The Affective Bias Test and Reward Learning Assay: Neuropsychological Models for Depression Research and Investigating Antidepressant Treatments in Rodents.

The Affective Bias Test (ABT) quantifies acute changes in affective state based on the affective biases they generate in an associative reward learning task. The Reward Learning Assay (RLA) provides a control assay for the ABT and reward-induced biases generated in this model are sensitive to changes in core affective state. Both tasks involve training animals to associate a specific digging substrate with a food reward. Animals learn to discriminate between two digging substrates placed in ceramic bowls, one rewarded and one unrewarded. In the ABT, the animal learns two independent substrate-reward associations with a fixed reward value following either an affective state or drug manipulation, or under control conditions. Affective biases generated are quantified in a choice test where the animals exhibit a bias (make more choices) for one of the substrates which is specifically related to affective state at the time of learning. The ABT is used to investigate biases generated during learning as well as modulation of biases associated with past experiences. The RLA follows a similar protocol, but the animal remains in the same affective state throughout and a reward-induced bias is generated by pairing one substrate with a higher value reward. The RLA provides a control to determine if drug treatments affect memory retrieval more generally. Studies in depression models and following environmental enrichment suggest that reward-induced biases are sensitive to core changes in affective state. Each task offers different insights into affective processing mechanisms and may help improve the translational validity of animal studies and benefit pre-clinical drug development. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Bowl digging and discrimination training Basic Protocol 2: The reward learning assay Basic Protocol 3: The affective bias test - new learning Basic Protocol 4: The affective bias test - modulation of affective biases associated with past experiences.

Characterizing the structure of mouse behavior using Motion Sequencing.

Spontaneous mouse behavior is composed from repeatedly used modules of movement (e.g., rearing, running or grooming) that are flexibly placed into sequences whose content evolves over time. By identifying behavioral modules and the order in which they are expressed, researchers can gain insight into the effect of drugs, genes, context, sensory stimuli and neural activity on natural behavior. Here we present a protocol for performing Motion Sequencing (MoSeq), an ethologically inspired method that uses three-dimensional machine vision and unsupervised machine learning to decompose spontaneous mouse behavior into a series of elemental modules called 'syllables'. This protocol is based upon a MoSeq pipeline that includes modules for depth video acquisition, data preprocessing and modeling, as well as a standardized set of visualization tools. Users are provided with instructions and code for building a MoSeq imaging rig and acquiring three-dimensional video of spontaneous mouse behavior for submission to the modeling framework; the outputs of this protocol include syllable labels for each frame of the video data as well as summary plots describing how often each syllable was used and how syllables transitioned from one to the other. In addition, we provide instructions for analyzing and visualizing the outputs of keypoint-MoSeq, a recently developed variant of MoSeq that can identify behavioral motifs from keypoints identified from standard (rather than depth) video. This protocol and the accompanying pipeline significantly lower the bar for users without extensive computational ethology experience to adopt this unsupervised, data-driven approach to characterize mouse behavior.

Disease-associated comorbidities, medication records and anthropometric measures in adults with Duchenne muscular dystrophy.

We investigated the comorbidities, associated factors, and the relationship between anthropometric measures and respiratory function and functional abilities in adults with Duchenne muscular dystrophy (DMD). This was a single-centre cross-sectional study in genetically diagnosed adults with DMD (>16 years old). Univariate and multivariate analyses identified factors associated with dysphagia, constipation, Body Mass Index (BMI), and weight. Regression analysis explored associations between BMI, weight, and respiratory/motor abilities. We included 112 individuals (23.4 ± 5.2 years old), glucocorticoid-treated 66.1 %. The comorbidities frequency was 61.6 % scoliosis (61.0 % of them had spinal surgery), 36.6 % dysphagia, 36.6 % constipation, and 27.8 % urinary conditions. The use of glucocorticoids delayed the time to spinal surgery. The univariate analysis revealed associations between dysphagia and constipation with age, lack of glucocorticoid treatment, and lower respiratory and motor function. In the multivariate analysis, impaired cough ability remained as the factor consistently linked to both conditions. Constipation associated with lower BMI and weight. BMI and weight positively correlated with respiratory parameters, but they did not associate with functional abilities. Glucocorticoids reduce the frequency of comorbidities in adults with DMD. The ability to cough can help identifying dysphagia and constipation. Lower BMI and weight in individuals with DMD with compromised respiratory function may suggest a higher calories requirement.

Characterisation of behaviours relevant to apathy syndrome in the aged male rat.

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy. Using the effort for reward and progressive ratio tasks we found that aged male rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task. While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.

Preclinical animal models and assays of neuropsychiatric disorders: Old problems and New Vistas - introduction to the special issue.

Preclinical research is an essential aspect of biomedical science that aids in clarifying the pathophysiology of underlying illness and devising new treatments. This special issues brings together original research and review papers that pertain to the development of novel models and behavioral assays of symptoms of neuropsychiatric disorders, which may help to refine preclinical studies and to improve their translatability to the human condition.

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth.

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multimodal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development at term-equivalent age. Compared with term-born controls, preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.

Societal costs of untreated perinatal mood and anxiety disorders in Vermont.

PURPOSE: To estimate the societal costs of untreated perinatal mood and anxiety disorders (PMADs) in Vermont for the 2018-2020 average annual birth cohort from conception through five years postpartum. METHODS: We developed a cost analysis model to calculate the excess cases of outcomes attributed to PMADs in the state of Vermont. Then, we modeled the associated costs of each outcome incurred by birthing parents and their children, projected five years for birthing parents who do not achieve remission by the end of the first year postpartum. RESULTS: We estimated that the total societal cost of untreated PMADs in Vermont could reach $48 million for an annual birth cohort from conception to five years postpartum, amounting to $35,910 in excess societal costs per birthing parent with an untreated PMAD and their child. CONCLUSION: Our model provides evidence of the high costs of untreated PMADs for birthing parents and their children in Vermont. Our estimates for Vermont are slightly higher but comparable to national estimates, which are $35,500 per birthing parent-child pair, adjusted to 2021 US dollars. Investing in perinatal mental health prevention and treatment could improve health outcomes and reduce economic burden of PMADs on individuals, families, employers, and the state.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Rapid-acting antidepressant drugs modulate affective bias in rats.

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model.

The importance of community-specific survey data in understanding behavioral and social drivers of COVID-19 vaccination: Lessons learned from urban neighborhoods in four United States cities.

This descriptive study examined patterns and trends in coronavirus (COVID-19) vaccination rates and drivers among people living, working, or socializing in urban neighborhoods of predominantly Black and Hispanic communities and compared them with the results of two national surveys. Data for these communities came from a routine survey conducted as part of the Equity-first Vaccination Initiative (EVI) in urban neighborhoods within four United States (U.S.) cities during four phases of the pandemic between July 2021 and April 2022. Our sample included 5,970 responses, which were weighted to account for design effects and compositional differences among surveyed people across the four periods. We wanted to compare the results from the EVI survey to nationally representative surveys, therefore, we did not demographically weight the sample to look like the national surveys. As a result, the EVI survey included larger proportions of people identifying with non-white racial and ethnic groups than those groups' proportions of the national population per the last U.S. Census (African American or Black: 49.8% vs. 13.7%, Hispanic or Latino/Latinx 36.5% vs. 18.9%, respectively). More EVI respondents reported concern about vaccines and fewer reported trust in COVID-19 information key messengers than national averages. The EVI survey found variation in the proportions as well as the magnitude and directionality of increases or decreases in beliefs about vaccination safety and effectiveness, the influence of religious beliefs, and intentions to get vaccinated. These differences highlight the granular insight that community-specific data can help better tailor interventions to communities disproportionately impacted by disease.

The Full Continuum of Robotic Breast Surgery: Robotic-assisted Mastectomy, Robotic DIEP Flap, and Robotic Supermicrosurgery.

In recent years, robotic surgery has rapidly expanded to improve surgical outcomes in a variety of surgical subspecialties. Although plastic surgery has taken longer to integrate robotic surgery into practice, the advantages of robotic-assisted surgery, including improved visualization and resolution, minimally invasive approaches, and the ability to surpass human precision and scale, have driven its more recent adoption into plastic surgery. Currently, procedures performed with robotic assistance that are considered part of the continuum of surgical treatment of breast cancer include robotic-assisted nipple-sparing mastectomy, reconstruction with the robotic latissimus dorsi flap or the deep inferior epigastric artery perforator flap, and robotic microsurgery for the flap anastomosis and/or the surgical treatment of lymphedema. The authors provide an overview of robotic surgery and how it has been integrated into the field of plastic surgery, as well as a review of the most common procedures within the field where robotic assistance can be incorporated: nipple-sparing mastectomy, robotic latissimus flap, robotic deep inferior epigastric artery perforator flap breast reconstruction, and microvascular anastomoses.

Neuropsychological Effects of Antidepressants: Translational Studies.

Pharmacological treatments that improve mood were first identified serendipitously, but more than half a century later, how these drugs induce their antidepressant effects remains largely unknown. With the help of animal models, a detailed understanding of their pharmacological targets and acute and chronic effects on brain chemistry and neuronal function has been achieved, but it remains to be elucidated how these effects translate to clinical efficacy. Whilst the field has been dominated by the monoamine and neurotrophic hypotheses, the idea that the maladaptive cognitive process plays a critical role in the development and perpetuation of mood disorders has been discussed since the 1950s. Recently, studies using objective methods to quantify changes in emotional processing found acute effects with conventional antidepressants in both healthy volunteers and patients. These positive effects on emotional processing and cognition occur without a change in the subjective ratings of mood. Building from these studies, behavioural methods for animals that quantify similar cognitive affective processes have been developed. Integrating these behavioural approaches with pharmacology and targeted brain manipulations, a picture is beginning to emerge of the underlying mechanisms that may link the pharmacology of antidepressants, these neuropsychological constructs and clinical efficacy. In this chapter, we discuss findings from animal studies, experimental medicine and patients investigating the neuropsychological effects of antidepressant drugs. We discuss the possible neural circuits that contribute to these effects and discuss whether a neuropsychological model of antidepressant effects could explain the temporal differences in clinical benefits observed with conventional delayed-onset antidepressants versus rapid-acting antidepressants.

Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans.

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.