1) Enhanced attentional focus and attenuated stress-induced motor impulsivity
in rodents under chronic lithium treatment.
Presenter: Dominique Levesque, M.Sc. Student, Graduate Program in Neuroscience.
Faculty Sponsor: Allan Young

Background: The mood stabilizer lithium is an effective treatment for bipolar disorder, particularly mania, during which lithium attenuates impulsive behaviours such as pathological gambling, drug addiction and suicidality.  However, whether lithium directly decreases impulsivity is unclear.  We determined the effects of chronic lithium administration on performance of the five-choice serial reaction time task, a rodent analogue of the continuous performance test.

Methods: Animals learned to respond to a brief visual stimulus presented in one of five locations to earn a reward.  The accuracy of target detection measured attentional ability, while responses made prior to stimulus presentation provided an index of motor impulsivity. 

Results: Lithium-treated rats were significantly better at target detection, though not more impulsive.  Lithium treatment significantly attenuated the ability of yohimbine, a pharmacological stressor, to induce impulsive responding.  Real-time PCR analyses revealed decreased mRNA expression of various genes in the medial prefrontal cortex and orbital frontal cortex following lithium-treatment.

Conclusion: Chronic lithium treatment may enhance cognitive function, attenuate stress-induced increases in motor impulsivity, effects which could further our understanding of lithium’s clinical efficacy.  This system will allow us to explore the temporal and neurobiological mechanism underlying these effects, an approach which may lead to better treatments for BD.

2) Functional Analysis of Variants in Neurexin Genes in  Neurodevelopmental Disorders
Presenter: Tabrez J Siddiqui  (Postdoctoral fellow)
Faculty Sponsor: Ann Marie Craig

Introduction: Psychiatric disorders such as autism spectrum disorders (ASD), schizophrenia (SCZ), and intellectual disability (ID) are being recognized as disorders of brain connections or synapses. On the presynaptic axon,  neurexins have emerged as key molecules regulating synapse development.  Copy number variations and deleterious mutations in NRXN1 have been associated with ASD, SCZ, and ID but no such associations have been reported for NRXN2 or NRXN3.

Methods: We resequenced the 3 known neurexin genes (NRXN1, NRXN2, NRXN3) in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94) and 285 ethnically matched controls. We functionally tested variants for surface trafficking, binding partner interaction and synaptogenic activity in rat neuron culture and fibroblast coculture.

Summary of results: We identified a truncating mutation in NRXN2 in a patient with ASD, inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that are non-functional.

Conclusions: Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in both SCZ and ASD, supporting the notion of a common genetic mechanism in these disorders.

2)Valproate reopens critical-period learning of absolute pitch   
Presenter: Bradley W. Vines, Research Associate
Authors: Bradley W. Vines
Faculty Sponsor: Allan H. Young

Introduction: Studies have shown that histone-deacetylase (HDAC) inhibitors enable adult mice to learn perceptual abilities that normally can only be acquired during a critical period early in life. We investigated whether an HDAC inhibitor could reopen critical-period learning in adult humans as well. Absolute pitch (AP), which is the ability to identify or produce the pitch of a sound without any reference, is a critical-period phenomenon. Valproate (VPA), which is a medical treatment for bipolar disorder and epilepsy, is an HDAC inhibitor.

Methods: The experiment was a randomized, double-blind, placebo-controlled study. Twenty-four adult males (18 to 27 years old) received either placebo or VPA treatment. Subjects took capsules for 15 days (building up to a 1000mg dose), underwent a training regimen for AP during the second week of treatment (30 minutes/day), and took a post-treatment test for AP.

Results: The VPA group performed significantly better on the AP test compared to the placebo group (F(1,21) = 6.37, p = .02). There was no difference between the groups in general cognitive function or mood.

Conclusion: This result provides evidence that VPA facilitates critical-period learning in the adult human brain. It also establishes AP as a potential behavioral correlate of critical-period neuroplasticity.

1) White Matter Hyperintensities in an Inner City Population
Presenter: Maia Love, Resident in UBC Psychiatry Year 3
Faculty Sponsor: William Honer

Introduction: White matter hyperintensities (WMH) are incidental findings on brain magnetic resonance imaging. WMH can be associated with stroke, cognitive dysfunction, symptom severity in psychiatric disorders and underlying small vessel disease. In an ongoing large longitudinal study of interactions between psychosis, addiction and viral infection, we have begun preliminary investigations into the frequency and distribution of WMHs.

Methods: All subjects were recruited from single-residency occupancy hotels. Structural scans, including FLAIR, MRA and 3D T1-weighted SPGR) MR on a 3.0T Philips scanner were obtained at baseline. A quantitative survey of 85 FLAIR images was conducted.

Results: Over 50% of the subjects had WMH's. Twenty-one of 85 subjects had more than 10 WMHs, and 9 scans had over 30 WMHs in total. The degree of visible pathology beyond the normal expected number and size of WMH for age, as clinically rated by a neuroradiologist (ATV), was abnormally high.

Conclusions: In comparison to population averages (the majority of the general population presents with 2-3 WMH at the 6th decade, with increases by two or three WMH's per decade with aging; Longstreth et al. in Stroke 1996), our data indicate a significant degree of white matter abnormalities in the population of interest.

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1) The Need for a Perinatal Specific Generalized Anxiety Scale   
Presenter: Jasmin Abizadeh, BA
Authors: Jasmin Abizadeh, Gillian Albert, Arjun Nnanda, Shaila Misri   
Faculty Sponsor: Shaila Misri

Perinatal anxiety disorders regularly accompany perinatal mood disorders. However, as patients frequently fail to report these illnesses, they are often under-diagnosed by clinicians. These comorbid maternal mental disorders are significantly associated with maternal morbidity and adverse neonatal/developmental outcomes.
One of the most common anxiety disorders is Generalized Anxiety Disorder (GAD), which greatly interferes with daily functioning. Rates in the general population are much lower (3-5%) than in pregnancy and postpartum (4.4-8.5%). Differentiation of perinatal GAD from normal worry is difficult, possibly because women fail to disclose GAD symptoms, normalizing or minimizing them. 
Existing validated measures of anxiety include: State Trait Anxiety Inventory, Beck Anxiety Inventory, Hamilton Anxiety Measure, Goldberg Anxiety Scale and Penn State Worry Questionnaire (PSWQ). None of these are specific to the perinatal period and only the PSWQ is GAD-specific. The Edinburgh Postnatal Depression Scale is the conventional postnatal mental health scale; however, it contains only two anxiety sub-questions to screen anxiety. The Pregnancy Anxiety Scale measures anxiety during pregnancy, but is minimally validated and limited to retrospective answers non-specific to GAD. Clinicians often use DSM-IV structured interviews to capture perinatal GAD symptoms. This presentation will review current screening tools and advocate for a self-rated perinatal-specific GAD scale.

2) Promoting health through the Beautiful Game: Engaging with and advocating for residents of Vancouver's Downtown Eastside through Street Soccer   
Presenter: Alan Bates, Resident
Authors: Alan T. Bates, Fidel Vila-Rodriguez, Siavesh Jafari, Lurdes Tse, Rachel Ilg, Dominique Falls, William G. Honer
Faculty Sponsor: William Honer

Introduction: Mental illness and addictions contribute significantly to marginalization and social disadvantage in the Downtown Eastside. Street Soccer for people affected by homelessness re-engages marginalized people into communities . Since 2003, the Homeless World Cup has repeatedly demonstrated that, through soccer, over 70% of people affected by homelessness are able to significantly improve their lives. Following this international movement, the Vancouver Street Soccer League provides friendship for the homeless, physical fitness for the ill and addicted, direction for at-risk youth, and cultural focus for other unique populations such as inner-city First Nations people.

Method: Questionnaires were completed by Street Soccer players, Street Soccer volunteers, and healthcare providers and trainees who participated in a Street Soccer event. The data were supplemented by individual case reports.

Results: Over the last three years, the authors have seen players create lasting relationships, find jobs, get better housing, reconnect with heritage, and recover from illness. Data collected through the questionnaires also suggests that significant benefits to Street Soccer participants include increased physical fitness, improved mental health, reduction of substance use, increased social contacts, and improved housing.

Conclusion: Street Soccer is an effective means of engaging and helping people affected by homelessness in Vancouver.

3) Resilience Factors Related to Successful Community Reintegration among Forensic Psychiatric Patients   
Presenter: Caroline Greaves, Post-docotoral Fellow
Authors: Caroline Greaves, Tonia Nicholls, Simone Viljoen, Johann Brink
Faculty Sponsor: Tonia Nicholls & Johann Brink   

The present research sought to identify factors that contribute to resilience and successful reintegration in a group of persons with severe mental illness adjudicated under the forensic mental health system. File reviews of 100 patients on conditional discharge (CD) from the Forensic Psychiatric Hospital compared individuals who received renewals of CD orders with those readmitted to the hospital due to a breach of discharge conditions during a three-year timeframe. The ‘successful’ (n=44) and ‘in recovery’ (n=56) groups did not differ on aspects of previous mental health contacts or medication adherence. The ‘in recovery’ group were almost twice as likely to have used substances and/or to have displayed aggressiveness or impulsivity at admission. In contrast, group differences were noted in terms of personal and environmental characteristics following community release for the ‘successful’ group - they were more engaged with the supervision process, attended meetings and complaint with recommendations at significantly higher rates, indicating the clinical importance of pro-social attitudes. The Short-Term Assessment of Risk and Treatability ‘strength’ scores demonstrated predictive utility for successful community integration, indicating the relevance of these factors for comprehensive assessments of functioning, and for prevention and treatment strategies in line with the recovery model of service provision.

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4) Regional Gray Matter Abnormalities in First-Episode Mania   
Presenter: Tae Hyon Ha, Clinical Research Fellow       
Authors: Tae Hyon Ha   
Faculty Sponsor: Lakshmi N. Yatham

Introduction: Although underlying neurobiology is poorly understood, bipolar disorder has been frequently associated with abnormalities in regional brain structures. To exclude effects of illness progression on brain structure, regional gray matter alterations were investigated in patients with first-episode mania.

Methods: Magnetic resonance images from 58 patients with first-episode mania and 32 healthy controls were normalized and segmented into gray matter and white matter tissue maps using statistical parametric mapping software (version 8). Then, segmented gray matter images were compared between patients and controls groups.

Summary of Results: Compared to controls, patients with first-episode mania had a decreased gray matter density in the bilateral medial prefrontal, anterior cingulate, posterior cingulate, right insular, and left frontal regions. There were no group differences in total intracranial volume and in total volumes of segmented brain tissues.

Conclusions: Results suggest that brain abnormalities in neural nodes having important roles in emotion processing may be evident from the first-episode of bipolar disorder.

5) Creativity in BD:'Touched with fire, or burnt out? Igniting a dialogue'   
Presenter: Sharon Hou, Research Coordinator   
Authors: Sharon Hou   
Faculty Sponsor: Erin Michalak

Introduction: When asked about the advantages of having bipolar disorder (BD), over 80% of people describe creativity as one of the benefits. BD is often characterized by periods of highly creative thoughts and behaviours; many individuals living with BD choose careers in a creative field and some achieve prominence in creative pursuits. While we know that many people who have BD are creative, or that many creative people have BD, very little research has explored this relationship.

Methods: As a part of a CIHR Knowledge-to-Action grant, CREST.BD planned a series of innovative research events to begin to fill this gap, utilizing integrated knowledge exchange (KE) methods to engage patients with BD and their family members in various aspects of the research process. We held an annual community consultation day whereby community members (N=22) provided their perspective on the role of creativity in BD through focus group discussions. Data was audio-recorded, transcribed, and sent for thematic qualitative analysis. Two subsequent inter-linked events included a film screening of documentaries exploring the understanding of creativity and BD, and a music night celebrating the creative life of musicians living with BD.

Summary and conclusion: Data collected suggests that individual experiences of people with BD and creativity are as diverse as BD itself, and that the community is highly supportive of research into the more positive aspect of the condition. Thus, concentrated research efforts in this area may be worthwhile, as it will be an opportunity to begin to dismantle BD stigmas and stereotypes, and to hone BD treatment interventions to suit creative individuals.

6) Social Network Characteristics and Effect on Severity of Psychosis in a Community Sample with High Prevalence of Stimulant Use   
Presenter: Willough Jenkins, PGY2 Psychiatry Resident   
Authors: Willough Jenkins   
Faculty Sponsor: William Honer

As little is known about the social network composition in urban environments with high prevalence of serious mental illness and substance abuse, the objectives of this study are to collect descriptive information and to determine if network size has a buffering effect on the severity of psychotic symptoms.

Participants were recruited from four hotels in Vancouver from November 2008 until September 2010.  Participants completed interviews providing information on demographics, substance use, mental health and social network characteristics. Regression analysis was used to determine whether there was a correlation between network size and symptoms of psychosis.

The study population (n=146) had the following characteristics: 24% female, 76% male and 0.4% transgendered, 95% stimulant use, 54% opiate use, 52% cannabis use, 53% both stimulants and opiates, 13% alcohol, and 51% IVDU.

Using a categorical approach and specific PANSS items 53% of subjects were determined to be psychotic at baseline. The mean available network membership (ANWM) was 4.66 (range 0-18) people. Regression models were used to predict PANSS score, with predictors ANWM score, gender, and an ANWM by gender interaction. Statistically significant results were obtained for ANWM and the negative symptom PANSS score (p=0.01).

In an environment where exposure to stimulant drugs increases the risk of psychosis, social network size may be a protective factor that could be a target for future development of interventions.

 7) Relationship of psychopathology and substance use changes in a tertiary treatment settings.    
Presenter: Davit Khachatryan, Clinical Trainee        
Authors: Davit Khachatryan, Majid Al Desouki, kathy Lee, Elton Ngan, Michael Krausz, Christian G. Schutz    
Faculty Sponsor: Christian G. Schutz

Introduction: The BCMHA is a 100 bed tertiary care facility. At intake all individuals are assessed with standardized assessments, including the Addiction Severity Index (ASI) and the Brief Psychiatric Symptom Scale (BSI). The current exploratory examination focuses on the following two questions: Which psychiatric dimensions show the largest alterations over a three month treatment period? Are these alterations related to successful reduction of substance use?

Methods: The average length of stay at BCMHA is approximately 4-5 months. Based on 28 assessments completed at baseline and again at 3 months t-tests were used to compare means of symptom dimensions (BSI) and Parsons Correlation to measure the association between alcohol and substance use (ASI) and symptom dimensions (BSI).

Summary of results: Overall clients report a significant reduction in the depressive symptoms and some reduction in paranoid ideations. Reduction in alcohol consumption was significantly related to an increase in the obsessive compulsive, phobic anxiety and overall symptom dimensions. Similarly reduction in substance use was associated with an increase in phobic anxiety. Preliminary analysis of the follow up assessment indicates, that after three months of treatment despite an overall tendency of reduction of psychopathology, individuals still reported increases in symptom dimensions related to a decrease in alcohol and substance use.

8) Positive Interactions Between Individuals with a Mental Illness and the Police    
Presenter: Sara Lapsley MEd Candidate, UBC   
Authors: Michelle Pritchard, Sara Lapsley   
Faculty Sponsor: Erin Michalak

Background: Encounters between an individual with a mental illness and police have the potential to turn violent and result in injury to those involved (Watson, Corrigan, & Ottati, 2004). Conversely, people with mental illness will evaluate their encounters with the police positively when treated with dignity and respect (Watson, Angell, Morabito, & Robinson, 2008).  Our study is unique in that it focuses on the perspectives of those that have come into contact with the police when acutely mentally ill.  This poster will concentrate on the positive components of these interactions as seen by the individual with a mental illness. 

Methods: This poster describes qualitative results from a mixed methods, participatory action research study in which 60 individuals with severe mental illness were interviewed about their experiences with the police in British Columbia.

Results: The qualitative data indicates that many participants have received assistance from the police during severe episodes of mental illness.  Examples of this include being rescued from suicide attempts or being dealt with in a compassionate manner while experiencing psychotic symptoms. Participants expressed that the police were often respectful, treated them humanely, provided food, and made sure they received proper medical attention. When acutely ill, participants had difficulty appreciating this service. In retrospect however, many expressed gratitude that the police had prevented them from harming themselves or others.

Conclusion: Despite the fact that media attention is often focused on negative encounters with the police, our data provides evidence that the police can have a positive impact on the lives of many individuals who live with mental illness.

9) Component structure of cognitive deficits in schizophrenia   
Presenter: Katie M. Lavigne,  Graduate Student (MSc)   
Faculty Sponsor: Todd S. Woodward

Cognitive impairment in schizophrenia is a robust finding; however, it is unclear whether differences between schizophrenia patients and healthy controls reflect a general cognitive impairment, a range of domain-specific impairments, or a combination of both. In the current study, 1210 participants (334 schizophrenia patients, 395 siblings, 481 healthy controls) completed a battery of neuropsychological tests as part of the National Institute of Health’s Clinical Brain Disorders Branch (CBDB) Sibling Study. Constrained Principal Component Analysis (CPCA) was used to determine which cognitive domains were predictable from group differences. The results revealed five cognitive domains (working memory, visual memory, verbal memory, digit span, and fluency), but these were independent of group differences. Instead, a general cognitive component, dominated by WAIS-R Digit Symbol and WMS-R Logical Memory subscales but involving all neuropsychological test measures to some extent, accounted for 97% of test score variance predictable from group differences. Schizophrenia patients were significantly impaired relative to controls and siblings, while siblings scored closer to (but below) controls. These results suggest that (a) grouping neuropsychological tests into traditional cognitive domains is not helpful for understanding cognitive impairments in schizophrenia and their siblings, and (b) group differences can be described by a single domain of cognitive impairment.

10) Yoga as a complementary and alternative therapy for improving quality of life in perinatal women: a review    
Presenter: Arjun Nanda, Undergraduate Student    
Authors: Arjun Nanda, Jasmin Abizadeh
Faculty Sponsor: Shaila Misri

Perinatal depression affects a mother’s mood, relationships, and mental stability. While remission is used as a gauge to determine treatment efficacy, measurement of quality of life (QoL) is important in order to understand an overall sense of wellbeing. Treatments of mental disorders are complex and often require multiple approaches to restore functionality. In addition to standard pharmacotherapy, complementary and alternative therapy (CAM), including yoga, is often recommended by clinicians.  The purpose of this study is to examine the current literature on the effect of CAM therapies, specifically yoga, on depressed perinatal populations and their quality of life. Six online databases were searched using a combination of words specific to yoga, QoL, and perinatal depression, yielding 20 relevant articles. No articles specifically integrated the topics of yoga, QoL, and depression in the perinatal population. Sixteen articles showed reductions in anxiety and depression symptoms and an increase in QoL after yoga therapy.  The remaining 4 reviewed papers outlined other CAM treatments that showed positive effects alongside conventional treatment for depression. While several studies have suggested that yoga and other CAM therapies are efficacious as a supplement to pharmacotherapy for depression, more research is required in the treatment of perinatal populations.

11) Loxapine for treatment of acute agitation: a systematic review and meta-analysis of efficacy and safety   
Presenter: David Sherman, PGY-1
Faculty Sponsor: Raymond W. Lam

The acutely agitated patient is a medical emergency that is faced by nearly all medical specialties but is a common problem on psychiatry wards and in psychiatric emergency room settings.  Standard care as to the selection of a particular medication varies geographically as loxapine is prescribed more commonly in British Columbia and France  whereas haloperidol is used frequently throughout the rest of Canada and the United States.  Aerosolized loxapine is now available as an alternative non-oral medication.  A systematic review of the literature and meta-analysis was performed to examine the efficacy and safety of non-oral formulations of loxapine compared to first-generation anti-psychotics and placebo.  Intramuscular loxapine did not differ in efficacy (OR 0.66) or safety (extra-pyramidal side-effects OR 0.23, anti-cholenergic side-effects OR 2.14) from other intramuscular first-generation anti-psychotics.  Aerosolized loxapine was more effective than placebo (OR 2.83).  The data available for intramuscular loxapine is limited and of poor quality but does not support its use over other first-generation medications.  Aerosolized loxapine may provide an effective, non-oral alternative medication for the treatment of acute agitation.
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12) Investigating the Field Reliabiltiy of a Short-Term Assessment of Risk and Treatability Measure (START) in an Outpatient Forensic Clinic    
Presenter: Simone Viljoen, M.Sc.    
Authors: Viljoen, S., Launeanu, M., Hendry, M., Nicholls, T.L., Brink, J.    
Faculty Sponsor: Tonia Nicholls and Johann Brink

The Short-Term Assessment of Risk and Treatability (START) is a structured assessment measure intended to inform evaluation of multiple-risk domains relevant to psychiatric clinical practice. The START considers both vulnerability (risk) and strength (protective) related factors and has shown very promising psychometric results, however it is yet to be examined with outpatient populations. This study investigated the fidelity of implementing START in a forensic outpatient clinic by evaluating the psychometric properties of this measure in a forensic community sample. Specifically, we looked at structural reliability of the START and the inter-ratter reliability between STARTs completed by treating clinicians and experienced START researchers and coders. Results indicate good to excellent reliability between the clinic professionals and researcher raters (ICC =.56 - .83). With regard to structural reliability we found similar internal consistency levels consistent with prior research; our mean strength and vulnerability scores are similar to those found in open ward facilities. The START has previously been found to be a useful treatment planning and risk management tool, however, effective and accurate coding is essential to the usefulness of the measure. This study is among the first to demonstrate that this tool can be reliably utilized in clinics after proper training.

13) The role of oscillatory activity in the comparison of cometing hypotheses during a probabilistic reasoning task   
Presenter: Jennifer C. Whitman, Graduate Student   
Authors: Jennifer C. Whitman
Faculty Sponsor: Todd S. Woodward

Introduction: The comparison of evidence for competing hypotheses is impaired in delusional schizophrenia patients. We investigated the brain systems involved in such comparisons, laying the groundwork for future investigations involving clinical populations. We also addressed a question of more general relevance to neuroscience; namely, the relationship between oscillatory activity and levels of blood oxygenation within a given brain system.
 
Methods: The Blood Oxygen Level Dependent (BOLD) response was measured in 20 healthy participants via functional MRI (fMRI). Constrained Principal Component Analysis (fMRI-CPCA) identified functionally connected brain systems. Oscillatory activity measured via magnetoencephalography (MEG) in the same participants was localized to grey matter via a beamformer algorithm using structural MRIs.
 
Results: Hypothesis comparison increased the BOLD response in the widely reported task-positive network, and decreased it in the task-negative or ‘default’ network. Task-positive network BOLD increases corresponded to reduced alpha (10 Hz) and beta (21 Hz) oscillatory power. Task-negative network BOLD decreases corresponded to increased theta (5 Hz) and gamma (45 Hz) oscillatory power.
 
Conclusion: The relation between the BOLD signal and oscillatory activity is more complex than suggested by previous reports emphasizing gamma oscillations. Future research will explore how these networks function in delusional schizophrenia patients during hypothesis comparison.

14) Homeless Women I - Mental Health, Suicidality, and Self-Harm in Homeless Women   
Presenter: Verena Strehlau, MD   
Authors: Verena Strehlau, Iris Torchalla, Kathy Li, Michael Krausz   
Faculty Sponsor: Michael Krausz

Background: Prevalence rates of mental health disorders and suicidality in the female homeless population are little described. Detailed knowledge of this prevalence rates may improve our understanding of the mental health of homeless women and may inform the development of new treatment strategies that better meet their specific needs. The objectives of the current study were to assess prevalence rates of mental health disorders and suicidality in a sample of homeless women.

Methods: A cross-sectional study of 196 adult homeless women living on the street and in the shelters of Vancouver, Victoria, and Prince George were assessed using structured clinical interviews.

Results: 22% had current high or moderated suicide risk, 26% had suicidal thoughts in the past 12 months and 50% ever attempted suicide. 17% met diagnostic criteria in accordance to the DCM-IV for Depressive Episode, and 10% for mania. Furthermore, 12% of participants met diagnostic criteria for Panic Disorder, 32% for Agoraphobia, 20% for Social Phobia, 24% for General Anxiety Disorder, 28% for PTSD, 12% for Psychosis and 29% for adult ADD (all current prevalence rates). Lifetime prevalence rates for these disorders were notably higher. Prevalence rates for thoughts about self-harm and recent self-harm will also be presented and discussed.

Discussion: 72% of the participants met criteria for at least one mental health disorder, confirming the higher end of the range previously suggested in literature. There is a notable disparity between the mental health of the women in our sample compared to general female Canadian population: Prevalence rates of the homeless female population were substantially higher than in the general female population. Although we did not apply a mental health symptom severity measure, the high number of participants with current suicide risk hints towards the fact that the participants experience more severe mental health symptoms. Housing programs should be accompanied by multidisciplinary, specialized interventions, which account for high rates of mental health disorders.

15) Homeless Women II - Substance Use and Predictors of Substance Dependence in Homeless Women 
Presenter: Iris Torchalla, PhD       
Authors: Iris Torchalla, Verena Strehlau, Kathy LI, Michael Krausz   
Faculty Sponsor: Michael Krausz

Introduction: Canadian estimates indicate that 150,000-300,000 people in Canada are homeless. In international studies, high rates of substance use disorders were reported among the homeless, but only a few Canadian studies exist on substance abuse prevalence rates in this population. Furthermore, a growing body of research indicates that homeless women differ from homeless men in their substance use and mental health. In-depth analyses of substance use problems among homeless women may shed light on the heterogeneity of the homeless population, improve our understanding of addictive behaviours in homeless women, and inform the development of new treatment strategies that better meet their specific needs.

Objective: The objectives of the current study were a) to assess substance use behaviour and prevalence rates of substance use disorders in a sample of homeless women, and b) to investigate demographic and clinical correlates of current substance dependence.

Methods: In a cross-sectional study of 196 homeless women, each subject was assessed using structured clinical interviews. A multivariate regression model was applied to determine predictors of substance use.

Results: Crack cocaine (58%) was the most common substance used, followed by Alcohol
(53%), Cannabis (41%), and by Heroin (30%). Overall, 82.4% of the sample had at least one type of current substance use disorder, of which 70.5% had drug dependence and 37.8% had alcohol dependence. 76.7% of those individuals with current alcohol dependence had concurrent drug dependence. Multivariate analyses showed that younger age, living on the street, engaging in sex work, and having ever attempted suicide were associated with current drug dependence.

Conclusion: Prevalence rates for substance use and dependence were exceptionally high in this sample. There was a substantial co-occurrence of drug use disorders and alcohol use disorders. Innovative programs need to be developed which are accessible and tailored to the needs of this specific population, accounting for polysubstance dependence and additional vulnerabilities.

16) Acceptability of Telephone-Delivered Cognitive Behavioural Therapy for Major Depression
Presenter: Tanya L. Poitras, Research Coordinator
Authors: Tanya L. Poitras, Erin E. Michalak, Sagar V. Parikh, Raymond W. Lam
Faculty Sponsor: Raymond W. Lam

Introduction: Cognitive-behavioural therapy (CBT) and antidepressants are first-line treatments for major depressive disorder (MDD), with some recent meta-analyses suggesting combination approaches as the most effective. However, providing CBT presents significant cost and access barriers. To explore the merits and feasibility of telephone CBT, we conducted the WORKER Study.
Objective: Describe the limits and advantages of tel-CBT; identify completer rates and satisfaction with tel-CBT; and explore service delivery challenges in providing tel-CBT.
Methods: A 12-week randomized control treatment of escitalopram plus CBT in working patients with MDD, followed by a 12-week open observation period. All patients are treated with 10-20 mg of escitalopram and then randomized to the addition of 8 sessions of tel-CBT or 8 adherence reminder telephone calls. Data were obtained from 52 subjects randomized to tel-CBT. Therapists scored patient involvement in each session. A Satisfaction Survey measured patient satisfaction.
Results:  Telephone CBT was well accepted with 70% of all tel-CBT subjects completing all 8 sessions. Therapist ratings show an overall high engagement of patient involvement. Satisfaction Surveys indicate that 79% of patients reported being satisfied with tel-CBT.
Conclusions: Data suggests that patient compliance, engagement, and satisfaction with tel-CBT are high. While most would recommend tel-CBT to a friend, only slightly more than half indicated they would prefer future CBT by telephone over in person.

17) The LIFE Trial: Light, Ion, and Fluoxetine Efficacy in Depression
Presenter: Jane McLeod
Authors: Jane McLeod, MEd; Cindy Woo, BA.; Erin Michalak, PhD; Edwin Tam, MD; Raymond W. Lam, MD1
Faculty Sponsor: Raymond W. Lam

Objective: There are many effective treatments for depression; however, antidepressants may be associated with significant side effects, are expensive, and effective in only about 50% of cases. Further, many people with Major Depressive Disorder (MDD) prefer to use non-pharmacological treatments when available.  As a result, the use of combination treatments is increasingly being examined. This presentation will focus on the rationale and methodology of a clinical trial investigating the benefits of light and negative ion therapy in MDD.
Methods: In this double-blind, randomized, placebo-controlled trial, adult outpatients meeting criteria for MDD (HAMD17≥20) will receive light therapy or negative ion therapy alone or in combination with antidepressant (fluoxetine 20mg) for 8 weeks. Outcomes of study treatment will include clinical response and remission rates, adverse events, quality of life, work absence and productivity, and health services utilization.
Conclusions: Light and ion therapy show promise as monotherapy or adjunct treatment for MDD; however, studies to date have produced inconsistent results. The data gathered in this trial will further our understanding of these treatments for nonseasonal depression, and provide directions for future research.

1) Heantos Attenuates the stimulant and rewarding effects of amphetamine while paradoxically enhancing drug-evoked dopamine efflux in the nucleus accumbens and prefrontal cortex.   
Presenter: Soyon Ahn       
Authors: Soyon Ahn, Carine Dias, Tran Van Sung, Anthony G. Phillips   
Faculty Sponsor: Anthony G. Phillips

Heantos is a mixture of herbal extracts derived from traditional medicine used to treat opiate addiction.  Ongoing preclinical research in our laboratory has demonstrated significant effects of Heantos on the rewarding properties of morphine and the physical withdrawal symptoms precipitated by naloxone in rats treated repeatedly with morphine.  As yet, it is unknown whether Heantos has effects on other substances of abuse.  The present study focused on behavioural properties of d-amphetamine (d-amph) and the following results were observed. 
d-Amph-induced hyperactivity:  Heantos (250 mg/kg PO) alone had no behavioural stimulant properties.  Pretreatment with Heantos at the same dose significantly attenuated hyperactivity induced by d-amph (1 mg/kg IP).    
Intravenous self-administration of d-amph:  Animals trained with stable patterns of d-amph self-administration (0.1 mg/kg/inj IV) increased both responding and number of drug infusions significantly following pretreatment with Heantos at a dose of 250 mg/kg (PO).   Under a progressive ratio schedule, animals pretreated with Heantos (250 mg/kg PO) significantly decreased both the total number of responses for d-amph reward and the “break point” values.  Collectively, these data indicate that Heantos decreased both the rewarding properties of d-amph and the motivation to work for this drug.
Amph-evoked changes in DA efflux:  In separate experiments, microdialysis confirmed that there was a significant increase in DA efflux in the nucleus accumbens (NAc) as well as in the prefrontal (PFC).  Paradoxically, Heantos (250 mg/kg PO) pretreatment potentiated significantly the increase in DA efflux evoked by d-amph (1 mg/kg IP) in both regions.  Previous experiments using the selective D2 antagonist sulpiride, in combination with d-amph have shown augmented DA efflux relative to d-amph alone (Jaworski et al., 2001).   Accordingly, our findings imply that Heantos may have properties of a D2 antagonist.

2) Glucocorticoid receptors selectively modulate stress-evoked dopamine release in the prefrontal cortex   
Presenter: Kelly Butts, PhD Candidate
Authors: Kelly Butts
Faculty Sponsor: Anthony G. Phillips

The mechanism by which the mesocortical dopamine system is activated by stressful stimuli is unknown. We hypothesized that stress-evoked prefrontal dopamine release would be reduced by blockade of mesocortical glucocorticoid receptors. Methods. Stress was induced in rats by applying a mild tail pinch. Total corticosterone (bound plus free) levels were measured from blood samples taken from the tail vein using a commercially available radioimmunoassay kit. In vivo microdialysis was performed in freely-moving rats subjected to an acute stress. A glucocorticoid receptor antagonist, RU-38486, was reverse-dialyzed into the ventral tegmental area or medial prefrontal cortex while dopamine was continuously sampled from the medial prefrontal cortex. Dopamine in microdialysates was separated by high-pressure liquid chromatography and quantified by electrochemical detection. Results. Stress induced by tail-pinch caused a significant increase in corticosterone levels that remained elevated after the stressor was removed. Blocking glucocorticoid receptors in the medial prefrontal cortex with RU-38486 significantly attenuated stress-evoked dopamine release in that same area. However, blocking glucocorticoid receptors in the ventral tegmental area did not lead to an attenuation of stress-evoked dopamine release in the medial prefrontal cortex. Taken together, these data suggest that prefrontal glucocorticoid receptors selectively regulate stress-evoked mesocortical dopamine release.

3) Disrupting long-term depression attenuates expression and maintenance of behavioural sensitization to amphetamine in a context-dependent manner   
Presenter: Fiona Choi, Graduate Student, PhD Candidate
Authors: Fiona Choi
Faculty Sponsor: Anthony Phillips

Environmental factors provide a critical contribution to the effects of drugs and the process of addiction. Repeated exposure to amphetamine (AMPH) results in a progressive and enduring enhancement of drug-induced effects known as behavioral sensitization.  It is now well-established that behavioural sensitization is context-specific.
Learning and memory mechanisms regulating context-specific sensitization may be attributed to neuroplasticity at the synapse and long-term depression (LTD) in the brain has been proposed to be a cellular substrate for learning and memory.  More importantly, recent evidence has demonstrated that LTD in the nucleus accumbens can be blocked by a GluR2-derived peptide (Tat-GluR23Y), through interference with regulated AMPAR endocytosis.  In this series of experiments, the Tat-GluR23Y interference peptide designed to disrupt kinase activity required for AMPA receptor endocytosis was used to block LTD and thereby determine its role in the association of AMPH with a specific test-environment context.

Using an animal model of behavioral sensitization, we demonstrate that Tat-GluR23Y attenuated the development and expression of AMPH sensitization.  In addition, the further development of sensitization to subsequent AMPH injections was blocked.  However, initial exposure to Tat-GluR23Y has no effect on the development of AMPH sensitization in a new environment.  Interestingly, when rats were concurrently sensitized in two contexts, AMPH challenge in the non-peptide-paired context induced a significantly enhanced behavioral response. 

Collectively, these findings suggest that disrupting LTD persistently blocks behavioral sensitization by inhibiting the formation of an association between drug and the particular environment in which the pairing occurred.  However, upon exposure to AMPH in a novel context, behavioral sensitization and its related neural adaptations fully return. Use of the GluR23Y peptide to disrupt synaptic and behavioral plasticity related to drug addiction provides a possible novel target for drug-development strategies in the treatment of substance abuse.

4) Preclinical assessment of beneficial effects of Heantos on opiate reward and withdrawal precipitated by naloxone.
Presenter: Carine Dias, PhD, Research Associate
Authors: C. Dias, T. Sung, A.G. Phillips
Faculty Sponsor: Anthony Phillips

Heantos is an herbal remedy used in Vietnam to facilitate opiate detoxification and recovery. We assessed the effect of Heantos on the rewarding properties of morphine and on the aversive effect of morphine withdrawal, using condition place preference (CPP) and aversion (CPA) procedures. Once a day for 8 days, rats received alternatively morphine or saline in a specific compartment of the CPP boxes. Following the conditioning period, untreated rats explored freely the whole apparatus. Animals spent significantly more time in the morphine-associated compartment showing a CPP. Heantos administered prior to the test had no significant effect on the expression of morphine-induced CPP. However, Heantos administered during the conditioning phase blocked the rewarding effect of morphine. We also examined the effects of Heantos on CPA and physical symptoms induced by naloxone-precipitated withdrawal. Rats were injected with morphine for 7 days. On the 8th day, Heantos was administered just before naloxone. The animals receiving the low dose of naloxone were confined to one compartment and were tested 3 days later. Heantos had no effect on the naloxone-induced aversion. However, Heantos decreased the physical withdrawal symptoms precipitated by high dose of naloxone. Thus, Heantos appears to be a promising remedy for opiates addiction.

5) P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease   
Presenter: Jing Fan, Graduate Student
Authors: Jing Fan
Faculty Sponsor: Lynn A. Raymond

Huntington disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the protein huntingtin (htt). Previous studies have shown enhanced N-methyl-D-aspartate (NMDA)-induced excitotoxicity in neuronal models of HD (Zeron et al. 2001; Zeron et al. 2002; Shehadeh et al. 2006), mediated in part by increased NMDA receptor (NMDAR) NR2B subunit binding with the postsynaptic density protein-95 (PSD-95) (Fan et al. 2009). In cultured hippocampal neurons, the NMDAR-activated p38 Mitogen-activated Protein Kinase (MAPK) death pathway is disrupted by a peptide (Tat-NR2B9c) that uncouples NR2B from PSD-95, whereas NMDAR-mediated activation of c-Jun N-terminal Kinase (JNK) MAPK is PSD-95-independent (Soriano et al., 2008). Immunocytochemical experiments have shown that p38 is activated in the striatal neurons of R6/2 mice at 12 weeks of age (Gianfriddo et al., 2004) On the other hand, it has been found that wild type huntingtin interacts with MLK2 (JNK activator), while expanded polyQ interferes with this interaction (Liu et al., 2000) and facilitates JNK activation. To investigate the mechanism by which Tat-NR2B9c protects striatal medium spiny neurons (MSNs) from mutant htt-enhanced NMDAR toxicity, we compared striatal tissue and cultured MSNs from presymptomatic Yeast artificial chromosome (YAC) mice expressing htt with 128 polyQ (YAC128) to those from YAC18 and/or WT mice as controls. We found increased PSD-95 in the striatal non-PSD (extrasynaptic) fraction from YAC128 mice, similar to the previously published shift of NR2B-containing NMDARs to extrasynaptic sites. Notably, basal levels of both activated p38 and JNK MAPKs were elevated in YAC128 striatum. NMDA stimulation of acute corticostriatal slices increased activation of p38 and JNK in WT and YAC128 striatum, but Tat-NR2B9c pretreatment reduced only the p38 activation in YAC128. In cultured MSNs, inhibition of p38 reduced NMDAR-mediated cell death of YAC128 to WT levels, and occluded the Tat-NR2B9c peptide protective effect; in contrast, inhibition of JNK had a similar protective effect in cultured MSNs from both WT and YAC128 mice. Our results suggest that altered activation of p38 MAPK underlies mutant htt enhancement of NR2B/PSD-95 toxic signaling. However, the JNK pathway may also contribute to increased sensitivity of YAC128 striatal neurons to excitotoxicity.

6) Patterns of brain gene expression, cell types and wiring with relevance to neurodevelopmental disorders   
Presenter: Leon French
Authors: Leon French
Faculty Sponsor: Paul Pavlidis

There is growing evidence that neurodevelopmental disorders such as autism may involve connectivity abnormalities. We hypothesize that the brain connectome has relationships to gene expression patterns, and that such genes are potentially of interest as candidates in the study of neurodevelopmental disorders. To start addressing this question, we used large publicly-available databases of gene expression and brain wiring in the adult rodent brain. We show that expression patterns of genes are correlated with patterns of connectivity. In agreement with our hypothesis, the genes with the strongest relationships between expression and connectivity often play roles in brain development and axon guidance. These genes include homologs of NTRK1, REELIN and EN2 which have been previously linked to autism. We also demonstrate that the degree of connectivity is related to cell type distributions across the brain. We found two anti-correlated sets of genes that are neuron-enriched and oligodendrocyte-enriched. The neuron-enriched set is highly expressed in the frontal brain regions having many projections. In contrast, the oligodendrocyte-enriched set are expressed at higher levels in posterior regions with fewer connections. Our study shows how combining multi-modal data using neuroinformatics approaches can be used to uncover previously hidden patterns in gene expression profiles.

7) Linking imprinted genes to schizophrenia using coexpression networks   
Presenter: Jesse Gillis, Postdoctoral Fellow   
Authors: Jesse Gillis   
Faculty Sponsor: Paul Pavlidis

Genes which are expressed based on which parent they were inherited from are referred to as “imprinted” (i.e., maternally or paternally).  Because development involves an asymmetric parental investment, imprinted genes have been hypothesized to play an important role in development; a theory confirmed in several specific cases.  Recent research has suggested imprinted genes are both dramatically more prevalent than previously thought and of specific regional importance within the brain.  Based on this, and corresponding theories of the origins of schizophrenia, we investigated the role imprinted genes play in schizophrenic gene networks.  We constructed gene coexpression networks using control and schizophrenia brain samples from several pre-existing studies.  These networks represent the (inferred) functional interactions between genes in schizophrenia and, separately, control brain.  We find that the imprinted genes have extremely distinctive network properties in the control brain, which vary strongly in the schizophrenia brain. Primarily, we study these effects using the gene node degree which measures the gene’s importance to the network, but also has strong functional implications (e.g.,  pleiotropy, central lethality, etc).  In summary, we find that imprinted genes exhibit a stronger change in node degree in the schizophrenic brain than any other of thousands of functional groups of genes.

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8) Inhibitory effects of proton pump inhibitors on astrocytic neurotoxicity: Potential of proton pump inhibitors for treatment of Alzheimer disease   
Presenter: Sadayuki Hashioka, MD, PhD
Authors: Sadayuki Hashioka
Faculty Sponsor: Patrick L. McGeer

Objectives: Accumulating evidence indicates that proton pump inhibitors
(PPIs) posses anti-inflammatory properties. Lansoprazole (LPZ), a typical PPI, has been identified as an agonist of nuclear liver X receptor and has been suggested to inhibit aggregation of amyloid beta peptide. PPIs could be therapeutic for Alzheimer disease (AD). We have previously reported that human astrocytes exert neurotoxicity when stimulated by interferon (IFN)-g through STAT3 activation. To further establish the potential of PPIs to treat AD, we investigated their effects on IFN-g-induced neurotoxicity of astrocytes and STAT3 phosphorylation. The effects of PPIs on astrocytic production of IFN-g-inducible T cell a chemoattractant (I-TAC) and intercellular adhesion molecule-1 (ICAM-1) were also examined.
Methods: Human astrocytes, astrocytoma U118-MG and U373-MG cells were incubated with or without LPZ or omeprazole (OPZ) for 15 min. Subsequently, astrocytes and U118-MG cells were incubated with IFN-g for 48 h. U373-MG cells were incubated with IFN-g for 24 h. Their supernatants were transferred to human neuroblastoma SH-SY5Y cell cultures. After 72 h incubation, the viability of SH-SY5Y cells was assessed by the MTT assay and phase contrast microscopy. Cell lysates of astrocytes stimulated with IFN-g for 30 min with or without the PPI pretreatment were immunoblotted for phospho-Tyr701-STAT1, total STAT1, phospho-Tyr705-STAT3 and total STAT3.
Astrocytes incubated with IFN-g for 48 with or without the PPI pretreatment were used for the ICAM-1 assay and their supernatants were collected for enzyme-linked immunosorbent assay to determine the I-TAC concentrations.
Results: Both LPZ and OPZ significantly attenuated IFN-g-induced neurotoxicity of astrocytes and astrocytoma cells. These drugs significantly inhibited IFN-g-induced phosphorylation of STAT 3, but not that of STAT1.
LPZ, but not OPZ, significantly reduced astrocytic secretion of I-TAC.
Neither LPZ nor OPZ suppressed astrocytic expression of ICAM-1.
Conclusion: These findings suggest PPIs attenuate IFN-g-induced astrocytic neurotoxicity through inhibition of STAT3 activation. PPIs that possess anti-neurotoxic properties could be a useful treatment for AD and other neurodegenerative diseases associated with activated astrocytes.

9) Genome-wide expression profiling of schizophrenia using a large combined cohort   
Presenter: Meeta Mistry, PhD Candidate   
Authors: Meeta Mistry
Faculty Sponsor: Paul Pavlidis

Background: Many previous studies have examined gene expression profiles in post-mortem human brain samples from individuals with schizophrenia compared to healthy controls. There have been limited efforts to compare or meta-analyze these studies. Here we present the most comprehensive analysis to date of expression patterns in schizophrenia, combining seven studies of prefrontal cortex in affected individuals and unaffected controls.

Methods: We obtained seven studies which use closely related expression platforms (Affymetrix U133A or U133 Plus 2) and similar brain regions (BA10/46), for a total of 153 affected and 153 control individuals. Data was re-analyzed from CEL files and examined using a fixed effects model designed to account for the effects of covariates such as age and for batch effects. We evaluated the biological relevance of our results and additionally put them in context of each individual study and existing expression profiling studies of schizophrenia.

Results: Our combined analysis revealed a signature of 39 probes that are up-regulated in schizophrenia and 86 down-regulated. Some of these genes were previously identified in studies that were not included in our analysis, while others are novel to our analysis.

Conclusions: By combining data across studies we have increased the power required to detect small but significant changes associated with schizophrenia. Our results provide a new set of genes with expression changes associated with schizophrenia, and may be of interest as potential candidates for future genetic study.

10) Investigating the role of calpain in increased extrasynaptic NMDA receptor expression in a mouse model of Huntington Disease   
Presenter: Marja Sepers, Post doc   
Authors: Marja Sepers, Clare Gladding   
Faculty Sponsor: Lynn Raymond

In Huntington disease (HD), mood, cognition and movement deteriorate as neurodegeration occurs in the brain. Evidence suggests that increased activity and mislocalization of the NMDA receptor, in particular the NR2B subtype, to extrasynaptic sites, contributes to neuronal dysfunction and degeneration in the striatum in HD animal models. Here, we investigate whether NR2B cleavage by calpain contributes to aberrant expression and localization of NMDA receptors in the YAC128 mouse model of HD. Striatal synaptic (as defined by postsynaptic density --PSD) and extrasynaptic (non-PSD) neuronal fractions were isolated from 1-month old WT, YAC18 and YAC128 mice, or from a cortico-striatal acute brain slice preparation with or without treatment with a calpain inhibitor. The effect of calpain inhibition was also determined on surface NR2B expression in cortical-striatal co-cultures by immunocytochemistry. At baseline, YAC128 non-PSD NR2B expression was significantly increased compared to WT/YAC18 striatal tissue. Calpain-cleaved NR2B was also more abundant in YAC128 non-PSD and PSD compared to WT mice. Calpain inhibition led to a significant reduction in NR2B surface expression by immunocytochemistry, as well as expression in the non-PSD fraction by subcellular fractionation in YAC128 striatal neurons, without affecting NR2B expression in WT medium spiny neurons. Consistent with these results, whole-cell patch clamp recording revealed a significantly altered NMDA-evoked peak current density recorded from YAC128 medium spiny neurons in cortical-striatal co-cultures.   These results may aid understanding of critical molecular mechanisms underlying exaggerated NMDA receptor signaling in HD.

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11) A screen for synaptic organizers: discovery of TrkC-PTPo complex and Slitrk2, candidate genes in neuropsychiatric disorders   
Presenter: Hideto Takahashi
Authors: Hideto Takahashi
Faculty Sponsor: Ann Marie Craig

Dysfunction of a number of molecules implicated in synapse development is linked to many neuropsychiatric disorders. A synaptic organizing complex, the trans-synaptic adhesion complex that both mediates axon-dendrite contact and organizes pre- and post-synaptic differentiation, has been suggested to function as the fundamental molecular basis for normal synapse development. Here we discovered non-catalytic TrkC in an unbiased hippocampal neuron-fibroblast coculture screen as a novel synaptic organizer for excitatory synapse development. All TrkC isoforms, but not TrkA or TrkB, function directly in excitatory synaptic adhesion by neurotrophin-independent trans-binding to axonal PTPσ tyrosine phosphatase receptor. PTPσ triggers and TrkC mediates clustering of postsynaptic molecules in dendrites, indicating bidirectional synaptic organizing functions. Effects of a TrkC neutralizing antibody that blocks TrkC-PTPσ interaction and TrkC knockdown in culture and in vivo reveal essential roles of TrkC-PTP in excitatory synapse formation. Thus, postsynaptic TrkC trans-interaction with presynaptic PTPσ generates bidirectional adhesion and recruitment essential for excitatory synapse development. Interestingly, we also discovered Slitrk2 as another synaptogenic adhesion molecule through the coculture screen combined with bioinformatics. Given that TrkC and Slitrk family are linked to several neuropsychiatric disorders, our findings suggest that the dysfunction of synaptic organizers may underlie the basic pathogenesis of neuropsychiatric disorders.

12) Mood stabilizer lithium prevents amphetamine-increased adductions of 4-hydroxynonenal with presynaptic proteins in rat frontal cortex   
Presenter: Hua Tan
Authors: Hua Tan, Li Shao, Hong-Ying Li, L. Trevor Young, William G Honer, Jun-Feng    
Faculty Sponsor: William G. Honer

Monoamine neurotransmitters play an important role in the pathology of bipolar disorder (BD). Vesicular monoamine transporter 2 (VMAT2) and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) are critical in packaging and releasing monoamine neurotransmitters. Recent studies indicate that BD is associated with mitochondrial dysfunction and oxidative stress. Previous studies in our laboratory have shown that mood stabilizer lithium inhibits oxidative stress. The α, β-unsaturated aldehyde 4-hydroxy-2-nonenal (4-HNE), an end product of lipid peroxidation, is able to exert cytotoxicity and disturb cellular function by forming protein adducts. The purpose of this study is to determine whether 4-HNE forms protein adducts with VMAT2 and SNARE proteins, including synaptobrevin, synaptosomal-associated protein-25 (SNAP-25) and syntaxin, and whether lithium treatment can prevent amphetamine-induced 4-HNE-protein adductions in an animal model of mania. We found that repeated amphetamine stimulation significantly induced hyperactive mania-like behavior, decreased activities of mitochondrial complex I and III, and increased 4-HNE-protein adducts in rat frontal cortex, and that chronic lithium treatment inhibited both amphetamine-induced hyperactivity and 4-HNE-protein adducts. In addition, we found that 4-HNE can form protein adducts with VMAT2 and SNAP-25, but not synaptobrevin and syntaxin. Repeated amphetamine stimulation significantly increased 4-HNE-VMAT2 and 4-HNE-SNAP-25 adducts, while chronic lithium treatment inhibited amphetamine-induced 4-HNE-VMAT2 and 4-HNE-SNAP-25 adducts in rat frontal cortex. Our findings suggest that lithium may be able to normalize amphetamine-induced dysregulation of monoamine neurotransmitters by preventing 4-HNE adductions with VMAT2 and SNAP-25. This indicates that prevention of 4-HNE-VMAT2 and 4-HNE-SNAP-25 adductions by lithium may also contribute to pharmacological treatment of BD.

13) "NF-kB signaling regulates macrophage migration inhibitory factor (MIF) gene"   
Presenter: Si Zhang, Graduate Student
Authors: S. Fiona Zhang
Faculty Sponsors:  Weihong Song

Macrophage migration inhibition factor (MIF) is a 12kDa cytokine expressed by T cells, macrophages, monocytes and endothelial cells. Previous work from our lab has demonstrated that MIF gene expression was upregulated after stroke through the hypoxia signaling pathway. Since MIF has been suggested to play a protective role in heart ischemic injury, it is of interest to further investigate other signaling pathways that can regulate MIF gene expression. NF-κB, a transcriptional factor, has been shown to be activated after stroke. Analysis of upstream of MIF gene sequence reveals that several putative NF-κB consensus binding sites locates in the MIF promoter region. Therefore, our objective is to investigate whether NF-κB regulates the transcription of MIF. Using luciferase as the reporter gene, we compared the promoter activity of the MIF gene with or without the presence of NF-κB, which is induced by overexpression or drug treatment, and demonstrated that MIF promoter is responsive to NF-κB treatment. In addition, gel shift and super shift assays have confirmed the functionality of the putative consensus binding sites. The effects of NF-κB on MIF gene and protein expression will be further confirmed in cell lines. The results of the current results suggested NF-κB can enhance the expression of MIF gene.

14) Two versions of RCAN1 isoform 1 play differential role in global gene expression regulation
Presenter: Yili Wu, Postdoc Fellow
Faculty Sponsor: Weihong Song

RCAN 1(regulator of calcineurin 1), also known as Down Syndrome Critical Region 1 (DSCR1), is an endogenous regulator of calcineurin and involved in many physiological processes and disease pathogenesis, particularly neurodegenerative disorders including Alzheimer’s disease and Huntington disease. Two major transcripts of RCAN1, transcript 1 and transcript 4, are generated by alternative splicing. Transcript 1 can be translated into two species of RCAN1 isoform 1, RCAN1.1S and RCAN1.1L, by alternative usage of two in-frame translation start codon. Features of RCAN 1 protein include a leucin-rich amino terminal region, two proline-rich regions and a glutamic acid carboxy terminal domain, which suggests that RCAN1 might be a potential transcription regulator. In order to elucidate this, we first define the subcellular location of two species isoform 1 in human cells by western blot and immunoflurescence staining. Our study shows that two species of exogenous RCAN1 isoform 1 are located in both cytoplasm and nucleus. To further investigate their role in global gene expression regulation, microarray experiments were performed by using RCAN1.1L and RCAN1.1S stable cells derived from HEK293 cells. Comparing to parental cell line, around 1000 genes expression has been up- or down-regulated in RCAN1.1L or RCAN1.1S stable cell line, which involved in different signaling pathways.