An associative analysis of recognition memory

Recognition memory is a fundamental cognitive process which is often impaired in conditions such as Alzheimer’s disease. In rodents, recognition memory is often studied using spontaneous object recognition tasks (SOR) in which objects that differ in terms of their novelty, recency, or prior location, are explored by animals. The theoretical basis and explanations of performance in these tasks remain controversial, often based on theories of familiarity and recollection. Sometimes opponent process (SOP) offers an alternative explanation and postulates that two priming processes underlie recognition memory. Self-generated priming occurs when a current stimulus has been recently experienced, and retrieval-generated priming arises when an object is predicted by another stimulus through prior association. In this thesis, I examined specific predictions of SOP using SOR task variants in mice. I explored associative and recency-based processes defined by SOP which may occur during object recognition memory. I used variants of the object in context task, which map onto retrieval-generated priming, to explore blocking and indirect object recognition effects, and used variants of the relative recency task, which map onto self-generated priming, to investigate distractor effects upon recency discrimination performance. I provided some evidence to support the use of SOP to study recognition memory during association-based and recency-based memory tasks. Further work is required to validate and develop these findings to establish this method as a suitable general framework for studying recognition memory

An associative analysis of recognition memory

Recognition memory is a fundamental cognitive process which is often impaired in conditions such as Alzheimer’s disease. In rodents, recognition memory is often studied using spontaneous object recognition tasks (SOR) in which objects that differ in terms of their novelty, recency, or prior location, are explored by animals. The theoretical basis and explanations of performance in these tasks remain controversial, often based on theories of familiarity and recollection. Sometimes opponent process (SOP) offers an alternative explanation and postulates that two priming processes underlie recognition memory. Self-generated priming occurs when a current stimulus has been recently experienced, and retrieval-generated priming arises when an object is predicted by another stimulus through prior association. In this thesis, I examined specific predictions of SOP using SOR task variants in mice. I explored associative and recency-based processes defined by SOP which may occur during object recognition memory. I used variants of the object in context task, which map onto retrieval-generated priming, to explore blocking and indirect object recognition effects, and used variants of the relative recency task, which map onto self-generated priming, to investigate distractor effects upon recency discrimination performance. I provided some evidence to support the use of SOP to study recognition memory during association-based and recency-based memory tasks. Further work is required to validate and develop these findings to establish this method as a suitable general framework for studying recognition memory

Animals can assign novel odours to a known category

The ability to identify a novel stimulus as a member of a known category allows an organism torespond appropriately towards it. Categorisation is thus a fundamental component of cognition andan essential tool for processing and responding to unknown stimuli. Therefore, one might expectto observe it throughout the animal kingdom and across sensory domains. There is much evidenceof visual categorisation in non-human animals, but we currently know little about this process inother modalities. In this experiment, we investigated categorisation in the olfactory domain. Dogswere trained to discriminate between 40 odours; the presence or absence of accelerants formed thecategorical rule. Those in the experimental group were rewarded for responding to substrates withaccelerants (either burnt or un-burnt) and inhibit responses to the same substrates (either burnt or unburnt)without accelerants (S+ counterbalanced). The pseudocategory control group was trained onthe same stimuli without the categorical rule. The experimental group learned the discrimination andanimals were able to generalise to novel stimuli from the same category. None of the control animalswere able to learn the discrimination within the maximum number of trials. This study provides the firstevidence that non-human animals can learn to categorise non-biologically relevant odour information

Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase

Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocatalyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism-inspired ligand. The structure supports two key features of the NCS "dopamine-first" mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance. The catalytically vital residue Glu-110 occupies a previously unobserved ligand-bound conformation that may be catalytically significant. The potential roles of inhibitory binding and alternative amino acid conformations in the mechanism have also been revealed. This work significantly advances our understanding of the NCS mechanism and will aid future efforts to engineer the substrate scope and catalytic properties of this useful biocatalyst

Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection.

Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection

Single step syntheses of (1 S)-aryltetrahydroisoquinolines by norcoclaurine synthases

The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A cocrystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQ

Truth is in the eye of the beholder: Perception of the Müller-Lyer illusion in dogs

Visual illusions are objects that are made up of elements that are arranged in such a way as to result in erroneous perception of the objects’ physical properties. Visual illusions are used to study visual perception in humans and nonhuman animals, since they provide insight into the psychological and cognitive processes underlying the perceptual system. In a set of three experiments, we examined whether dogs were able to learn a relational discrimination and to perceive the Müller-Lyer illusion. In Experiment 1, dogs were trained to discriminate line lengths using a two-alternative forced choice procedure on a touchscreen. Upon learning the discrimination, dogs’ generalization to novel exemplars and the threshold of their abilities were tested. In the second experiment, dogs were presented with the Müller-Lyer illusion as test trials, alongside additional test trials that controlled for overall stimulus size. Dogs appeared to perceive the illusion; however, control trials revealed that they were using global size to solve the task. Experiment 3 presented modified stimuli that have been known to enhance perception of the illusion in other species. However, the dogs’ performance remained the same. These findings reveal evidence of relational learning in dogs. However, their failure to perceive the illusion emphasizes the importance of using a full array of control trials when examining these paradigms, and it suggests that visual acuity may play a crucial role in this perceptual phenomenon

Developing scientific decision making by structuring and supporting student agency

Scientific expertise is manifested through extensive cycles of making and acting on decisions. To learn the processes and practices of science, therefore, students must have practice with scientific decision making. We argue that this can only happen if students are afforded agency: the opportunity to make decisions to pursue a goal. In this study, we compared two different introductory physics labs through the lens of structuring and supporting student agency. We explore both the role of decision making agency (students are afforded opportunities to make decisions about their lab investigations) and epistemic agency (students are afforded opportunities to generate knowledge). We found that the two labs differed in both the amount and type of structure provided to students: one lab (the intervention condition), with more overall structure, cued student decision making; the other lab (control condition), with less overall structure, made decisions for students. Students in the intervention condition documented, on average, ten times more decisions during their investigations, including more unprompted decisions. In contrast, in labs with less available epistemic agency (i.e., labs where they had to verify or demonstrate canonical models or constants), students in the intervention condition documented fewer decisions than in labs with more available epistemic agency. We associate the improved decision making with students taking up personal agency, based on significant shifts in students’ tone as they described their experimental methods (from passive, third-person narratives to active, first-person narratives). Students in the intervention condition also made higher-quality decisions in line with scientific practice. The study speaks to the important nuances between structure and agency in instructional labs and tests the generalizability of previous research on lab instruction to a two-year college population

EternaBrain: Automated RNA design through move sets and strategies from an Internet-scale RNA videogame.

Emerging RNA-based approaches to disease detection and gene therapy require RNA sequences that fold into specific base-pairing patterns, but computational algorithms generally remain inadequate for these secondary structure design tasks. The Eterna project has crowdsourced RNA design to human video game players in the form of puzzles that reach extraordinary difficulty. Here, we demonstrate that Eterna participants' moves and strategies can be leveraged to improve automated computational RNA design. We present an eternamoves-large repository consisting of 1.8 million of player moves on 12 of the most-played Eterna puzzles as well as an eternamoves-select repository of 30,477 moves from the top 72 players on a select set of more advanced puzzles. On eternamoves-select, we present a multilayer convolutional neural network (CNN) EternaBrain that achieves test accuracies of 51% and 34% in base prediction and location prediction, respectively, suggesting that top players' moves are partially stereotyped. Pipelining this CNN's move predictions with single-action-playout (SAP) of six strategies compiled by human players solves 61 out of 100 independent puzzles in the Eterna100 benchmark. EternaBrain-SAP outperforms previously published RNA design algorithms and achieves similar or better performance than a newer generation of deep learning methods, while being largely orthogonal to these other methods. Our study provides useful lessons for future efforts to achieve human-competitive performance with automated RNA design algorithms

First-generation antipsychotics:not gone but forgotten

Aims and method To identify training needs of the next generation of psychiatrists and barriers in prescribing first-generation antipsychotics (FGAs). We have surveyed psychiatry trainees in East Anglia with regard to their training experience, knowledge and attitudes to the use of oral FGAs as regular medication. Results Two-thirds of trainees were aware that first- and second-generation antipsychotics (SGAs) have similar efficacy, and a similar proportion perceived the older drugs to have more or ‘stronger’ side-effects. Lack of training experience was noted as the second leading concern for prescribing FGAs. A quarter of trainees received no training exposure to the older drugs and two-thirds had never initiated these drugs themselves. Although nearly 90% of trainees felt confident about initiating an oral SGA as a regular medication, only about 40% felt confident with FGAs (P<0.001). Clinical implications The survey highlights worrying gaps in training. FGAs can be used effectively, minimising side-effects, by careful dose titration, avoiding antipsychotic polypharmacy, high-dose, and high-potency drugs, thus ensuring they are not lost to future generations of psychiatrists