Year of Award

2010

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Neuroscience

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Diana I. Lurie

Commitee Members

Darrell Jackson, John Gerdes, Richard Bridges, Mark Grimes

Keywords

lead, serotonin, somatosensory cortex, superior olivary complex

Abstract

Low-level Pb exposure is a risk factor for neurobehavioral and cognitive deficits in both humans and animals. These neurological dysfunctions have been associated with deficits in auditory temporal processing. The developing central nervous system is particularly susceptible to Pb exposure, and Pb decreases the immunoreactivity of serotonin (5-HT) and VMAT2 in the lateral superior olive (LSO). During early developmental, "non-serotonergic" sensory neurons, including LSO neurons and thalamocortical neurons of the somatosensory system, transiently take up 5-HT from the extracellular environment through the transient expression of the serotonin reuptake transporter SERT. Maintenance of appropriate 5-HT levels is important for development of these sensory systems. The current study was undertaken to define the effect of developmental Pb exposure on the transient uptake of 5-HT in LSO and thalamocortical neurons and is the first of its kind. CBA mice were exposed to 0 mM (control), 0.01 mM (very low), and 0.1mM (low) Pb acetate from gestation through postnatal day 4 (P4), P8, or P21. Brainstem sections were immunostained for 5-HT, SERT, TPH, MAOA, VMAT2, SYP and GAP-43. Total brainstem levels of 5-HT and its metabolite 5-hydroxindole-3-acetic acid (5HIAA), were measured by HPLC. We found that Pb extends the normal developmental uptake of 5-HT by LSO neurons through prolonged expression of SERT. Total brainstem levels of 5-HT remain largely unchanged. Pb also decreases VMAT2, SYP, and GAP-43 immunostaining within the P8 LSO, indicating that modulation of SERT by Pb leads to impaired maturation of synapses in the LSO. These effects persist into adulthood. The major afferent target of the LSO, the Inferior Colliculus (IC), also shows altered immunoreactivity for 5-HT and VMAT2 following developmental Pb exposure. Finally, Pb decreases the immunoreactivity of 5-HT at the thalamocortical axon terminals (TCAs) in the region of the somatosensory cortical barrel field. In the forebrain, Pb appears to decrease 5-HT levels in general. This differs from its effect in the brainstem where Pb appears to specifically target central auditory nuclei.

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