|
Nicotine replacement therapy (NRT) for smoking cessation is currently recommended by the medical profession for the 15-25% of pregnant women who smoke. NRT during pregnancy provides a low but constant supply of nicotine, which is likely to concentrate in the embryo. It has been difficult to assess the dangers of NRT in clinical trials because of other risk factors associated with the pregnant mothers such as low socio-economic and/or minority status. Further, there has been no systematic assessment of whether NRT might impose early developmental disorders that could have lasting impact into adulthood.
Nicotine hijacks signaling pathways in the brain using a family of proteins called nicotinic acetylcholine receptors (nAChRs). Recent work from our group showed that normal activation of nAChRs during development is important for the establishment of connections between neurons (so called synapses), for the maturation of inhibitory transmission, which is responsible for preventing excessive activity in the brain, and for influencing neuronal fate. Numerous aspects of development may be put at risk by chronic early nicotine exposure. We found that chronic nicotine exposure is deleterious for adult-born neurons generated in the hippocampus, which is an area in the brain involved in short- and long-term memory formation. Moreover, postnatal exposure to nicotine (in doses comparable to those in smokers) hastens synapse formation. This premature neural wiring may underlie cognitive and behavioral aberrations found in adults exposed to nicotine during childhood, including attention deficit disorders, impulsivity, and lower IQ scores. This proposal is designed to answer how chronic low-level nicotine exposure associated with NRT during pregnancy influences neural development and wiring of the offspring.
Our preliminary results unexpectedly show that prenatal exposure to steady low levels of nicotine increases neuronal activity in the hippocampus. This increased activity at birth caused by nicotine exposure in utero may compromise the ability of the brain to resist conditions of low levels of oxygen and/or glucose that occur during delivery. Changes in activity levels during development can also have consequences for synaptic plasticity in neural circuits, extending into adulthood – changes that affect learning, memory, and other cognitive processes.
This project tests whether maternal exposure to NRT levels of nicotine changes the development of network activity in the hippocampus. Excitatory and inhibitory transmission, together with underlying structural components will be examined by electrophysiological recordings and immunostaining. Subsequent experiments will test how such changes depend on nicotine exposure time (prenatal vs postnatal) and their extension into adulthood. Electrophysiological recordings will also indicate whether cellular mechanisms that underlie learning and memory have been altered in neurons. If nicotine exposure in utero alters neural function in the newborn, the results will raise serious questions about possible cognitive deficits caused by maternal use of NRT. Finally, electrophysiological recordings will also test whether prenatal exposure to nicotine disturbs inhibitory signaling at birth. Additional tests will determine whether these changes reduce the viability of neonatal neurons challenged with insults likely to occur during the birth process.
These experiments will not only identify mechanisms by which NRT affects network development, but also will indicate the impact of NRT on the kinds of plasticity that underlie cognitive processes and brain resistance to ischemic/hypoxic insults. The results will provide important information about the consequences for the offspring of maternal NRT use during pregnancy. This information may change medical policy and stimulate the development of new therapeutics appropriate for pregnant women who want to safeguard their offspring. | 