PI's: J. David Jentsch, Ph.D., Assistant Professor, Dept. of Psychology, UCLA
Wael Salameh, M.D., Assistant Professor, Dept. of Endocrinology, Harbor-UCLA
Alan Fiske, Ph.D., Professor, Dept. of Anthropology, UCLA

Abstract

The psychopathology of autistic spectrum disorders includes mild to severe deficits in a set of processes related to sociability. Sociability is a function of social reinforcement, i.e., of the appetitive and aversive factors which affect the desire of a subject to engage in social interactions. We posit that the neurophysiology of sociability is evolutionarily conserved, controlling behavioral processes that become more complex and multilayered in higher mammals. Much is known about the general neurochemical mechanisms contributing to reinforcement triggered by food, sex, or pain. However, the neural substrates of social reinforcement are less understood, although neurophysins appear to play a key role. Recent advances in the neuroscience of parental behavior and pair bonding suggest that it might be possible to develop animal models of normal and deficient sociability [47,49,51], which may be useful tools for the study of autism [53]. Here, we propose to investigate the behavioral effects of (+)-3,4-methylenedioxymethamphetamine (MDMA). MDMA enhances the drive to engage in social relations in humans; it therefore appears that MDMA acts on neural mechanisms mediating social reinforcement. We propose to investigate the putative social reinforcement effects of MDMA in rats, as well as specific neurochemical mechanisms through which it may act. Neurophysins play an important role in the pathophysiology of autism, and MDMA has been shown to affect release of these neurohormones in humans. So we will determine the effects of MDMA on transmission of a key neurophysin in the brain that is known to mediate rodent sociability, vasopressin. Finally, we will evaluate the effects of MDMA on social reinforcement in a mutant rat that is deficient in vasopressin secretion and that shows abnormal social recognition. These pilot data are necessary to formulate a cogent hypothesis-based set of investigations into the neurochemistry of social reinforcement that may eventually generate insights into the etiology and treatment of autistic spectrum disorders.

Specific Aims

To characterize the effects of MDMA on social reinforcement in the normal rat; To examine MDMA-induced changes in vasopressin levels in a distributed brain network mediating social reinforcement and social cognition; To investigate the behavioral effects of MDMA in a mutant vasopressin-deficient strain of rat that shows abnormal social recognition.

PI's: Orna Rosenthal, Ph.D., Postdoctoral Fellow, Dept. of Psychology, UCLA
Ladan Shams, Ph.D., Assistant Professor, Dept. of Psychology, UCLA

Abstract and Specific Aims

Autistics show a broad range of cognitive and perceptual anomalies in addition to their characteristic social and communication disorders. In an attempt to find a common underlying neuronal processing factor for this broad phenotype we postulate a general impairment in interaction between distinct brain processing modules. Our working hypothesis is that interaction between the various processing modules is impaired in autism even at a low perceptual processing level. Key deficit at such a low-level can have ramifications for perceptual, cognitive, and social processes. Previous studies have suggested weak cross-modal binding in autism. Our investigation will focus on low-level cross-modal interaction processing in autism. We will examine behavioral performance and ERP signals of autistics and controls during performance of simple perceptual tasks. We predict that autistics will outperform normal participants in tasks that require ignoring cross modal information. To evaluate the possibility of a common underlying factor in different processing levels, we will examine the correlation between performance in tasks that require low and higher-level cross modal processing. Finally, contingent upon verification of our hypothesis, a later stage of our proposed study is aimed at investigating the role of extensive training with tasks that require low-level cross-modal interaction in improving perceptual and cognitive functioning in autism. This line of study may contribute to developing methods of therapeutic intervention.

PI: Stephanie White, Ph.D., Assistant Professor, Dept. of Physiological Science, UCLA

Abstract

A hallmark of autism is poor language development with abnormal social use. In order to understand the neurological basis for autism, it is necessary to identify those synaptic and molecular properties that respond to social experience, particularly in neurons that subserve learning and communication. However, to date we have little knowledge of the cellular and molecular processes underlying speech development since only a few animal groups including songbirds and humans, --but not other primates nor rodents-- learn their vocalizations. Like humans, songbirds must learn their vocalizations and do so during critical developmental periods that are triggered by specific auditory stimuli. These studies therefore use the zebra finch songbird to explore the molecular basis of social influences on vocal learning. Messenger RNA transcripts within neurons in a brain region recently shown to participate in encoding the tutor song model will be compared between two types of 65 day old zebra finches: those whose critical period for learning new song is closed because they have been reared with tutors (Controls), and those who retain the capacity to learn because they have been isolated from tutors (Isolates), a behavioral manipulation which extends the critical period for song memorization. Identification of transcripts unique to each state will provide candidate genes for functional testing of their effect on song learning behavior. By making use of a naturally-learned social behavior in the songbird, we will shed light on common mechanisms underlying learned vocalizations including those subserving speech development.

Specific Aims

Aim 1: Obtain mRNA transcripts from brain regions involved in song learning, from Isolate and Control birds.
1.1 Rear 65days post-hatch (65d) zebra finches in either a normal social and acoustic environment (Controls) or a socially and acoustically deprived condition (Isolates).
1.2 Ensure that the rearing paradigms produce 65d Controls whose critical period for vocal learning has closed and 65d Isolates that are capable of learning new song.
1.3 Develop a tissue punch technique to obtain separate and pure tissue samples from HVC, a cortical region required for song learning and recently demonstrated to contain the memory for the tutor song template.
1.4 Prepare mRNAs from HVC, using the brains of 65d Isolates and Controls.
1.5 Reveal transcripts that are uniquely or more abundantly expressed in either the learning (Isolate) or non-learning (Control) state using representational difference analysis (RDA).

Aim 2: Identify and characterize genes unique to a vocal learning state.
2.1 Verify that identified transcripts are more abundantly expressed in either the Isolate or Control brain using cDNA microarrays and hybridizing Isolate vs. Control transcript populations.
2.2 Identify genes unique to one state using sequence information databases.
2.3 Characterize the expression of unique genes via in situ hybridization with brain sections made from finches of known auditory and social experience.

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