Brain gene expression in a novel mouse model of postpartum mood disorder

Background Steroid sulfatase (STS) cleaves sulfate groups from steroid hormones; its expression/activity increases in late pregnancy and into the postpartum period. STS-deficient human and mouse mothers display elevated psychopathology and abnormal behaviour respectively; in mice, these effects can be partially normalised by antipsychotic (ziprasidone) administration. Methodology We compared brain gene expression in new mouse mothers administered the STS inhibitor 667-Coumate, or vehicle; significant changes were followed-up with pathway analysis and quantitative polymerase chain reaction (qPCR). Finally, the effects of combined 667-Coumate and ziprasidone administration on expression of the most robustly differentially-expressed genes were examined. Results Surprisingly, no between-group gene expression changes were detected at a False Discovery Rate (FDR)-corrected p<0.1. 1,081 unique expression changes were detected at p<0.05, two top hits were verified by qPCR, and pathway analysis indicated enrichment of genes involved in olfactory transduction. The expression of Stoml3 and Cyp2g1 was unaffected by ziprasidone administration. Conclusions Postpartum behavioural abnormalities in STS-deficient mothers are likely to be the culmination of many small gene expression changes. Our data are consistent with the idea that olfactory function is key to maternal behaviour in mice, and suggest that aberrant expression of olfactory system genes may underlie abnormal maternal behaviour in STS-deficient women

A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis

Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10 mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3–1.0 mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21–23cm on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0 mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for P

The effects of automatic spelling correction software on understanding and comprehension in compensated dyslexia: improved recall following dictation

Dyslexia is associated with difficulties in language-specific skills such as spelling, writing and reading; the difficulty in acquiring literacy skills is not a result of low intelligence or the absence of learning opportunity, but these issues will persist throughout life and could affect long-term education. Writing is a complex process involving many different functions, integrated by the working memory system; people with dyslexia have a working memory deficit, which means that concentration on writing quality may be detrimental to understanding. We confirm impaired working memory in a sample of university students with (compensated) dyslexia, and using a within-subject design with three test conditions, we show that these participants demonstrated better understanding of a piece of text if they had used automatic spelling correction software during a dictation/transcription task. We hypothesize that the use of the autocorrecting software reduced demand on working memory, by allowing word writing to be more automatic, thus enabling better processing and understanding of the content of the transcriptions and improved recall. Long-term and regular use of autocorrecting assistive software should be beneficial for people with and without dyslexia and may improve confidence, written work, academic achievement and self-esteem, which are all affected in dyslexia

Mood symptoms, neurodevelopmental traits, and their contributory factors in X-linked ichthyosis, ichthyosis vulgaris and psoriasis

Background High rates of adverse mood/neurodevelopmental traits are seen in multiple dermatological conditions, and can significantly impact patients’ quality of life. Understanding the sex-specific nature, magnitude, impact and basis of such traits in lesser-studied conditions like ichthyosis, is important for developing effective interventions. Objectives To a) quantify and compare relevant psychological traits, across males diagnosed with X-linked ichthyosis (XLI, n=54) or female XLI carriers (n=83), ichthyosis vulgaris (IV, male n=23, female n=59) or psoriasis (male n=30, female n=122) and b) to identify factors self-reported to contribute most towards depressive, anxious and irritability phenotypes. Methods Participants recruited via relevant charities or social media completed an online survey of established questionnaires. Data were compared to general population data, and were also analysed by sex and skin condition. Results The lifetime prevalence of mood disorder diagnoses across all groups, and neurodevelopmental disorder diagnoses in the XLI groups, was higher than in the general population. Groups exhibited similarly significantly-elevated recent mood symptoms (Cohen’s d: 0.95-1.28, p0.47, p≤0.002), and between feelings of stigmatisation and quality of life, particularly in males. Numerous factors were identified as contributing significantly to mood symptoms in a condition or sex-specific, or condition/sex-independent, manner. Conclusions Recognising mood/neurodevelopmental problems in ichthyosis and psoriasis, and addressing the predisposing factors identified herein, in clinical practice should benefit the mental health of affected individuals

Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications

Our willingness to take risks, our ability to wait or the speed with which to make decisions are central features of our personality. However, it is now recognized that impulsive and risk-taking behaviours are not a unitary construct, and different aspects can be both psychologically and neurally dissociated. The range of neurochemicals and brain systems that govern these behaviours is extensive, and this may be a contributing factor to the phenotypic range seen in the human population. However, this variety can also be pathological as extremes in risk-taking and impulsive behaviours are characteristics of many neuropsychiatric and indeed neurodegenerative disorders. This spans obsessive–compulsive disorder, where behaviour becomes ridged and non-spontaneous, to the nonsensical risk-taking seen in gambling and drug taking

Feeding behaviour, risk-sensitivity and response control:Effects of 5-HT2C receptor manipulations

People, like animals, tend to choose the variable option when given the choice between a fixed and variable delay to reward where, in the variable delay condition, some rewards are available immediately (Laura-Jean et al. 2019 Phil. Trans. R. Soc. B374, 20180141. (doi:10.1098/rstb.2018.0141)). This bias has been suggested to reflect evolutionary pressures resulting from food scarcity in the past placing a premium on obtaining food quickly that can win out against the risks of sometimes sustaining longer delays to food. The psychologies mediating this effect may become maladaptive in the developed world where food is readily available contributing, potentially, to overeating and obesity. Here, we report our development of a novel touchscreen task in mice allowing comparisons of the impact of food delay and food magnitude across species. We show that mice exhibit the typical preference, as shown by humans, for variable over fixed delays to rewards but no preference when it comes to fixed versus variable reward amounts and further show that this bias is sensitive to manipulations of the 5-HT2C receptor, a key mediator of feeding and impulse control. We discuss the data in terms of the utility of the task to model the psychologies and underlying brain mechanisms impacting on feeding behaviours. This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’

Common genetic effects on variation in impulsivity and activity in mice

Impulsivity is a complex psychological construct that impacts on behavioral predispositions in the normal range and has been shown to have a genetic element through the examination of hereditary patterns of abnormal conditions such as attention deficit/hyperactivity disorder and obsessive compulsive disorder. In this study, we took advantage of the isogenic nature of inbred strains of mice to determine the contribution of genes to impulsive behaviors by examining the performance of four separate mouse strains in a novel murine delayed-reinforcement paradigm, during which the animals had to choose between rewards that were relatively small but available immediately and larger but progressively delayed rewards. To control for maternal effects, all the mice were cross-fostered to a common strain immediately after birth. Under these conditions, we found significant differences between the strains on behaviors indexing impulsive choice and on independent measures of locomotor activity, which subsequent heritability analysis showed could be related, in part, to genetic effects. Moreover, the two aspects of behavior were found to co-vary, with the more active animals also displaying more impulsive behavior. This was not attributable to mundane confounds related to individual task requirements but instead indicated the existence of common genetic factors influencing variation in both impulsivity and locomotor activity. The data are discussed in terms of the coexistence of impulsivity and hyperactivity, interactions between environmental and genetic effects, and possible candidate genes

Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13. In addition to endocrine and developmental issues, PWS presents with behavioural problems including stereotyped behaviour, impulsiveness and cognitive deficits. The PWS genetic interval contains several brain-expressed small nucleolar (sno)RNA species that are subject to genomic imprinting, including snord115 which negatively regulates post-transcriptional modification of the serotonin 2C receptor (5-HT2CR) pre-mRNA potentially leading to a reduction in 5-HT2CR function. Using the imprinting centre (IC) deletion mouse model for PWS (PWSICdel) we have previously shown impairments in a number of behaviours, some of which are abnormally sensitive to 5-HT2CR-selective drugs. In the stop-signal reaction time task test of impulsivity, PWSICdel mice showed increased impulsivity relative to wild-type littermates. Challenge with the selective 5-HT2CR agonist WAY163909 reduced impulsivity in PWSICdel mice but had no effect on wild-type behaviour. This behavioural dissociation in was also reflected in differential patterns of immunoreactivity of the immediate early gene c-Fos, with a blunted response to the drug in the orbitofrontal cortex of PWSICdel mice, but no difference in c-Fos activation in the nucleus accumbens. These findings suggest specific facets of response inhibition are impaired in PWSICdel mice and that abnormal 5-HT2CR function may mediate this dissociation. These data have implications for our understanding of the aetiology of PWS related behavioural traits and translational relevance for individuals with PWS who may seek to control appetite with the new obesity treatment 5-HT2CR agonist lorcaserin

Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition, and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternally imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implications for potential therapeutic interventions

Unilateral lesions of the dorsal striatum in rats disrupt responding in egocentric space

Rats were trained in a specially designed, multichoice operant chamber on a visual choice reaction time task designed to assess performance on each side of the rat’s body. The task required animals to sustain a nose poke in a central hole, until a brief light stimulus was presented in either of two holes that were located on the same side of the box. Once the rats were trained to perform the task to both sides independently they received unilateral injections of quinolinic acid into the dorsal striatum. Postoperatively, lesioned animals were impaired when performing the task on the side contralateral to the lesion. The time taken to initiate contralateral responses was increased. Contralateral responses were also exclusively biased toward the nearer of the two response locations, regardless of the location of the stimulus. This was interpreted as a specific impairment in generating responses in contralateral space. In contrast, no comparable deficit was seen when the animals performed the task on the side ipsilateral to the lesion. Additional postoperative challenges, in which response options were presented bilaterally, showed this response deficit to be defined in egocentric coordinates, with the severest response deficits for the most contralateral locations