Maturing neural circuits are dramatically shaped by the environment, but this timing varies across brain regions and plasticity declines with age. Focusing on cellular/molecular mechanisms underlying these developmental trajectories, this lecture explores specific events controlling the onset and closure of such ‘critical periods’. The dynamic balance of emerging excitatory-inhibitory (E/I) circuitry triggers plasticity. Targeting particular GABA circuits by pharmacological or genetic manipulations can either accelerate or delay critical period onset. Instead, plasticity appears to wind down as brake-like molecular factors emerge to stabilize adult networks. Lifting these brakes reopens windows of circuit rewiring, carrying broad implications for understanding the etiology and potential therapeutic strategies toward neurodevelopmental disorders or recovery from brain injury in adulthood.

Schizophrenia, depression, bipolar disorder are all uniquely human conditions.  Psychiatric conditions include alterations in several different and overlapping domains (NIMH RDoC). Each domain may have unique biological bases. Drug development efforts are now based on addressing domains/RDoC.  Can we model psychiatric conditions in rodents? Schizophrenia, depression, bipolar disorder are all uniquely human conditions. Psychiatric conditions include alterations in several different and overlapping domains (NIMH RDoC).  Each domain may have unique biological bases. Drug development efforts are now based on addressing domains/RDoC.

Given the challenges of replicating Parkinson’s disease in animal models, returning to models that are human-based and highly clinically characterized may provide the most successful path forward. There is a critical need to differentiate Lewy body Parkinson’s disease from other non-Lewy body forms of parkinsonism. This is important because the underlying molecular pathomechanisms, and hence potential therapeutic targets, are unlikely to be similar for both.
One exciting new avenue regarding modeling human disease is the use of induced pluripotent stem cell (iPSC) technology utilizing individual donors with clear clinical diagnosis of disease. In regard to modeling Lewy body Parkinson’s disease, patient-specific iPSCs lay the foundation for differentiation into the tissue-type of interest, i.e. mid-brain dopaminergic neurons. Using such a collection of iPSCs that is thoroughly characterized with high-quality and comprehensive clinical data and eventually with confirmative neuropathology at autopsy is the key for successful interpretation of findings.
 
However, in order for iPSC modeling approach to produce validated results, several challenges must be addressed to reduce variability of intrinsic and extrinsic nature. This is why it is critical that the methods used to generate iPSCs are documented and performed in a consistent manner to minimize variability. Another critical area for improvement is the use of consistent (or at least well documented) methods for differentiation of these patient-derived iPSC lines into neuronal cultures. The field is in dire need of standardized and validated iPS laboratory practices to generate and characterize cells and phenotypes of interest to understand disease and to identify new targets.
 
Learning objectives:
•           Clinical and pathological characterization of Lewy body Parkinson’s disease
•           Critical factors of intrinsic and extrinsic variability for iPS cell modeling
 

The adolescent brain has been forged by evolution to have different features than those of a child or an adult, but it is not broken or defective.  Phenomenal ability to adapt to environmental demands (i.e. plasticity), dynamic changes in the brain’s reward circuitry, and dramatic alterations in how the different components of the brain interact with each other make adolescence a time of great opportunity but also a time of vulnerability.  Prominent amongst the vulnerabilities are the factors that make adolescence the most common time for emergence of many psychiatric conditions including anxiety and mood disorders, eating disorders, psychosis, and substance abuse. Neurobiological maturation in the highly adaptive teen brain drives behavioral changes of increased risk taking, heightened sensation seeking, and a move away from parent to peer affiliation.  These behavioral changes are not inherently bad but may contribute to an increased likelihood for difficulties during adolescence.  Neuroimaging investigations are beginning to map trajectories of brain development in health and illness, discern the influences, for good or ill, on these trajectories, and explore how the biological changes interact with the behavioral changes and social context to affect the risk for addiction.  In this presentation Dr. Giedd will summarize results from his 23 year ongoing longitudinal brain imaging/genetics/behavioral study encompassing over 8000 scans from 3000 people aged 3 to 30 years (¼ healthy singletons, ¼ healthy twins, ½ clinical populations such as Autism, ADHD, Childhood onset Schizophrenia) with the goal of generating discussion regarding future directions of research.

Learning objectives:
1) Understanding challenges to learning
2) Decision-making related to teen brain development

 

A key goal in psychiatry is to build new diagnostic, therapeutic and translational tools and capacity to reduce the impact of emerging mental disorders in young people on survival, distress, quality of life and productivity. Young people bear the major burden of onset for mental disorders with 75% of such illnesses appearing before age 25 years.  This can only be done within a novel non-stigmatising interface between young people and clinical care in mental health such as that recently created by headspace in Australia and increasingly in some other developed nations. We must also develop new terminology enabling early clinical phenotypes of mental disorders to be defined in a normalizing and health-promoting way that will promote trust and confidence. A transdiagnostic strategy is critical, transcending existing subthreshold risk syndromes, with new “pluripotential” criteria capturing clinical high risk for multiple syndromes. This strategy seeks to solve problems with specificity, power and reduce false positives. Secondly, we must focus on novel therapeutics. This starts with the development and evaluation of novel forms of psychosocial intervention for early stage illness. A complementary strategy needs to focus upon candidate biomarkers as therapeutic probes within a reverse translation strategy moving towards biosignatures or profiles of emerging disorder. Relationships between response and baseline levels of and changes in biomarkers may create a pathway to personalised/stratified medicine. Finally translation of existing expertise and systematic reform of clinical practice and cultures of care is something that is achievable with the present state of knowledge yet is poorly implemented.
 

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, Dr. Goldstein will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, positron emission tomography, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, Dr. Goldstein’s multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk Dr. Goldstein will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising novel fMRI studies, which combine pharmacological (i.e., oral methylphenidate, or Ritalin^TM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging in the empirical guidance for the development of effective neurorehabilitation strategies in cocaine addiction.

Learning objectives:

1. Identify the core neuropsychological mechanisms underlying the clinical symptomatology of drug addiction
2. Recognize the contribution of compromises in brain function and structure to human cocaine addiction; assess potential recovery with abstinence and other interventions.
3. Recognize the importance of impairments in response inhibition, salience attribution, and self-awareness/insight into illness in drug addiction

There is a growing appreciation of the relationship between gut microbiota, and the host in maintaining homeostasis in health and predisposing to disease. Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Over the past 5 years substantial advances have been made in linking alterations in microbiota to brain development and even behaviour and the concept of a microbiota-gut brain axis has emerged. Animal models have been essential in moving forward this frontier research area. In order to assess such a role we use studies involving, germ free mice and early-life microbiota manipulations and finally probiotic administration in adulthood. We assess neurochemical, molecular and behavioural effects following these manipulations. Our data show that the gut microbiota is essential for normal stress, antidepressant and anxiety responses. Moreover, microbiota is essential for both social cognition and visceral pain. Finally, there are critical time-windows early in life when the effects of microbiota on brain and behaviour appear to be more potent. Our data also demonstrates that these effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems. Such data offer the enticing proposition that specific modulation of the enteric microbiota by dietary means may be a useful "psychobiotic"-based strategy for stress-related neurodevelopmental disorders and possibly even neurodegenerative processes.
 

Schizophrenia (Sz) is a major mental disorder that affects ~1% of the population.  Although traditional models of Sz focused on dopaminergic dysfunction, newer models increasingly implicate glutamatergic systems, particularly N-methyl-D-aspartate receptors (NMDAR).    NMDAR models are supported by the ability of NMDAR antagonists (e.g. PCP, ketamine) to induce symptoms and neurocognitive deficits closely resembling those of Sz and by genetic and auto-immune findings. One key deficit related to NMDAR dysfunction in Sz is a failure in the generation of mismatch negativity (MMN).  Deficit in MMN generation have been extensively replicated in Sz and shown to predict functional outcome.  At the physiological level, MMN impairments are related to impaired theta (4-7 Hz) generation within somatomotor networks.  At the cognitive level, deficits in basic auditory processing contribute to impairments in phonological reading and auditory emotion recognition which, in turn, contribute to poor psychosocial function.In the visual system, NMDAR play a preferential role in non-linear gain which, in turn, particularly affects functioning of the magnocellular visual system.  Thus, consistent impairments are observed in ERP (e.g. visual P1) and fMRI response to magnocellular-biased visual static and motion stimuli, while responses to parvocellular-biased stimuli remain relatively intact.  Deficits in magnocellular function in turn lead to impairments in higher order visual information processing, including ability to detect and process facial expression.  As with auditory deficits, basic visual deficits contribute directly to social dysfunction and impaired functional outcome.  Overall patterns of dysfunction in Sz highlight the role played by NMDAR in information processing at the ensemble and network levels. 
 
Learning objectives:

1.  Understand the role played by NMDAR in basic auditory processing and implications for schizophrenia.
2. Understand the role played by NMDAR in basic visual processing and implications for schizophrenia

In this presentation, Arvid Carlsson, who was awarded the Nobel prize in 2000 for his discovery of the transmitter role of dopamine, will be interviewed by Elias Eriksson. The following aspects will be covered during their discussion: 1. How the transmitter role of dopamine was disclosed. 2. The importance of dopamine for Parkinson’s disease. 3. The importance of D2 antagonism for the symptom-reducing effect of typical and atypical antipsychotics. 4. Which other conditions, apart from Parkinson’s disease and psychosis, are likely to be closely related to brain dopaminergic neurotransmission? 5. The concept of partial D2 agonism. 6. Dopamine stabilizers: the next generation of dopamine-modulating drugs?
 
Learning objectives:
 
1. To provide a historical background for the current assumption that dopamine is a brain neurotransmitter of importance for a number of neurological and psychiatric conditions. 
2. To present the rational for introducing dopamine stabilizers as the next generation of dopamine-modulating agents.
 

Impulse control disorders (ICDs), also known as behavioural addictions, are common in the general population and can have marked consequences.  ICDs can also commonly occur with exposure to dopamine agonists and Levodopa used in the treatment of Parkinson’s disease and provide an intriguing pathophysiological insight.  These behaviours include pathological gambling, compulsive sexual behaviors, binge eating and compulsive shopping.  That the behaviours only occur in a subset of individuals argues for an interaction between the exogenous dopaminergic activity and either an individual vulnerability for addictions or a role for Parkinson’s disease.  Here I discuss evidence from rodent and human studies that chronic exogenous dopamine may interfere with physiological functions of dopamine and link preclinical and clinical data.  Where relevant I compare with behavioural and substance addictions in the general population. 
 
Enhanced ventral striatal dopaminergic activity is observed within specific contexts; this may be related to decreases in striatal dopamine transporter levels and presynaptic D2 autoreceptor sensitivity enhancing physiological dopaminergic activity or chronic Levodopa increasing dopaminergic gain.  Chronic D2 receptor stimulation is hypothesized to impair detection of negative prediction errors.  Converging evidence highlights the relative imbalance of ventral and dorsal striatal systems.  The reinforcing properties of dopaminergic medications are enhanced in rodent parkinsonian models.   In humans, this imbalance is captured in the better fit with ventral striatal critic models reliant on stimulus value rather than dorsal striatal actor models.  Greater impulsivity in the decisional rather than the motoric domain further reinforces this imbalance.  Stimulation of the subthalamic nucleus appears to moderate these behaviours, likely related to changes in dopaminergic medications but also possibly to an influence on cognitive mechanisms.  Understanding mechanisms underlying dopaminergic medication-induced ICDs provides critical insights into the role of dopamine on cognitive processes and the emerging conceptualization of behavioural addictions.
 
Learning goals:

1. To understand the role of exogenous dopamine on cognitive processes
2. To facilitate a discussion between similarities and differences of these behaviours and behavioural and substance addictions in the general population.

This talk will provide an overview of Fourier Transform InfraRed (FTIR) chemical imaging as a powerful and versatile method for obtaining information about CNS tissues. By combining imaging and spectroscopy, a spatial distribution of chemical components in biological samples can be assessed. Differences in cell types and disease states can be discovered through spectroscopic fingerprinting. Statistical software tools (PCA, ANOVA, etc.) may be employed to automatically distinguish subgroups with high sensitivity and specificity.  We have shown that certain protocols in tissue preparation and storage are critical for preservation of some chemically unstable biomarkers. With appropriate sample preparation, it is possible to study normal and diseased CNS material using only the biochemical signatures of naturally-occurring components in unstained, unfixed tissue.

In this presentation, the basis of FTIR spectrochemical imaging will be illustrated for mouse models of Alzheimer’s Disease (AD) and autopsy brain tissue of normal and AD cases, as well as a rat model of spinal cord injury and repair. Other interests in our research group include lymphocytes in Hodgkin’s Disease, development of scar tissue in wound healing, discovery of secondary metabolites in fungi and lichen, responses of sea ice algae to climate change, as well as the analysis of layered polymer coatings and blended polymers. The long term goal is to bring bench top FTIR spectrochemical imaging into mainstream practice by enabling characterization of the chemistry and biochemistry of systems at biologically relevant length and time scales.

 

Traditional models of basal ganglia disorders are grounded in the assumption that network dysfunction is driven by alterations in intrinsic excitability of striatal neurons. Recent work has challenged this assumption, showing that in mouse models of Parkinson’s disease there are profound alterations in synaptic strength and connectivity accompanying network pathophysiology. The talk will summarize this work in two steps. The first part of the talk will give a basic overview of basal ganglia structure and function, emphasizing the complementary roles of direct and indirect pathways in regulating goal directed and habitual movement. New insights into the cortical and thalamic connectivity of striatal direct and indirect pathway spiny projection neurons (SPNs) will be outlined along with the mechanisms governing their strength. The second part of the talk will provide a summary of work characterizing cell-specific alterations in the number and strength of synaptic connections driving SPN activity in the hypokinetic parkinsonian state and after administration of levodopa at doses sufficient to produce hyperkinetic dyskinesia. The interplay of homeostatic and dopamine-dependent synaptic plasticity in shaping these alterations in synaptic function will be examined and an attempt made to reconcile synaptic changes with the hypokinetic and hyperkinetic features of these states. Translational opportunities arising from these insights also will be mentioned.

Innovation in Psychopharmacology is Dead. Long Live Innovation in Psychopharmacology!  
What’s going on in our field? 

• Priorities of Big Pharma shifting away from CNS and especially from psychiatry
• Failed clinical trials littering the landscape
• Even known drugs don’t work in psychiatric trials
• Broken clinical trial apparatus
• Iterative step-wise improvements or ‘me-too’ agents not reimbursed
• Aggressive cost controls
• No new validated targets

Learning objectives - 

• Discuss the reasons for the slow down of innovative new treatments entering psychopharmacology and the exit of Big Pharma largely from psychiatry
• Show that future advances may be based on targeting symptoms that cut across a large array of psychiatric disorders
• Propose that effective new treatments will be based upon subpopulations defined mostly in the short run by symptoms but in the long run by genetic and imaging biomarkers

In the adult central nervous system (CNS) small populations of neurons are formed in the adult olfactory bulb and dentate gyrus of the hippocampus. In the adult hippocampus, newly born neurons originate from stem cells that exist in the subgranular zone of the dentate gyrus. Progeny of these putative stem cells differentiate into neurons in the granular layer within a month of the cells’ birth, and this late neurogenesis continues throughout the adult life of all mammals. Environmental stimulation can differentially effect the proliferation, migration and differentiation of these cells in vivo. These environmentally induced changes in the structural organization of the hippocampus, result in changes in electrophysiological responses in the hippocampus, as well as in hippocampal related behaviors. We are studying the cellular, molecular, as well as environmental influences that regulate neurogenesis in the adult brain. We have recently identified several molecules that work coordinately to regulate proliferation, survival and differentiation of these adult derived stem cells. In addition, we have demonstrated that specific types of activity can influence the behavior of these newly born cells. Finally, we have developed several methods to monitor the in vivo maturation of neurogenesis in vivo, which has provided insight to the functional importance of neurogenesis to behavior.  A consensus model of the function of adult neurogenesis is emerging

Learning Objectives: 

1. How is adult neurogenesis regulated?
2. What might the function of adult neurogenesis in the hippocampus?

We routinely face decisions requiring evaluation and choice of different actions may or may not yield different types of rewards. These situations trigger competitive decision biases that reflect interplay between different prefrontal cortical, amygdalar, striatal and habenular nodes within the brain’s dopamine system, which plays a critical role in action selection and reward processing. This lecture discusses some of the interactions between these circuits that shape decision biases and underlie conflicting urges when evaluating options that vary in terms of potential risks and rewards. Subcortical circuitry linking the amygdala and the ventral striatum appears to promote a more visceral bias towards larger, uncertain rewards, whereas prefrontal regions serve to temper these urges when riskier options become less profitable via top-down control over the amygdala. Dopamine transmission within these regions also makes dissociable, yet complementary, contributions to risk/reward judgments, promoting either exploitation of current favorable circumstances or exploration of more profitable ones when conditions change. In addition, phasic dopamine activity, regulated in part by the lateral habenula plays a key role in providing short-term information about recent outcomes that can bias subsequent choice behavior. These findings provide insight into the dynamic competition between these cortical/subcortical circuits that shape our decision biases and underlie conflicting urges when evaluating options that vary in terms of potential risks and rewards.
 
 
Learning Objectives
-Understand the functional connectivity between different cortical and subcortical systems that regulate different aspects of decision making in the context of reward seeking and
-Understand how different aspects of dopamine activity (modes of transmission, different receptor subtypes) regulate distinct aspects of action selection and reward processing.
 

Optogenetics or optophysiology is a rapidly growing technique used across an ever broadening array of research fields. Investigators now genetically modify many signalling pathway elements to enable precise and spatially targeted light control of biology down to a single cell or sub-cellular level.  Neuroscience is probably the largest research field using targeted light in order to control neuronal excitation and so gain better insight into how nerve cells communicate, how they behave within the context of a network, and the impact on the whole model organism.
This webinar will provide a brief background into what optogenetics is, and more specifically highlight some publications that combine microscopy with optogenetic manipulation.  This will demonstrate the power of these tools in neuroscience research.  We will then go on to show technology that enables the researcher to photo-stimulate optogenetically modified targets using microscopy, and the power of combining this with electrophysiology techniques in the combined technique of optophysiology.

Learning Objectives
• Benefits of combining microscopy with optogenetic manipulation
• How to mix photo-stimulation with electrophysiology  to enable optophysiological studies.
 

Our goal - To Understand the Neurobiology of Emotions and Affect  and Its Relevance to Psychiatric Disorders.  This includes:

• Understanding basic mechanisms of affect, stress and coping
• Investigation of Mood Disorders
• Investigation of Addictive Disorders
• Relying on both animal models and human studies