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Nicotine exposure during early brain development produces long-lasting behavioral changes that are detrimental in multiple ways. These include greater propensities for nicotine addiction, attention deficit hyperactivity disorder, anxiety, and depression. Nonetheless, nicotine-replacement-therapy is still recommended by the medical profession for pregnant women who smoke, and electronic cigarettes are becoming increasingly common as well. No clear understanding exists about the relationship between early nicotine exposure and the functional and structural changes it imposes on the developing nervous system, particularly those extending into adulthood. We are examining the underlying events in a model and find in preliminary work that early exposure to nicotine during nursing produces long-lasting increases in the number of brain electrical connections called “glutamatergic synapses” and increases in the ratio of excitatory-to-inhibitory signals that neurons receive in the hippocampus, a brain region essential for the formation of new “declarative” memories. The preliminary results also indicate abnormally large numbers of neurons that display elevated levels of ongoing activity even after nicotine has been removed for a long period of time. Most remarkable are preliminary results from imaging the hippocampus with a method called two-photon microscopy that appear to show increased spontaneous activity in the brain and that a brief infusion of nicotine can temporarily re-program the system to behave more like normal. This raises the possibility that the adult would seek nicotine as a kind of “self-medication”. These kinds of changes, both at the synaptic level and in network function have not previously been documented but are likely to contribute importantly to the long-lasting behavioral changes widely acknowledged. To pursue these preliminary results we propose the following as a High Impact Pilot Study. We will use two-photon microscopy to examine activity patterns in the hippocampus of our model. We will assess long-lasting consequences in the adult that are induced by nicotine exposure during early postnatal development, and we will assess the acute effects of a brief re-exposure to nicotine subsequently. The analysis will include quantifying the number, frequency, amplitude, and coordination of electrical events among neurons. We will also employ strategies to subsequently re-identify the active cells in specimens from the model to quantify electrical contacts and assess connections among neurons that form networks. A technique called retrograde labeling will be used to determine if the excessively active neurons have connections outside of the hippocampus that can drive an external brain region, e.g. the amygdala, which encodes fear learning. We will use genetic studies to determine if a class of brain molecules that are involved in nicotine addiction, α7-containing nicotinic receptors, are responsible for the early postnatal effects or the subsequent acute response in the adult. Taken together, the results will identify mechanisms and molecular pathways contributing to the long-lasting effects of early nicotine exposure, and will provide new insight into fundamental aspects of brain circuit formation and brain development. Importantly, the work will also have immediate biomedical relevance in helping to promote a re-evaluation of public policy on nicotine replacement therapy and e-cigarette usage. These findings will help clarify the consequences of early nicotine exposure and indicate new strategies to pursue. We expect the results to also generate a compelling basis for major follow-up proposals to federal agencies, as encouraged by the TRDRP mandate. |
