Research

Neurobiology: Setting the Set Point for Neural Homeostasis. Truszkowski TL, Aizenman CD. Curr Biol. 2015 Dec 7;25(23):R1132-3. doi: 10.1016/j.cub.2015.10.021. PMID: 26654372.

Fragile X mental retardation protein regulates olfactory sensitivity but not odorant discrimination. Schilit Nitenson A, Stackpole EE, Truszkowski TL, Midroit M, Fallon JR, Bath KG. Chem Senses. 2015 Jun;40(5):345-50. doi: 10.1093/chemse/bjv019. PMID: 25917509.

Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles. James EJ, Gu J, Ramirez-Vizcarrondo CM, Hasan M, Truszkowski TL, Tan Y, Oupravanh PM, Khakhalin AS, Aizenman CD. J Neurosci. 2015 Feb 18;35(7):3218-29. doi: 10.1523/JNEUROSCI.4050-14.2015. PMID: 25698756.

Research Summary:

1. Development of a robust, multi-faceted model to study the behavioral, circuit and single cell aspects of multisensory integration (dissertation research)

            To understand our environment, information from multiple sensory modalities needs to be combined in the brain. Previous studies have shown that multisensory integration occurs in single cells in the optic tectum, or its mammalian homologue, the superior colliculus. However, little is known about intracellular and network level processes giving rise to multisensory integration. My dissertation project stems from this history of studying multisensory integration in single neurons using extracellular recordings and human psychophysics tasks. Here, we address this question in the Xenopus laevis tadpole optic tectum. The tectum receives sensory information from the eyes, ears, skin and lateral line and integrates it to generate behavioral output. By assessing behavioral and cellular responses to multisensory input both ex vivo and in vivo, this model organism provides a robust, integrative model for understanding multisensory processing in the developing brain. Specifically, inverse effectiveness, a neural manifestation of multisensory integration, states that when weak sensory stimuli that are not individually salient are combined, the result is a supralinear response, and enhances its saliency, whereas combination of strong sensory stimuli does not result in additional benefit. We found that in tadpoles, when presented with a low contrast, low saliency visual stimulus, a subthreshold acoustic stimulus enhanced the tadpole’s startle response. However, when paired with a high contrast visual stimulus, the subthreshold acoustic stimulus resulted in similar startle response to the visual stimulus alone. We then probed this phenomenon at the cellular level. Using intracellular whole current clamp recordings, we found that combining large suprathreshold stimuli does not result in an increased response magnitude. However, when two subthreshold stimuli are combined, the resulting response is amplified in a supralinear manner, showing that the principle of inverse effectiveness holds at the intracellular level. We further showed that this response depends on NMDA receptor activation. To build on these results, we studied network activity in the tectum in response to visual and mechanosensory stimuli using Calcium imaging. Preliminary results show that integrating cells are distributed throughout the tectum, often adjacent to cells that only respond to a single modality and have varying levels of integration. In conclusion, our model provides novel evidence about the cellular, network and behavioral processes that manifest from multisensory processing. I have personally developed the project and completed all Calcium imaging experiments myself. In addition, six undergraduates have worked with me to contribute to the project in a variety of ways.

2. Investigation of Autism-related neural defects (side project and lab rotation projects)

During my lab rotation with Kevin Bath, I assessed deficits in olfactory learning in FMRP knockout mice. We determined that FMRP knockout mice have a deficit in sensitivity but not in discrimination, showing that the protein is not required for olfactory learning but loss of FMRP does result in an olfactory deficit. My specific contribution was completing the behavioral assays.

During my lab rotation with Carlos Aizenman, I worked on a project investigating the effects of valproic acid treatment on the activity-dependent properties of the neurons. The project defined and explored a useful model system in which to study the developmental effects of valproic acid. We found that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. My specific contribution was to assess the NMDA receptor-mediated responses to extrinsic stimuli in the valproic acid treated tadpoles. I determined that the response decay time, tau, is slower in valproic acid treated tadpoles.

Recently, the Aizenman lab has become interested in FMRP. Specifically, we observed behavioral deficits in the Xenopus laevis tadpole that indicated a problem with circuit refinement. To follow up on this data, I have collected single cell electrophysiology data on FMRP knockdown tadpoles and shown that the intrinsic and activity-dependent properties of the tadpoles are no different from control. However, we uncovered a deficit in feedforward inhibition. Therefore, our evidence supports the hypothesis that the deficit lies in the generation of several small, individually indistinguishable differences that give rise to a behavioral phenotype.