27.4 STRUCTURAL, FUNCTIONAL, AND BEHAVIORAL INSIGHTS OF DOPAMINE DYSFUNCTION REVEALED BY A DELETION IN SLC6A3

Abstract Background The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT are associated to neuropsychiatric disorders. We investigated the structural and behavioral bases of an in-frame deletion in hDAT at N336 (∆N336) associated with neuropsychiatric disorders. Methods This study bridges structural biology, molecular neuroscience and organism physiology culminating in a mechanistic model that relates precise alteration in a transport cycle with behavioral manifestations. Results We uncovered a previously unobserved conformation of the intracellular gate of the transporter promoted by ∆N336, representing likely the rate limiting step of the transport process. This state is defined by a “half-open and inward facing” state (HOIF) of the intracellular gate that leads to DA dysfunction. The HOIF state is regulated by a network of interactions conserved phylogenetically, as we observed it both in hDAT and in its bacterial homolog leucine transporter. We demonstrated these dysfunctions in brains of Drosophila melanogaster expressing hDAT ∆N336. These flies are hyperactive and display increased fear and impaired social interactions, traits associated with neuropsychiatric disorders. Discussion Here, we describe how a genetic variation causes DA dysfunction. In this study different techniques and discoveries came together to detail in a translational effort how rare variants in plasma membrane proteins affect complex behavior.


THE DOPAMINE MOTIVE SYSTEM IN ADDICTION
Nora Volkow* ,1 1 DHHS/National Institute on Drug Abuse Background: We have investigated the role of bidirectional interactions between the dopamine reward and motivation system and executive function in addicted individuals, with a particular focus on the intersection between the role of D2 receptor (D2R) signaling in the striatum and perturbations in prefrontal brain activity.
Methods: Using brain imaging we have studied these interaction for various types of addiction and explored how their involvement affect behavior including impulsivity and compulsiveness. We have also investigated the mechanisms associated with vulnerability to drug use disorders as linked with disrupted executive function including the effects of genetics and physiological factors such as circadian rhythms, sleep deprivation and obesity. Results: We found that: a) chronic drug use reduces striatal levels of D2R and perturbs metabolism in frontal brain regions, emotional reactivity and executive control; b) that higher-than-normal striatal D2R availability in nonalcoholic members of alcoholic families appear to play a protective role against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions; c) that chronic sleep deprivation is associated with increased striatal dopamine, lower D2R availability, and metabolic changes in several cortical brain regions; and, d) that newly characterized variable number tandem repeat (VNTR) polymorphisms in the genes coding for PER2 and the AKT1 proteins (a kinase that has been implicated in schizophrenia and psychosis) appear to modulate striatal D2R availability in the human brain. Discussion: Although the studies have focused on the effects of drugs, the DA striato cortical pathway is of direct relevance to schizophrenia as well as that of other psychiatric disorders. We will discuss the implications of our findings as they relate to the prevention and treatment of substance use disorders and schizophrenia.

DISCRETE AND COORDINATED ENCODING OF REWARDED ACTIONS BY PREFRONTAL CORTEX AND DOPAMINE NEURONS Bita Moghaddam* ,1 1 Oregon Health & Science University
Background: Co-morbidity of schizophrenia and drug use has been attribute to common pathophysiology of mesocortical circuit. We modeled a behavioral disruption to this circuit in rodents by using a task where actions were consistently rewarded but probabilistically punished. Our data reveal dynamic coding schemes of the VTA-mPFC neural circuit in representing risk of punishment and punishment-based modulation of rewarded actions. Methods: Spike activity and local field potentials were recorded during simultaneously from ventral tegmental area and medial prefrontal cortex (PFC), two reciprocally connected mesocortical regions, in rodents as they performed a task where actions were consistently rewarded but probabilistically punished. This model allowed us to reveal dynamic coding schemes of the VTA-mPFC neural circuit in representing risk of punishment and punishment-based modulation of rewarded actions. Results: At the single unit level (n=167 mPFC n=102 VTA units), we found that ensembles of VTA and mPFC neurons encode the contingency between action and punishment. At the network level, we found that coherent theta oscillations synchronize the VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment contingency Discussion: During reward-seeking actions, risk of an aversive outcome and anxiety disrupts dopamine neuron-driven synchrony between PFC and VTA

STRUCTURAL, FUNCTIONAL, AND BEHAVIORAL INSIGHTS OF DOPAMINE DYSFUNCTION REVEALED BY A DELETION IN SLC6A3
Aurelio Galli* ,1 1 Vanderbilt University Background: The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT are associated to neuropsychiatric disorders. We investigated the structural and behavioral bases of an inframe deletion in hDAT at N336 (∆N336) associated with neuropsychiatric disorders. Methods: This study bridges structural biology, molecular neuroscience and organism physiology culminating in a mechanistic model that relates precise alteration in a transport cycle with behavioral manifestations. Results: We uncovered a previously unobserved conformation of the intracellular gate of the transporter promoted by ∆N336, representing likely the rate limiting step of the transport process. This state is defined by a "halfopen and inward facing" state (HOIF) of the intracellular gate that leads to DA dysfunction. The HOIF state is regulated by a network of interactions conserved phylogenetically, as we observed it both in hDAT and in its bacterial homolog leucine transporter. We demonstrated these dysfunctions in brains of Drosophila melanogaster expressing hDAT ∆N336. These flies are hyperactive and display increased fear and impaired social interactions, traits associated with neuropsychiatric disorders. Discussion: Here, we describe how a genetic variation causes DA dysfunction. In this study different techniques and discoveries came together to detail in a translational effort how rare variants in plasma membrane proteins affect complex behavior.

BEYOND VOICES: MULTISENSORY BODILY SELF DISTURBANCES ACROSS THE SCHIZOPHRENIA SPECTRUM Sohee Park Vanderbilt University
Overall Abstract: Aberrant bodily self experiences are highly salient and disruptive to individuals with schizophrenia. Given that these self disturbances are already present at prodromal stage, persist throughout the course of illness, and impact functional outcome, they should be precisely targeted for intervention. However, in contrast to the prominence of auditory hallucination in schizophrenia research, bodily self disturbances have been largely neglected. This symposium aims to bridge this gap with new theoretical and experimental advances that allow us to capture the full extent of the phenomenology, and at the same time, mechanistically specify the etiology and nature of self disorders with an eye toward implementing new treatments. Nelson & Sass will present their revised theory of self disturbances in schizophrenia that reconciles phenomenology with neuropsychological and empirical evidence. Raballo and Poletti will present a comprehensive analysis of recent developmental psychopathological studies of self disorders in the schizophrenia spectrum. Giersch and colleagues provide the crucial experimental evidence for the close link between weakened temporal expectancy and the disruption of continuous and unitary self in schizophrenia. Temporal expectancy helps to link and transform a chain of discrete events into our perceptual experience of continuous flow of time, but it is disrupted in schizophrenia. These results point toward potential intervention strategies. Park and colleagues present exteroceptive, proprioceptive and interoceptive contributions to abnormal mapping of bodily sensation and peripersonal space in the schizophrenia-spectrum and argue that the core problems may lie in prediction coding errors across multisensory systems. Potential intervention may lie in studying trained "sensorimotor experts" (athletes) who show precise and sharpened awareness of embodied sensations. The discussant (Ferri) will integrate these findings to highlight a new framework and multi-level approaches for understanding the etiologies of self disturbances in the schizophrenia-spectrum.

VARIETIES OF SELF DISORDER: A BIO-PHENO-SOCIAL MODEL OF SCHIZOPHRENIA
Barnaby Nelson* ,1 , Louis Sass 2 1 Orygen Youth Health Research Centre; 2 Rutgers University Background: The self-disorder model offers a unifying way of conceptualizing schizophrenia's highly diverse symptoms (positive, negative, disorganized), of capturing their distinctive bizarreness, and of conceiving their longitudinal development. These symptoms are viewed as differing manifestations of an underlying disorder of 'core-self': hyperreflexivity/diminishedself presence with accompanying disturbances of "grip" or "hold" on reality.

Methods:
We have recently revised and tested this phenomenological model, in particular distinguishing primary versus-secondary factors, in offering a bio-pheno-social model of schizophrenia spectrum disorders. Results: The revised model is consistent with recent empirical findings and offers several advantages: 1) It helps account for the temporal variations of the symptoms or syndrome, including longitudinal progression, but also the shorter-term, situationally-reactive, sometimes defensive, and possibly quasi-agentive variability of symptom-expression that can occur in schizophrenia (consistent with understanding some aspects of self-disturbance as dynamic and mutable, involving shifting attitudes or experiential orientations). 2) It accommodates the overlapping of some key schizophrenic symptoms with certain non-schizophrenia spectrum conditions involving dissociation (depersonalization and derealization), including Depersonalization Disorder and Panic Disorder, thereby acknowledging both shared and distinguishing symptoms. 3) It integrates recent neurocognitive, neurobiological, and psychosocial (e.g., influence of trauma and culture) findings into a coherent but multi-factorial neuropsychological account.
Discussion: An adequate model of schizophrenia will postulate shared disturbances of core-self experiences that nevertheless can follow several distinct pathways and occur in various forms. Such a model is preferable to uni-dimensional alternatives-whether of schizophrenia or core self disturbance-given its ability to account for distinctive yet varying experiential and neurocognitive abnormalities found in research on schizophrenia, and to integrate these with recent psychosocial as well as neurobiological findings. Background: Basic disorders of the embodied self (BDES) encompass a cloud of related clinical constructs (e.g. cenesthesias, distortions of somatopsychic unity, anomalous bodily experiences in a broad sense) that are immanently related to a profound transformation of subjectivity and with the developmental modulation of bodily awareness. They have been historically ascribed a potential role in the emergence of schizophrenia spectrum disorders. However, the clinical-phenomenological level of description has been only marginally integrated with novel insights from developmental psychopathology and neurosciences. Methods: We conducted a conceptual literature review based on clinical analysis and heuristic synthesis. Results: Despite often occurring in prodromal/clinical at-risk states, as well as in full blown schizophrenia spectrum conditions (where BDES play a pivotal psychopathogenetic role in the genesis of productive symptoms), they are relatively neglected both in research and in routine clinical examination. Furthermore, BDES also discriminate non help-seeking genetic high risk subjects from normal controls. Discussion: Within the superordinate construct of Self-disorders, BDES are a potentially relevant dimensional phenotype for the characterization of broad Schizophrenia Spectrum vulnerability. Their contextualization within a developmental and neurophysiological perspective could further amplify their value for etio-pathogenetic research.