Major depressive disorder: a loss of circadian synchrony?

Circadian rhythms in the sleep/wake cycle, along with a range of physiological measures, are severely disrupted in individuals with major depressive disorder (MDD). Moreover, several central circadian genes have been implicated as potential genetic factors underlying the illness through candidate gene studies and some genome wide association studies. However, investigations into the molecular underpinnings of circadian disturbances in the human brain have been quite challenging. In their recent publication, Li and colleagues have used a novel approach to determine the rhythmic patterns of circadian gene expression in several regions of the human brain, and how these patterns are disrupted in MDD. Their findings demonstrate that in healthy subjects, several brain regions outside the suprachiasmatic nucleus (the master clock) exhibit diurnal gene expression patterns that are disrupted in the brains of MDD subjects. These findings will provide the foundation for future studies of gene-specific drug targets, and biomarkers for the disease.

A Comparison of Suicides in Public Safety Personnel With Suicides in the General Population in Ontario, 2014 to 2018.

Background: There is conflicting evidence on the suicide rates of different public safety personnel (PSP). There have been few studies that compare suicides in PSP with the general population and none that have used a detailed comparison of coroner records. Aims: The current study estimates suicide rates among different PSP and compares PSP suicides with the general population. Method: We identified coroner records of PSP suicides from January 2014 to December 2018 and compared each one to two matched general population controls. Results: We identified 36 PSP suicides and 72 general population controls. Police had a higher suicide rate than other PSP groups. PSP were more likely to die by firearm, be separated/divorced or married, die in a motor vehicle, have problems at work, and have a PTSD diagnosis. PSP were less likely to die by jumping. Limitations: The study may have not identified all PSP suicides. Apart from the cause of death, data in coroner records are not systematically collected, so information may be incomplete. Conclusion: PSP suicides appear different than the general population. Death records need to have an occupation identifier to enable monitoring of trends in occupational groups, such as PSP.

Workplace Assessment Scale: Pilot Validation Study.

First responders, such as police officers, paramedics, and firefighters are at an increased risk of experiencing negative mental health outcomes compared to the general population. This predisposition can partially be attributed to common occupational stressors, which may provoke strong feelings of betrayal and humiliation. The Workplace Assessment Scale (WAS) was developed as there is currently no appropriate measure to assess such feelings in the first responder population. Initial development of the WAS included a Betrayal Subscale and the Humiliation Subscale, each comprised of 5 Likert scale questions which ask participants to report the frequency at which they experience specific feelings associated with their workplace. This pilot validation study was conducted to determine if there is preliminary evidence to support a large-scale validation study. To determine this, we assessed the internal structure and the convergent, concurrent, and predictive validity of the WAS. Based on 21/22 (95%) participant responses, a factor analysis did not support the two-factor model we anticipated, with only one factor and seven items retained from the original version of the scale. However, the internal consistency of the remaining items was strong. The validity analysis found moderate convergent validity and weak predictive validity based on correlations between the WAS and other psychometric scales. Minimal concurrent validity was noted. Additional research is needed for further analysis and validation of the WAS.

Interventions to treat post-traumatic stress disorder (PTSD) in vulnerably housed populations and trauma-informed care: a scoping review.

OBJECTIVES: The goals of this study are to identify and analyse interventions that aim to treat post-traumatic stress disorder (PTSD) and complex PTSD in people who are vulnerably housed and to describe how these treatments have been delivered using trauma-informed care. DESIGN: Scoping review. SEARCH STRATEGY: We searched electronic databases including MEDLINE, Embase, PsycINFO, CINAHL, the Cochrane Library, Web of Science and PTSDpubs for published literature up to November 2021 for any studies that examined the treatment of PTSD in adults who were vulnerably housed. Websites of relevant organisations and other grey literature sources were searched to supplement the electronic database search. The characteristics and effect of the interventions were analysed. We also explored how the interventions were delivered and the elements of trauma-informed care that were described. RESULTS: 28 studies were included. We identified four types of interventions: (1) trauma focused psychotherapies; (2) non-trauma psychotherapies; (3) housing interventions and (4) pharmacotherapies. The trauma-informed interventions were small case series and the non-trauma focused therapies included four randomised controlled trials, were generally ineffective. Of the 10 studies which described trauma-informed care the most commonly named elements were physical and emotional safety, the experience of feeling heard and understood, and flexibility of choice. The literature also commented on the difficulty of providing care to this population including lack of private space to deliver therapy; the co-occurrence of substance use; and barriers to follow-up including limited length of stay in different shelters and high staff turnover. CONCLUSIONS: This scoping review identified a lack of high-quality trials to address PTSD in people who are vulnerably housed. There is a need to conduct well designed trials that take into account the unique setting of this population and which describe those elements of trauma-informed care that are most important and necessary.

Feasibility and acceptability of Narrative Exposure Therapy to treat individuals with PTSD who are homeless or vulnerably housed: a pilot randomized controlled trial.

BACKGROUND: Diagnosed PTSD rates in people who are homeless are more than double that of the general population, ranging between 21 and 53%. Complex PTSD (cPTSD) also appears to be more common than PTSD. One treatment option is Narrative Exposure Therapy (NET), a brief trauma-focused psychotherapy which attempts to place trauma within a narrative of the person's life. Our primary aim was to assess the feasibility and acceptability of recruiting people to a randomized controlled trial (RCT) of NET alone compared to NET augmented by a genealogical assessment. We hypothesized that incorporating a genealogical assessment may be more effective than NET alone in a population with predominately complex PTSD. METHODS: This pilot RCT enrolled participants who were 18 years of age or older, currently homeless or vulnerably housed, and with active symptoms of PTSD. Participants were randomized to NET alone or NET plus a genealogical assessment. Rates of referral, consent, and retention were examined as part of feasibility. Demographic and clinical data were collected at baseline. Symptoms of PTSD, drug use, and housing status were re-assessed at follow-up visits. We conducted a thematic analysis of qualitative interviews of service providers involved in the study which explored barriers and facilitators of study participation. RESULTS: Twenty-two potential participants were referred to the study, with 15 consenting to participate. Of these, one was a screen failure and 14 were randomized equally to the treatment arms. One randomized participant was withdrawn for safety. Attrition occurred primarily prior to starting therapy. Once therapy began, retention was high with 80% of participants completing all six sessions. Seven participants completed all follow-up sessions. Service providers identified a clear need for the treatment and emphasized the importance of trauma-informed care, a desire to know more about NET, and more communication about the process of referral. CONCLUSION: Recruiting participants who were vulnerably housed to an RCT of a trauma-based therapy was possible. Once therapy had started, participants were likely to stay engaged. We will incorporate the results of this trial into a conceptual model which we will test in a factorial study as part of the optimization phase of MOST. TRIAL REGISTRATION: ClinicalTrials.gov NCT03781297 . Registered: December 19, 2018.

The BEACON study: an update to the protocol for a cohort study as part of an evaluation of the effectiveness of smartphone-assisted problem-solving therapy in men who present with intentional self-harm to emergency departments in Ontario.

BACKGROUND: Men who present to the emergency department (ED) with self-harm are at high risk of dying by suicide, with 2.7% of men dying in the year following their presentation, more than double the rate for women (1.2%). Despite this, care received after an ED visit is highly variable and many are not assessed for psychological needs. Furthermore, the limited psychological care that is available is often not covered by provincial health insurance. Even when referrals for follow-up care are made, engagement rates are low. Previous recommendations to improve engagement include written discharge plans, caring contacts, and focused interventions targeting middle-aged men at elevated risk of dying by suicide. Blended care, the incorporation of technology into traditional care, has also been proposed as a method to increase engagement in and clinical benefits from psychotherapy. This project aims to determine whether the delivery of an evidence based treatment (problem-solving therapy (PST)) is enhanced by the addition of a custom smartphone application (BEACON) compared to usual care. Due to the impact of the COVID-19 pandemic on site participation and the planned implementation, we have made several changes to the study design, primary outcome, and implementation. METHOD: We originally proposed a cohort study nested within a larger cluster randomized trial wherein intervention sites would deliver the blended care, and control sites, whose personnel were not aware of their participation, would continue delivering usual care. The cohort study evaluated participant level outcomes as previously described by Hatcher et al. (2020). Due to pandemic-related constraints, our number of participating sites dropped to five potential sites which left the cohort study underpowered. As such, we changed the study design to a multi-site, individual randomized controlled trial (RCT) among the five remaining sites. Participants will be randomized to six sessions of therapy (PST) alone, or to the therapy plus BEACON, and followed up for 6 months. Our primary outcome was changed to evaluate feasibility and acceptability with the aim of designing a definitive RCT. Study implementation was reimagined to allow for completely virtual/online conduct to comply with local COVID-19 and institutional restrictions on in-person activities. CONCLUSION: This updated protocol will provide strong results for the planning of a definitive RCT of the blended care intervention in the future, addressing areas of difficulty and concern prior to its implementation. We will evaluate the feasibility of the study intervention, assess recruitment and retention of participants, and address challenges with implementing the protocol. Lastly, we will evaluate the appropriateness of our primary outcome measure and accurately determine a sample size for a definitive RCT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03473535 . Registered on March 22, 2018.

Enhancing COVID Rehabilitation with Technology (ECORT): protocol for an open-label, single-site randomized controlled trial evaluating the effectiveness of electronic case management for individuals with persistent COVID-19 symptoms.

BACKGROUND: As of May 2022, Ontario has seen more than 1.3 million cases of COVID-19. While the majority of individuals will recover from infection within 4 weeks, a significant subset experience persistent and often debilitating symptoms, known as "post-COVID syndrome" or "Long COVID." Those with Long COVID experience a wide array of symptoms, with variable severity, including fatigue, cognitive impairment, and shortness of breath. Further, the prevalence and duration of Long COVID is not clear, nor is there evidence on the best course of rehabilitation for individuals to return to their desired level of function. Previous work with chronic conditions has suggested that the addition of electronic case management (ECM) may help to improve outcomes. These platforms provide enhanced connection with care providers, detailed symptom tracking and goal setting, and access to relevant resources. In this study, our primary aim is to determine if the addition of ECM with health coaching improves Long COVID outcomes at 3 months compared to health coaching alone. METHODS: The trial is an open-label, single-site, randomized controlled trial of ECM with health coaching (ECM+) compared to health coaching alone (HC). Both groups will continue to receive usual care. Participants will be randomized equally to receive health coaching (± ECM) for a period of 8 weeks and a 12-week follow-up. Our primary outcome is the WHO Disability Assessment Scale (WHODAS), 36-item self-report total score. Participants will also complete measures of cognition, fatigue, breathlessness, and mental health. Participants and care providers will be asked to complete a brief qualitative interview at the end of the study to evaluate acceptability and implementation of the intervention. DISCUSSION: There is currently little evidence about the optimal treatment of Long COVID patients or the use of digital health platforms in this population. The results of this trial could result in rapid, scalable, and personalized care for people with Long COVID which will decrease morbidity after an acute infection. Results from this study will also inform decision making in Long COVID and treatment guidelines at provincial and national levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT05019963. Registered on 25 August 2021.

The Impact of Infectious Disease-Related Public Health Emergencies on Suicide, Suicidal Behavior, and Suicidal Thoughts.

Background: Infectious disease-related public health emergencies (epidemics) may increase suicide risk, and high-quality evidence is needed to guide an international response. Aims: We investigated the potential impacts of epidemics on suicide-related outcomes. Method: We searched MEDLINE, EMBASE, PsycInfo, CINAHL, Scopus, Web of Science, PsyArXiv, medRxiv, and bioRxiv from inception to May 13-16, 2020. Inclusion criteria: primary studies, reviews, and meta-analyses; reporting the impact of epidemics; with a primary outcome of suicide, suicidal behavior, suicidal ideation, and/or self-harm. Exclusion criteria: not concerned with suicide-related outcomes; not suitable for data extraction. PROSPERO registration: #CRD42020187013. Results: Eight primary papers were included, examining the effects of five epidemics on suicide-related outcomes. There was evidence of increased suicide rates among older adults during SARS and in the year following the epidemic (possibly motivated by social disconnectedness, fears of virus infection, and concern about burdening others) and associations between SARS/Ebola exposure and increased suicide attempts. A preprint study reported associations between COVID-19 distress and past-month suicidal ideation. Limitations: Few studies have investigated the topic; these are of relatively low methodological quality. Conclusion: Findings support an association between previous epidemics and increased risk of suicide-related outcomes. Research is needed to investigate the impact of COVID-19 on suicide outcomes.

The BEACON study: protocol for a cohort study as part of an evaluation of the effectiveness of smartphone-assisted problem-solving therapy in men who present with intentional self-harm to emergency departments in Ontario.

BACKGROUND: Patients who present to emergency departments after intentional self-harm are at an increased risk of dying by suicide. This applies particularly to men, who represent nearly two-thirds of those who die by suicide in Ontario. One way of potentially addressing this gap is to offer a course of blended problem-solving therapy, comprised of a brief course of evidence-based psychotherapy for individuals at risk for suicide, facilitated by the use of a patient-facing smartphone application and a clinician-facing "dashboard." This approach has the potential to combine the benefits of face-to-face therapy and technology to create a novel intervention. METHODS: This is a cohort study nested within a larger pragmatic multicentre pre- and post-design cluster randomised trial. Suicidal ideation assessed by the Beck Scale for Suicide Ideation is the primary outcome variable. Secondary outcome measures include depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-item scale), post-traumatic stress disorder (Primary Care PTSD Screen), health-related quality of life (EuroQol 5-dimension 5-level questionnaire), meaning in life (Experienced Meaning in Life Scale), perceived social supports (Multidimensional Scale of Perceived Social Support), alcohol use (Alcohol Use Disorders Identification Test), drug use (Drug Abuse Screening Test Short Form 10), problem-solving skills (Social Problem-Solving Inventory-Revised Short Form), and self-reported healthcare costs, as well as health service use measured using Ontario administrative health data. A process evaluation will also be conducted following study completion. DISCUSSION: The cohort study will test whether better adherence to the intervention results in better outcomes. The value of the cohort study design is that we can examine in more detail certain subgroups or other variables that are not available in the larger cluster randomised trial. This trial will aim to improve standards by informing best practice in management of men who self-harm and present to hospitals in Ontario. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03473535 . Registered on March 22, 2018.

NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors.

Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward- and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in Npas2 (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay). We assessed the effects of acute or chronic stress on striatal Npas2 expression, and found that both stressors increased levels of Npas2. Moreover, knockdown of Npas2 in the ventral striatum resulted in a similar reduction of anxiety-like behaviors as seen in the Npas2 null mutant mouse. Additionally, we identified Gabra genes as transcriptional targets of NPAS2, found that Npas2 null mutant mice exhibit reduced sensitivity to the GABAa positive allosteric modulator, diazepam and that knockdown of Npas2 reduced Gabra1 expression and response to diazepam in the ventral striatum. These results: (1) implicate Npas2 in the response to stress and the development of anxiety; and (2) provide functional evidence for the regulation of GABAergic neurotransmission by NPAS2 in the ventral striatum.

Chronic Stress Induces Brain Region-Specific Alterations of Molecular Rhythms that Correlate with Depression-like Behavior in Mice.

BACKGROUND: Emerging evidence implicates circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD). The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates rhythms throughout the brain and body. On a cellular level, rhythms are generated by transcriptional, translational, and posttranslational feedback loops of core circadian genes and proteins. In patients with MDD, recent evidence suggests reduced amplitude of molecular rhythms in extra-SCN brain regions. We investigated whether unpredictable chronic mild stress (UCMS), an animal model that induces a depression-like physiological and behavioral phenotype, induces circadian disruptions similar to those seen with MDD. METHODS: Activity and temperature rhythms were recorded in C57BL/6J mice before, during, and after exposure to UCMS, and brain tissue explants were collected from Period2 luciferase mice following UCMS to assess cellular rhythmicity. RESULTS: UCMS significantly decreased circadian amplitude of activity and body temperature in mice, similar to findings in MDD patients, and these changes directly correlated with depression-related behavior. While amplitude of molecular rhythms in the SCN was decreased following UCMS, surprisingly, rhythms in the nucleus accumbens (NAc) were amplified with no changes seen in the prefrontal cortex or amygdala. These molecular rhythm changes in the SCN and the NAc also directly correlated with mood-related behavior. CONCLUSIONS: These studies found that circadian rhythm abnormalities directly correlate with depression-related behavior following UCMS and suggest a desynchronization of rhythms in the brain with an independent enhancement of rhythms in the NAc.

Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry.

BACKGROUND: Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology. METHODS: Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples. RESULTS: Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity. CONCLUSIONS: This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders.

Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex.

Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying "emotionality" of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models.

The roles of sex and serotonin transporter levels in age- and stress-related emotionality in mice.

Mood disorders are influenced by genetic make-up and differentially affect men and women. The s/l promoter polymorphism in the serotonin transporter (SERT) gene moderates both trait emotion and the vulnerability to develop depressive states in humans. Similarly, male mice lacking SERT (Knockout/KO) display an elevated emotionality phenotype. We now report that the SERT-KO phenotype is maintained throughout late-adulthood, and that female KO mice develop a larger emotionality phenotype with increasing age. Thus, to test the hypothesis that these findings reflected a putative sexual dimorphism in SERT-mediated modulation of emotionality, we submitted adult male and female wild-type, heterozygous (HZ) and KO mice to unpredictable chronic mild stress (UCMS) and assessed behavioral changes. In males, the elevated SERT-KO emotion-related behavior converged with other groups after UCMS. Conversely, female SERT-KO displayed a normal non-stressed baseline, but highest UCMS-induced emotionality. SERT-HZ displayed variable and intermediate phenotypes in both experiments. Thus, consistent results across different biological modalities (age, stress) revealed a high contribution of SERT genotype for baseline "trait" emotionality in males, and low contribution for females. In contrast, age-correlated and stress-induced behavioral changes resulted in a high SERT genotype-mediated behavioral variance in females, but low in males. This suggests that high emotionality states associated with low SERT were differentially achieved in males (high baseline/trait) compared to females (increased vulnerability to develop high emotionality). This sex-by-SERT double dissociation provides a framework to investigate molecular substrates of emotionality regulation in concert with serotonin function and may contribute to the sexually dimorphic features of mood disorders.

Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal.

Gene microarrays may enable the elucidation of neurobiological changes underlying the pathophysiology and treatment of major depression. However, previous studies of antidepressant treatments were performed in healthy normal rather than 'depressed' animals. Since antidepressants are devoid of mood-changing effects in normal individuals, the clinically relevant rodent transcriptional changes could remain undetected. We investigated antidepressant-related transcriptome changes in a corticolimbic network of mood regulation in the context of the unpredictable chronic mild stress (UCMS), a naturalistic model of depression based on socio-environmental stressors. Mice subjected to a 7-week UCMS displayed a progressive coat state deterioration, reduced weight gain, and increased agonistic and emotion-related behaviors. Chronic administration of an effective (fluoxetine) or putative antidepressant (corticotropin-releasing factor-1 (CRF1) antagonist, SSR125543) reversed all physical and behavioral effects. Changes in gene expression differed among cingulate cortex (CC), amygdala (AMY) and dentate gyrus (DG) and were extensively reversed by both drugs in CC and AMY, and to a lesser extent in DG. Fluoxetine and SSR125543 also induced additional and very similar molecular profiles in UCMS-treated mice, but the effects of the same drug differed considerably between control and UCMS states. These studies established on a large-scale that the molecular impacts of antidepressants are region-specific and state-dependent, revealed common transcriptional changes downstream from different antidepressant treatments and supported CRF1 targeting as an effective therapeutic strategy. Correlations between UCMS, drug treatments, and gene expression suggest distinct AMY neuronal and oligodendrocyte molecular phenotypes as candidate systems for mood regulation and therapeutic interventions.

Identification of a battery of tests for drug candidate evaluation in the SMNDelta7 neonate model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is characterized by selective loss of alpha-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNDelta7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2(+/+);SMNDelta7(+/+);Smn(-/-) mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders.

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.

Magnetic compass orientation in C57BL/6J mice.

We report evidence for a robust magnetic compass response in C57BL/6J mice. Mice were trained to build their nests in one of four magnetic directions by creating a light gradient along the long axis of a rectangular cage and positioning a nest box at the opposite (dark) end. The mice were then tested overnight in a circular, visually symmetrical arena in one of four magnetic field alignments. The positions of the nests built in the test arena showed strong unimodal orientation in the magnetic direction coinciding with the dark end of the training cage.