Cortico-Thalamic Connectivity is Vulnerable to Nicotine Exposure During Early Postnatal Development through α4/β2/α5 Nicotinic Acetylcholine Receptors (original) (raw)
Related papers
2010
Tobacco smoke exposure during development can result in lasting alterations in sensory processing and attention. This suggests that some constituent of smoke, such as the primary addictive component, nicotine, alters neurodevelopment. Although many effects of developmental nicotine exposure have been identified in humans and animal models, very few mechanistic studies have identified the molecular and anatomical basis for a defined behavioral consequence of developmental exposure. We show in this study that a mouse model of developmental nicotine exposure results in hypersensitive passive avoidance in adulthood. We have used transgenic mice in which b2 subunit containing nicotinic acetylcholine receptors (b2* nAChRs) are expressed exclusively on corticothalamic neurons (b2 tr(CT) mice) to identify the receptor subtypes involved and also to define the circuit level site of action responsible for this persistent, nicotine-induced behavioral phenotype. Further characterization of the native nAChRs expressed in this circuit indicates that both (a4) 2 (b2) 3 and (a4) 2 (b2) 2 a5 nAChR subtypes are present in corticothalamic projections. Consistent with a role for (a4) 2 (b2) 2 a5 nAChRs in mediating the effect of developmental nicotine exposure on adult passive avoidance behavior, constitutive deletion of the a5 nAChR subunit also alters this behavior. A critical period for this developmental consequence of nicotine exposure was defined by limiting exposure to the early post-natal period. Taken together, these studies identify a novel consequence of developmental nicotine exposure in the mouse, define the nAChR subtypes and neural circuit involved in this behavioral change and delimit the neurodevelopmental period critical for vulnerability to a behavioral alteration that persists into adulthood.
Developmental Brain Research, 1991
The effects of neonatal nicotine exposure on spontaneous and nicotine-induced behaviour in 4-month-old mice and on the development of brain nicotinic receptors were studied. The behaviour study showed that mice treated with nicotine 66/~g (-)nicotine base/kg body weight (bw) s.c. twice daily between 10 and 16 days postnatally displayed a hypoactive condition, whereas mice treated with saline displayed a hyperactive condition. When the nicotinic receptors in the brain cortex were analyzed, the displacement curves for [ 3H]nicotine/(-)nicotine revealed an almost equal proportion of high-and low-affinity binding sites in 17-day-old mice, while the high-affinity sites predominated in 4-month-old mice, with affinity constants for both high-and low-affinity binding sites 10 times higher in 4-month-old mice than in 17-dayold-mice. A decrease in the number of nicotinic receptors was observed from day 17 to 4 months, mainly of the low-affinity nicotinic type. Interestingly, the displacement curves in neonatally nicotine-treated mice showed only one population of high-affinity binding sites in 17-dayand 4-month-old mice though the total binding sites in 4-month-old mice were the same for the neonatally nicotine-treated and saline-treated mice. These results indicate that neonatal nicotine treatment prevents the development of low-affinity nicotinic sites in the brain and this earlier exposure to nicotine induces a different behaviour response in adult animals to a test dose of nicotine. Days 10-16 postnatally appear to be a critical period for the effects of nicotine on the brain.
2003
Prenatal nicotine exposure has been linked to attention deficit hyperactivity disorder and cognitive impairment, but the sites of action for these effects of nicotine are still under investigation. High-affinity nicotinic acetylcholine receptors (nAChRs) contain the 2 subunit and modulate passive avoidance (PA) learning in mice. Using an inducible, tetracycline-regulated transgenic system, we generated lines of mice with expression of high-affinity nicotinic receptors restored in specific neuronal populations. One line of mice shows functional 2 subunit-containing nAChRs localized exclusively in corticothalamic efferents. Functional, presynaptic nAChRs are present in the thalamus of these mice as detected by nicotine-elicited rubidium efflux assays from synaptosomes. Knock-out mice lacking high-affinity nAChRs show elevated baseline PA learning, whereas normal baseline PA behavior is restored in mice with corticothalamic expression of these nAChRs. In contrast, nicotine can enhance PA learning in adult wild-type animals but not in corticothalamic-expressing transgenic mice. When these transgenic mice are treated with doxycycline in adulthood to switch off nAChR expression, baseline PA is maintained even after transgene expression is abolished. These data suggest that high-affinity nAChRs expressed on corticothalamic neurons during development are critical for baseline PA performance and provide a potential neuroanatomical substrate for changes induced by prenatal nicotine exposure leading to long-term behavioral and cognitive deficits.
Neuropharmacology, 2009
Despite a great deal of progress, more than 10% of pregnant women in the USA smoke. Epidemiological studies have demonstrated correlations between developmental tobacco smoke exposure and sensory processing deficits, as well as a number of neuropsychiatric conditions, including attention deficit hyperactivity disorder. Significantly, data from animal models of developmental nicotine exposure have suggested that the nicotine in tobacco contributes significantly to the effects of developmental smoke exposure. Consequently, we hypothesize that nicotinic acetylcholine receptors (nAChRs) are critical for setting and refining the strength of corticothalamicthalamocortical loops during critical periods of development and that disruption of this process by developmental nicotine exposure can result in long-lasting dysregulation of sensory processing. The ability of nAChR activation to modulate synaptic plasticity is likely to underlie the effects of both endogenous cholinergic signaling and pharmacologically-administered nicotine to alter cellular, physiological and behavioral processes during critical periods of development.
Children of women who smoked during pregnancy are at increased risk of dependence when smoking is initiated during adolescence. We previously reported that gestational nicotine exposure attenuated dopamine release induced by nicotine delivered during adolescence. In this study, we determined the effects of gestational nicotine exposure on nicotinic cholinergic receptor (nAChR) expression. Timed pregnant rats received nicotine (2 mg ⁄ kg ⁄ day) or vehicle via mini-osmotic pumps during gestation. Treatments continued in pups via maternal nursing during postnatal days (PN) 2-14 (equivalent to the human in utero third trimester). On PN35, 125 I-epibatidine binding to nAChR was measured. The B max values (fmol ⁄ mg) in prefrontal cortex (PFC), nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) were reduced by 26.6% (P < 0.05), 32.6% (P < 0.01), 23.0% (P < 0.01) and 27.6% (P < 0.05), respectively. In addition, gender differences were found in vehicle-treated groups; in SN and VTA, females were 79.3% (P < 0.005) and 82.9% (P ¼ 0.08) of males, respectively. The expression of nAChR subunit mRNAs was measured using real-time RT-PCR on laser-capture microdissected tissues. In adolescent VTA, gestational nicotine exposure reduced (P < 0.05) nAChR subunit mRNAs encoding a3 (53.0%), a4 (23.9%), a5 (46.7%) and b4 (61.4%). In NAcc core, the treatment increased a3 mRNA (75.8%). In addition, the number of neurons in VTA was reduced by 15.0% (P < 0.001). These studies indicate that gestational exposure to nicotine induces long-lasting changes in nAChR expression that may underlie the vulnerability of adolescents to dependence on nicotine.
Molecular Brain Research, 1999
. Our previous studies demonstrated that nicotine induces c-fos expression in the suprachiasmatic nucleus SCN of the rat during a narrow developmental window occurring in the perinatal period. We have extended these observations by showing that c-fos cannot be induced in the adult SCN by nicotine even during the subjective night, when phase shifts do occur. In contrast to the SCN, significant induction of c-fos and NGFI-A was observed in the medial habenula and paraventricular nucleus at all circadian times. In the fetal rat SCN we show that NGFI-A and junB are also induced by nicotine, but not c-jun. To investigate whether changes in nicotinic Ž . acetylcholine receptor nAChR expression in the SCN may underlie this change in sensitivity during the perinatal period, we examined nAChR mRNAs across this developmental period. By Northern analyses, a 2, a 3 and a4 subunit mRNAs are relatively abundant in the fetal SCN but decline substantially in the adult. a7 mRNA increases substantially while b2 mRNA is relatively abundant throughout development. We also examine expression in the whole mouse brain beginning at embryonic day 11. Many mRNA sizes for nAChR subunits in both the rat and mouse are characterized here for the first time by Northern analyses and some show very large changes in expression across development. In particular, a small 1.4 kb a 2-related mRNA is highly expressed during early development, perhaps indicating an important novel function for this subunit. q
Prenatal Nicotine Exposure Modifies Behavior of Mice Through Early Development
Pharmacology, biochemistry and behavior, 1998
Studies in humans and animal models (including rodents) have revealed lasting behavioral and cognitive impairments in offspring prenatally exposed to nicotine. Offspring of pregnant mouse dams prenatally subjected to 9–10 daily subcutaneous injections into the nape of the neck during pregnancy have been postnatally subjected to several developmental and behavioral tests to investigate the effects of prenatal nicotine exposure on those offspring at various stages of their life. The prenatal exposure to nicotine has resulted in significant reduced postnatal body weight gain, as well as in significant delay in eye opening, in the appearance of body hairs, and in sensory motor reflexes. However, motor activity was significantly stimulated in early adulthood of mouse pups prenatally exposed to nicotine, and such exposure proved to have long-lasting hyperactive effects on mice. Thus, exposure to nicotine during a critical prenatal period of brain development deduced from the present study in mice raises the alarm of the possible hazard of prenatal exposure to nicotine in humans. Hence, smoking by pregnant women might constitute a serious hazard to their in utero developing children.
Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced n...
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.
Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons
Neuroscience, 2007
We have combined anatomical and functional methodologies to provide a comprehensive analysis of the properties of nicotinic acetylcholine receptors (nAChRs) on developing dopamine (DA) neurons. Double-labeling in situ hybridization was used to examine the expression of nAChR subunit mRNAs within developing midbrain DA neurons. As brain maturation progressed there was a change in the pattern of subunit mRNA expression within DA neurons, such that α3 and α4 subunits declined and α6 mRNA increased. Although there were strong similarities in subunit mRNA expression in substantia nigra (SNc) and ventral tegmental area (VTA), there was higher expression of α4 mRNA in SNc than VTA at gestational day (G)15, and of α5, α6 and β3 mRNAs during postnatal development. Using a superfusion neurotransmitter release paradigm to functionally characterize nicotine-stimulated release of [ 3 H]DA from striatal slices, the properties of the nAChRs on DA terminals were also found to change with age. Functional nAChRs were detected on striatal terminals at G18. There was a decrease in maximal release in the first postnatal week, followed by an increase in nicotine efficacy and potency during the second and third postnatal weeks. In the transition from adolescence (postnatal days (P) 30 and 40) to adulthood, there was a complex pattern of functional maturation of nAChRs in ventral, but not dorsal, striatum. In males, but not females, there were significant changes in both nicotine potency and efficacy during this developmental period. These findings suggest that nAChRs may play critical functional roles throughout DA neuronal maturation.