Hanna E. Stevens, Ph.D. - US grants

DESCRIPTION (provided by applicant): The broad aims of this project are to understand normal auditory processing of speech sounds, information that can be used to understand and provide rehabilitation for deficits in hearing and speech comprehension. Responses to speech sounds by the auditory nerve (AN) of an animal model, the chinchilla, demonstrate how information about speech sounds is encoded by the mammalian auditory system. A peripheral auditory system like most mammals and the ability of the chinchilla to demonstrate phoneme perception and categorization make it an excellent animal model. Unique temporal patterns of encoding in the AN will be identified for each phoneme across variable acoustics. Co-articulation with a vowel and the absence of normal voicing in whispered speech both alter the acoustics of a consonant. These temporal patterns will demonstrate the role that the auditory system plays in accurate human perception of one phoneme across acoustic profiles and what information is necessary for hearing-impaired people to understand speech. Responses of single AN fibers to normally-voiced and whispered speech will be recorded and analyzed to demonstrate phoneme-specific patterns of response. The specific questions to be asked for each aim: 1) What temporal patterns are characteristic of the AN response to each phoneme /d/ and /t/ across different acoustic profiles? This will be addressed by using as the stimuli four syllables /da/, /ta/, /dae/, and /tae/, from two speakers produced in both whispered and normal voicing. The AN responses to the eight tokens of each consonant will be compared using a global average peri-stimulus time (PST) histograms and local average PST histograms. 2) Are these temporal patterns unique to /d/ and /t/ or unique to the categories of voiced and unvoiced consonants? Four tokens of /b/ and /p/ will be used as stimuli to compare the AN response to consonants within and between voicing categories.

DESCRIPTION (provided by applicant: This application presents a career development award that integrates clinical child and adult psychiatry, animal models of developmental neuroscience, and stress neurobiology. The immediate goal is to create a program investigating the developmental mechanisms of the neurobiological effects of prenatal stress, focused on inhibitory neurons. The long term objective is to contribute to the understanding of early developmental events that contribute to severe childhood and adult psychiatric illness, the pathophysiology that underlies disorders such as schizophrenia and Tourette syndrome, and how interventions can modify early developmental changes. The candidate completed a Ph.D. in neuroscience with individual NIH funding and has now been involved in comprehensive training in clinical and research psychiatry for the past 5 years at the Yale Child Study Center (YCSC) and Department of Psychiatry. This award will provide critical support for the continuation of her integrated research in the YCSC Developmental Neurobiology Laboratory and the transition to an independent career in basic developmental neuroscience within the framework of understanding child and adult psychiatric illness. In the research proposal, an animal model of prenatal stress will be used to study the mechanisms of widespread, persistent effects on CNS structure and function. GABAergic systems will be the focus of the research plan, as patients with schizophrenia and other behavioral disorders linked to prenatal stress in humans have abnormal GABAergic neuron populations. Dr. Stevens will complete the first stage of the research plan on the anatomical effects of prenatal stress on inhibitory neurons with the support of this award and the skills she has developed in her postdoctoral work. She will then go on to make assessments of molecular mechanisms of prenatal stress affecting GABAergic populations both during the embryonic time period and during adult development. Functioning of inhibitory neuronal systems will be examined with behavioral and electrophysiological measures. This experimental work also comprises the career development plan for this candidate to obtain the necessary skills for an independent career in basic neuroscience research that can investigate important questions about the neurodevelopment of mental illness. The candidate has recruited an outstanding group of mentors and advisors that will guide the research plan in design, performance of experiments, and analysis of results. For career development, this mentor and advisor team will continue to support the candidate as she develops an independent laboratory program at the YCSC relevant to the neurodevelopment of mental illness and as she pursues additional training in molecular, behavioral, and electrophysiological techniques through coursework, intensive workshops and national conferences. PUBLIC HEALTH RELEVANCE: At a minimum, this work will address important gaps in the knowledge base regarding the neurodevelopmental basis of conditions related to prenatal stress, including schizophrenia. Broader implications include a more sophisticated understanding of the regulation of inhibitory neuron development and systemic and environmental effects on this regulation. Results of this work will inform child, adolescent and adult psychiatric treatment and the treatment of pregnant women with both pharmacologic and psychotherapeutic interventions.

Autism spectrum disorder (ASD) is linked with enlargement of striatum and deficits in learning processes that depend on striatal function. We have found increased striatal volume, greater striatal neuron generation, and changes in striatal-dependent learning in mice exposed to prenatal maternal repetitive restraint stress. Prenatal disruptions including maternal stress are risk factors for negative developmental outcomes in children (e.g. ASD). There are gaps in knowledge about whether enlarged striatum is causative of ASD-related problems with learning and what maternal, placental and brain factors during prenatal development contribute to increased striatal morphogenesis. We have preliminary data showing that prenatal stress increases levels of maternal interleukin-6, a proinflammatory cytokine implicated in ASD, which independently increases striatal neuron generation. We also show that increased IGF signaling between placenta and embryonic brain is implicated in our prenatal stress model and independently increases striatal neuron generation. We hypothesize that increased striatal morphogenesis plays a central role in prenatal risk for neurodevelopmental problems and that these changes are mediated by maternal interleukin-6 and IGF signaling. Our focus on striatal morphogenesis in embryonic brain is particularly novel and significant; we will examine multiple levels of its regulation and consequences when striatal growth is increased. We also will test the same mechanisms across multiple maternal stress models?restraint, foot-shock, and chronic variable stress--to generalize these stress findings beyond a single paradigm. First in Aim 1, we will assess the necessity and sufficiency of elevated maternal interleukin-6 for increased striatal neuron generation as a component of prenatal stress effects. We will also determine the importance of exposure timing, a critical question during rapid embryonic development. Second in Aim 2, we will assess the necessity and sufficiency of increased IGF signaling for prenatal stress effects on striatal progenitors. We will also assess growth factor changes in maternal circulation and placenta across maternal stress models. Lastly in Aim 3, we will examine the sufficiency of increased striatal neuron generation in vivo for changes in animal learning and striatal physiology. We will use a novel strategy to increase striatal neuron generation in utero: intracerebroventricular injection of a selective metabotropic glutamate receptor agonist, CHPG, with specificity for increasing cell proliferation in striatal progenitors. In offspring with this exposure, we will test striatal dependent types of learning?procedural, habit, reversal, and interval timing through operant training. We will also measure striatal neuronal ramping activity during learned interval timing. With our expertise in understanding prenatal stress, embryonic brain morphogenesis, growth factors, and rodent learning, we are well-situated to address how the proposed mechanisms could be targets for prevention and treatment.