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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2015)

Approximately 10 percent of the children born in the United States each year are exposed to cigarette smoke in utero, putting them at heightened risk for many physical and cognitive problems. Here we used mouse and rat models of early developmental nicotine exposure in order to elucidate the hippocampal changes that underlie nicotine-induced memory impairment. We observed that mice exposed to nicotine during their first two postnatal weeks showed significantly impaired long-term hippocampus-dependent spatial memory, but normal short-term spatial memory and long-term hippocampus-independent recognition memory. We also observed several changes in CA1 hippocampal function in these nicotine-treated mice, including facilitated LTP, heightened network activity, and dysfunctional nicotinic modulation of network activity and LTP. Thus, we next used an α2 knockout mouse line to explore the hypothesis that early life nicotine exposure, by downregulating α2-containing nicotinic acetylcholine receptors (nAChRs), causes this spatial memory deficit and these changes in hippocampal function. We found that α2 knockout mice showed a similar pattern of memory impairments as did those treated with early postnatal nicotine. Additionally, our findings suggest that abnormal activation of α2-containing nAChRs by early life nicotine is necessary to bring about the facilitation of LTP and heightened CA1 network activity we observed in nicotine-exposed mice. Because α2-containing nAChRs are only found in the hippocampus on oriens-lacunosum moleculare (OLM) interneurons, which modulate inputs to the CA1 region of the hippocampus from the CA3 and entorhinal cortex, these findings add to the recently emerging body of evidence that OLM cells play a critical role in learning and memory. Furthermore, our work suggests that α2-containing nAChRs are important mediators of the effect of developmental nicotine on the hippocampus, and may therefore be a valuable target for the development of therapeutics to treat the cognitive impairments induced by in utero nicotine exposure.

    Cover page: The Impact of Developmental Nicotine on Hippocampus-Dependent Memory: Evidence for a Critical Role of alpha2-Containing Nicotinic Acetylcholine Receptors
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2015)
    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.
      Cover page: Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP.
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2016)
      Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understood. In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired long-term hippocampus-dependent memory, functional loss of α2-containing nicotinic acetylcholine receptors (α2∗ nAChRs) in oriens-lacunosum moleculare (OLM) cells, increased CA1 network excitation, and unexpected facilitation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Here we demonstrate that α2 knockout mice show the same pattern of memory impairment as previously observed in wild-type mice exposed to early postnatal nicotine. However, α2 knockout mice and α2 knockout mice exposed to early postnatal nicotine did not share all of the anomalies in hippocampal function observed in wild-type mice treated with nicotine during development. Unlike nicotine-treated wild-type mice, α2 knockout mice and nicotine-exposed α2 knockout mice did not demonstrate increased CA1 network excitation following Schaffer collateral stimulation and facilitated LTP, indicating that the effects are likely adaptive changes caused by activation of α2∗ nAChRs during nicotine exposure and are unlikely related to the associated memory impairment. Thus, the functional loss of α2∗ nAChRs in OLM cells likely plays a critical role in mediating this developmental-nicotine-induced hippocampal memory deficit.
        Cover page: Impaired function of α2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments.
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