Studying the genetics of rare congenital disorders disrupting cognitive function has led to the identification of multiple disease genes that helped us better understand the mechanisms underlying prenatal and postnatal development. While genetic studies have revealed great heterogeneity, the advent of next-generation sequencing genetic studies has greatly increased the pace of discovery.

Our research focuses on a group of genetically heterogeneous neuromuscular disorders, termed dystroglycanopathies. In these disorders loss or reduction of glycosylation of the transmembrane glycoprotein alpha-dystroglycan cause muscular dystrophy, associated with severe brain and ocular malformations and intellectual disability. The study of the genetics of dystroglycanopathies has been instrumental in defining that dystroglycan’s interactions with the extracellular matrix (ECM) are a key regulator of cell differentiation in the brain and retina. Twenty different genes can be mutated in dystroglycanopathies and most of these genes have a direct role in controlling assembly of glycans on the dystroglycan protein. These glycans mediate interactions with laminin and other ECM components, and different glycosylation patterns instruct protein-protein interactions. However, to date only half of dystroglycanopathy cases can be explained by mutations in the known genes and it is still unclear how most of these genes affect glycosylation processes involved in ECM function in the brain.

This presentation will focus on our recent work on gene identification in dystroglycanopathies and related neuromuscular disorders using a combination of next-generation sequencing and functional validation in the zebrafish to study how the mutated genes affect brain development.

Alterations in homeostatic functions such as energy balance and sleep patterns are frequently seen in the elderly and these changes may precede and predict subsequent cognitive decline.  A novel hypothesis is that some of these seemingly disparate manifestations of age-related deficits may share common underlying neurobiological mechanisms; that is, brain regions that are involved in homeostasis regulate the activity of brain regions that mediate the appropriate behavioral and cognitive responses to physiological challenges, and these interactions may be impacted in aging.  The hypothalamic orexin/hypocretin neuropeptide system regulates energy balance, arousal and cognition via widespread ascending and descending projections.  We have shown in animal models that the orexin system plays an important role in modulating cognitive—particularly attentional—function and that aging is associated with dramatic reductions in the number of orexin neurons and deficits in activation of cortical and hippocampal circuitry by homeostatically-relevant stimuli.  Recent clinical literature has also shown significant loss of these neurons in age-related neurological disorders, including Alzheimer’s and Parkinson’s disease.  Here, I will review and expand on these findings and discuss the potential of the orexin system as a therapeutic target for “healthy brain aging”, with effects on both cognitive and physiological correlates of aging.

Epigenetics refers to the study of nuclear architecture and gene regulation. Epigenetic mechanisms govern many physiological processes such as cell differentiation, x-inactivation, and genomic imprinting, and pathophysiological processes such as loss of imprinting. Epigenetic mechanisms are especially relevant in psychiatry and neuroscience, as exposure to stress, trauma, or toxicants are thought to alter brain function through epigenetic mechanisms. However, there are substantial challenges to studying epigenetics in the brain, as the brain is a highly heterogeneous organ whose constituent cells and circuits perform diverse functions such as storage of memory, behavioral and emotional response, and regulation of homeostasis among many others.

In this presentation, Dr. Lee will first provide a brief overview of epigenetics and several commonly used approaches to study epigenetic mechanisms in gene regulation. In particular, he will focus on the implementation of an unbiased, genome-wide platform called Methyl-Seq to study DNA methylation, which is one of the more commonly studied epigenetic modifications, to identify targets of stress and glucocorticoid exposure in the brain. Dr. Lee will then discuss some of the challenges associated with implementing epigenetic tools to answer questions in psychiatry and neuroscience, such as limiting starting material, cellular heterogeneity, and neuronal subtypes. Dr. Lee will also focus on enrichment methods using genetic labeling and flow cytometry to isolate relatively homogenous populations of cells for downstream epigenetic applications. Epigenetic tools, when combined with concepts and powerful analytical tools in neuroscience, have the potential to elucidate the molecular underpinnings of neuronal function.

For Research Use Only.  Not for use in diagnostic procedures.

As we experience our environments, our brains are constantly computing inferences about the most likely state of the world: Are those lights in the distance headlights or streetlights?  If headlights, how fast are they going?  Is it safe to cross the street?  These perceptual decisions are often accompanied by subjective evaluations of certainty: Are you sure those are headlights? Are you sure they’re approaching slowly enough?  But there are other subjective aspects of perception, too, such as how bright the lights seem to be, regardless of their identity.  Are the neural representations and computations underlying these two kinds of subjective experiences linked in any way, or is a light’s brightness completely separable from your uncertainty about whether it is a headlight or a streetlight?

Despite increasing efforts to answer these questions, how the brain computes metacognitive judgments of certainty versus other subjective evaluations is not well understood.  In this talk, I will present behavioral, neural, and computational evidence that the neural computations underlying subjective confidence are inextricably intertwined with those underlying other subjective experiences, including perceptual awareness.  This fundamental link explains many puzzling and seemingly sub-optimal metacognitive behaviors seen across species by providing a biologically plausible substrate that can parsimoniously describe perception, metacognition, and subjective awareness

Specialized aggregations of extracellular matrix called perineuronal nets (PNNs) appear during juvenile stages of development and surround primarily fast-spiking, parvalbumin (PV)-containing GABAergic interneurons in the central nervous system. These PNNs are an exciting structure to explore in drug abuse research because previous studies show that removing them in certain brain regions re-establishes juvenile-like states of plasticity; therefore, we may be able to alter the brain plasticity imposed by drugs of abuse. Our studies in rats show that removal of PNNs within the prelimbic region of the medial prefrontal cortex (mPFC) impairs the consolidation and reconsolidation of cocaine-associated memories in a cocaine-induced conditioned place preference (CPP) task. In addition, removal of PNNs blunts the acquisition of cocaine self-administration and appears to blunt the reconsolidation of the memory associated with cocaine cues. Conversely, cocaine exposure alters the intensity (thickness) of PNNs and the intensity of PV cells in the prelimbic mPFC. While acute cocaine injection decreases the intensity of PNNs and PV cells, repeated cocaine injection increases the intensity of PNNs and PV cells. Some of these changes observed after cocaine may be mediated by oxidative stress. Overall, our studies suggest that PNNs within the mPFC are highly dynamic and modulate cocaine-induced plasticity.

A fundamental challenge in developing brain machine interfaces (BMIs) is building a decoder between patterns of brain activity and movement in patients with spinal cord injury, ALS, and amputation because these patients cannot move their intact limb .   We demonstrate two approaches to solving this problem.  First, we show that visual observation of action can automatically trigger mirror-like responses in primary motor cortex that are similar to the responses that occur during action.  Using these mirror-like responses, we show that brain activity can be mapped to movement without overt arm movement.  Second, we demonstrate that amputees can learn an arbitrary mapping between brain activity and movement of a robot after long-term exposure to a BMI.  Moreover, we also show how the functional connectivity among neurons controlling the robot undergo modifications during BMI learning which may provide an interesting model of motor skill acquisition.

Working memory ability matures late in life, in adolescence or early adulthood, and may be enhanced even in adulthood through cognitive training. The mechanisms through which working memory is mediated, and how it is modified so as to mediate such cognitive changes have been a matter of debate in recent years. To address this question, my laboratory has performed a series of experiments recording neuronal activity in adolescence and adulthood, as well as before and after training on working memory tasks. Neural activity comparisons between adolescent and adulthood revealed unchanged representation of visual stimuli, increased activation during working memory, but decreased representation of distracting stimuli. After task training, more prefrontal neurons were activated by the stimuli, and increased activity was present during working memory maintenance. These results reveal the nature of changes in neural activity that underlie cognitive enhancement in development and as a result of task training.

Miniaturized microscopes in combination with genetically encoded calcium indicators now allow recordings of activity from hundreds of neurons simultaneously in freely moving animals. We are building new generation open source miniaturized microscopes with expanded capabilities.  First, we have built and wireless miniaturized microscopes allow unfettered recordings for over 15 minutes.  These microscopes will allow recordings from a number of behaviors that have been thus far been impossible. For example, the microscopes will allow recordings from mice behaving in very large naturalistic arenas or complex tunnel complexes.  Second, we are building microscopes with combined optogenetics and calcium imaging capabilities, so that the activity of neurons can be manipulated while recording from the same group of cells.  Third, we are developing microscopes with combined electrophysiology and imaging capabilities to correlate imaging findings with electrophysiological signatures.  Finally, our first generation microscopes have already been released into our open-source wiki (miniscope.org) and over 150 labs are currently building and using the microscopes.  As the new generation microscopes are tested and optimized they will also be released to the community.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder exhibiting both motor and behavioral impairment. Like most neuropsychiatric disorders, its pathophysiology has yet to be elucidated. Such disorders are best understood, nonetheless, by looking at the altered network dynamics confounding normal information processing. To this end, the cortico-basal ganglia–thalamo–cortical network (CBGTC), which is purported to be essential for action gating and the conversion of goal-directed behavior to automated behaviors, is fundamentally implicated in the pathophysiology of GTS, as well as many other neuropsychiatric disorders.

Often targeting the CBGTC, deep brain stimulation (DBS) – a relatively new therapy - has proven to be a successful application for the amelioration of refractory symptoms in various neuropsychiatric disorders, including GTS. Although its mechanism of action is not well understood, it is suggested to occur via the modulation of dysregulated networks. This theory is supported by the reports of correlation between improved symptomatology and the observed changes in synchronization of oscillatory rhythms. While these data consequently suggest an important role for oscillatory rhythms, the scope of these rhythms in the pathological network and the mechanisms which exact their modification in the improved disease state has yet to be determined.

In this talk, we will discover the strength of DBS as an investigative tool by examining recordings from the brains of GTS patients undergoing therapy. We will furthermore explore how alterations in the coordination matrix of the CBGTC network are reflected in the oscillatory dynamics correlated with therapeutic response to DBS, thus gleaning powerful new insights into the neuropathodynamics of the biological basis of this disorder.

Basal forebrain cholinergic inputs to the cortex are known to contribute to attentional performance. A major focus of my laboratory has been to study the receptors mediating the effects of acetylcholine on attention. The goal of this research is to develop novel therapeutic approaches for treating cognitive disorders associated with dysfunctional attentional processing. A second research area has been to understand the roles of the neuropeptides, orexins (or hypocretins), in attention. Specifically, our major focus has been on the role of orexins that project to the basal forebrain. Collectively, these experiments have provided evidence that declines in orexinergic activity impair attention whereas enhancement of orexinergic activity can enhance attention under some conditions. A final emerging area that will be discussed is the use of attentional training to enhance learning of other tasks.

Dr. Kasthuri is a Neuroscience Researcher at Argonne National Labs and an Assistant Professor (adjunct) in the Dept. of Neurobiology, University of Chicago.  He has an MD from Washington University School of Medicine and a D.Phil. from Oxford University where he studied as a Rhodes scholar.  As a post-doctoral fellow, Dr. Kasthuri developed an automated approach to large volume serial electron microscopy (‘connectomics’).  Currently, the Kasthuri lab continues to innovate new approaches to brain mapping  including making connectomics samples more amenable to automatic segmentation and combining proteomic and genomic approaches with electron microscopy.  We are also now exploring the use of high-energy x-rays from synchrotron sources for mapping brains in their entirety. The Kasthuri lab is applying these techniques to developing, adult, and aged brains in service of answering the question: how do brains grow up and age?

The idea of schizophrenia typically conjures up images of people who hear voices, see visions and have delusional beliefs. However, clinicians have long recognized cognitive dysfunction as one of the most fundamental and debilitating aspects of the disorder.  Among the numerous brain abnormalities thought to underlie these symptoms, perturbations of the inhibitory neurotransmitter GABA within the frontal lobes are some of the most reliable alterations observed in the post-mortem brains of schizophrenic patients. These alterations may result in a hyperactive or ‘noisy’ cortex that may impair attention and other cognitive functions regulated by the frontal lobes.  However, our understanding of exactly how prefrontal cortical GABA may regulate these different aspects of cognition is sparse.  To better understand how these pathophysiological alterations may contribute to schizophrenia symptomology, work by our group has investigated how GABA transmission within the prefrontal cortex of rodents regulates a variety of cognitive, emotional and motivational functions known to be impaired in schizophrenia, using translational assays similar to those used with human patients.  Our findings indicate that reducing prefrontal GABA transmission recapitulates many of the cognitive, behavioural and dopaminergic abnormalities associated with schizophrenia, suggesting that dysfunction within this system may be a major contributing factor to variety of symptoms of the disorder.

Learning objectives

-Describe the evidence for dysfunction of inhibitory (GABAergic) transmission in schizophrenia

-Explain how prefrontal cortical GABA transmission regulates a variety of cognitive and executive functions

-Explore how translational research with animals can elucidate the neuropathology underlying mental illness

Parkinson’s disease (PD) is characterized by the loss of dopamine and the disruption of brain circuits (basal ganglia and cortex) that are responsible for normal cognitive and motor performance.  Investigations utilizing animal models of PD serve as an important first translational research step for identifying therapeutic targets that can be used to identify and guide novel therapeutic treatments for modifying disease progression in PD. Studies from our lab and others have demonstrated that exercise can improve motor and cognitive function in PD.  Using animal models of PD, our lab has also shown evidence of exercise-induced neuroplasticity through modulating dopaminergic and glutamatergic neurotransmission and enhancing basal ganglia synaptic connections. Animal studies in our lab also suggest that the type of exercise performed, e.g. aerobic vs. skill based exercise, may play differential roles on these repair mechanisms.  Specifically, using a rodent model of striatal dopamine depletion we have provided the first evidence that skilled exercise compared to simple aerobic exercise increases functional recruitment of prefrontal cortex (PFC), a brain region central to cognition, and in particular executive function.  Ongoing studies in our lab investigate the molecular mechanisms that underlie exercise-induced alterations of regional blood flow and neuronal metabolic demand including the transcription factor hypoxia inducible factor HIF-1α.  Findings from these studies will elucidate mechanism(s) of exercise-induced neuroplasticity and repair and help guide exercise interventions in PD.

Learning Objectives:

1. Define Neuroplasticity and understand it’s potential role in mechanisms of repair of Parkinson’s disease.
2. Understand the role that exercise may play in modulating dopamine and glutamate neurotransmission within the basal ganglia.
3. Understand the role of exercise on synaptogenesis in animal models of PD.
4. Describe different types of exercises that may be beneficial in enhancing cognitive function in PD.

Our decisions are governed by a balance between prospective instrumental goal-oriented and retrospective habitual learning strategies. This arbitration is relevant dimensionally across psychiatric disorders characterized by compulsive behaviours. The balance can be influenced by stress, working memory, cognitive control and neurochemistry such as dopamine and serotonin, features highly relevant to psychiatric disorders. Neural substrates underlying goal-directed and habit learning including conventional overtraining and devaluation and sequential learning tasks overlap with rodent preclinical models. The concept of model-based learning can be extended to include Pavlovian learning processes. Together these findings highlight a role for model-based learning across psychiatric disorders and a potential target for therapeutic intervention.

We are nearing three decades of research on the neural circuits of Pavlovian fear conditioning. The advent of new techniques such as genetic and optogenetic manipulations have greatly advanced our understanding of these circuits and their potential applicability to anxiety disorders such as PTSD and OCD.  Under natural conditions, however, animals (and humans) make decisions to avoid potential threats, which compete with goal-directed behaviors.  Research on active avoidance dates back to the 1960’s, but this research is experiencing a resurgence, building upon advances in Pavlovian fear conditioning.   In rats, the key areas for avoidance appear to be the medial prefrontal cortex, ventral striatum, and amygdala, as evidenced by recording, immunocytochemical, and optogenetic findings.  Despite its decision-based complexity, active avoidance is amenable to the approaches of modern neuroscience.

Sensorimotor integration is important for the acquisition and performance of motor skills. Here,we show the emergence of neuroplastic changes in the interactions between the motor andsomatosensory areas of the primate cortex during learning. Inter-areal coherence is frequencyand network-specific and exhibits a spatiotemporal organization. Time-sensitive sensorimotor integration and plasticity may rely on coherence of local and large-scale sensorimotor networks in order for cortical processes to operate at multiple temporal and spatial scales. Understanding cortico-cortical interactions may be important for developing therapies for sensorimotor disorders, such as those affecting feeding and speech that are commonly found in stroke and Parkinson's disease.