathway in patients with symptomatic gallstones and their satisfaction of it. METHODS: In 2012, Bay of Plenty general practitioners (GP) were invited to refer fit patients (ASA 1 or 2, BMI <35 and <60 years old) with symptomatic cholelithiasis directly to a surgical list. One surgeon oversaw each referral and the process. The patients GP provided written and visual information and pre-operative health preoperative health questionnaire. Patients presented on the day of surgery, were seen, consented and underwent day stay cholecystectomy. Post-operative follow up was GP lead. RESULTS: 41 patients were referred via the Direct Access Surgery pathway. 37 patients were deemed appropriate with 35 proceeded to surgery. Waiting time from referral to operation was reduced from 120 (standard pathway) to 59.3 days. 30 patients (86%) had day stay procedures. Three patients (8%) re-presented with ongoing right upper quadrant pain within one year requiring further investigation. A written voluntary questionnaire was sent to all patients who underwent DAS with an 80% response rate. Overall the majority of patients (24/28; 85%) agreed or strongly agreed that they felt fully informed regarding the operation and were happy with the process. CONCLUSION: Direct Access Surgery is an effective way to streamline healthy patients' access to operative intervention.

Environmental Enrichment From Birth Impacts Parvalbumin Expressing Cells and Wisteria Floribunda Agglutinin Labelled Peri-Neuronal Nets Within the Developing Murine Striatum.

Environmental enrichment can dramatically affect both the development and function of neural circuits. This is accomplished, at least in part, by the regulation of inhibitory cellular networks and related extracellular matrix glycoprotein structures known as perineuronal nets. The degree to which enhanced housing can influence brain areas involved in the planning and execution of actions is not well known. We examined the effect of enriching mice from birth on parvalbumin expression and perineuronal net formation in developing and adult striatum. This input nucleus of the basal ganglia consists of topographically discernible regions that serve different functions, providing a means of simultaneously examining the influence of environmental factors on discrete, but related networks. Greater densities of striatal parvalbumin positive cells and wisteria floribunda agglutinin labelled perineuronal nets were present in enriched pups during the second postnatal week, primarily within the lateral portion of the nucleus. Housing conditions continued to have an impact into adulthood, with enriched mice exhibiting higher parvalbumin positive cell densities in both medial and lateral striatum. Curiously, no differences due to housing conditions were detected in striatal perineuronal net densities of mature animals. The degree of overlap between striatal parvalbumin expression and perineuronal net formation was also increased, suggesting that heightened neural activity associated with enrichment may have contributed to greater engagement of networks affiliated with cells that express the calcium binding protein. Brain derived neurotrophic factor, an important regulator of inhibitory network maturation, is also subtly, but significantly affected within the striatum of enriched cohorts. Together, these findings suggest that environmental enrichment can exert cell specific effects within different divisions of an area vital for the regulation of action.

Environmental Enrichment Expedites Acquisition and Improves Flexibility on a Temporal Sequencing Task in Mice.

Environmental enrichment (EE) via increased opportunities for voluntary exercise, sensory stimulation and social interaction, can enhance the function of and behaviours regulated by cognitive circuits. Little is known, however, as to how this intervention affects performance on complex tasks that engage multiple, definable learning and memory systems. Accordingly, we utilised the Olfactory Temporal Order Discrimination (OTOD) task which requires animals to recall and report sequence information about a series of recently encountered olfactory stimuli. This approach allowed us to compare animals raised in either enriched or standard laboratory housing conditions on a number of measures, including the acquisition of a complex discrimination task, temporal sequence recall accuracy (i.e., the ability to accurately recall a sequences of events) and acuity (i.e., the ability to resolve past events that occurred in close temporal proximity), as well as cognitive flexibility tested in the style of a rule reversal and an Intra-Dimensional Shift (IDS). We found that enrichment accelerated the acquisition of the temporal order discrimination task, although neither accuracy nor acuity was affected at asymptotic performance levels. Further, while a subtle enhancement of overall performance was detected for both rule reversal and IDS versions of the task, accelerated performance recovery could only be attributed to the shift-like contingency change. These findings suggest that EE can affect specific elements of complex, multi-faceted cognitive processes.

Smart Clothing for Falls Protection and Detection: User-Centred Co-Design and Feasibility Study.

The prevalence and impact of hip fractures on the health and wealth of nations is a global problem and source of health inequalities. This paper reports on the co-design and feasibility testing of a new range of protective, smart clothing. The feasibility of research in a population of older adults in supported living is explored, as are the conceptualisation and measurement of adherence.

α9-nAChR knockout mice exhibit dysregulation of stress responses, affect and reward-related behaviour.

The α9α10-subtype of nicotinic acetylcholine receptor (nAChR) has recently garnered interest in biomedicine and is being pursued as an analgesic target. However, the receptor exhibits diverse tissue distribution, the function of which is known to varying degrees, and targeting this receptor for clinical treatments without a broad understanding of its function may have adverse consequences. The α9α10-nAChR is expressed in the adrenal and pituitary glands, suggesting a potential role in the stress response, but little is known about its function in this tissue. Here we determined a role for the α9α10-nAChR in behavioural and physiological stress responses, by comparing the stress- and affect-related phenotypes of wildtype and α9-nAChR knockout mice. Naïve knockout mice exhibited largely normal behaviour on standard tests of affective behaviour. However, after sub-chronic restraint stress knockout mice showed significantly decreased stress-induced arousal and increased anxiety-like behaviour when compared to wildtype animals. Physiologically, corticosterone responses were muted in knockout mice after an acute stressor, but exaggerated in response to the same stressor after undergoing sub-chronic stress. Behavioural profiling of the α9-nAChR knockout mice in the home-cage revealed that circadian patterns of activity were altered when compared to wildtype controls. Furthermore, knockout mice showed altered responses to a period of reward discounting, resulting in anhedonia-like behaviour in a sucrose preference test where WT mice continued to seek reward. These experiments uncover a novel role for the α9α10-nAChR in mounting a normal stress response and in the regulation of affective- and reward-related behaviour, and suggest that pursuing the receptor for clinical treatments may not be as straightforward as has been suggested.

The razor's edge: Australian rock music impairs men's performance when pretending to be a surgeon.

OBJECTIVE: Over the past few decades there has been interest in the role of music in the operating theatre. However, despite many reported benefits, a number of potentially harmful effects of music have been identified. This study aimed to explore the effects of rock and classical music on surgical speed, accuracy and perceived distraction when performing multiorgan resection in the board game Operation. DESIGN: Single-blind, three-arm, randomised controlled trial. SETTING: Imperial Festival, London, May 2016. PARTICIPANTS: Members of the public (n = 352) aged ≥ 16 years with no previous formal surgical training or hearing impairments. METHODS: Participants were randomised to listen through noise-cancelling headphones to either the sound of an operating theatre, rock music or classical music. Participants were then invited to remove three organs from the board game patient, Cavity Sam, using surgical tweezers. MAIN OUTCOME MEASURES: Time taken (seconds) to remove three organs from Cavity Sam; the number of mistakes made in performing the surgery; and perceived distraction, rated on a five-point Likert-type scale from 1 (not at all distracting) to 5 (very distracting). RESULTS: Rock music impairs the performance of men but not women when undertaking complex surgical procedures in the board game Operation, increasing the time taken to operate and showing a trend towards more surgical mistakes. In addition, classical music was associated with lower perceived distraction during the game, but this effect was attenuated when factoring in how much people liked the music, with suggestions that only people who particularly liked the music of Mozart found it beneficial. CONCLUSIONS: Rock music (specifically Australian rock music) appears to have detrimental effects on surgical performance. Men are advised not to listen to rock music when either operating or playing board games.