CE37 - Neurosciences intégratives et cognitives

Impact of Prolonged Nicotine Exposure on the Adolescent and Adult Brain with Relevance for Psychiatric Disorders – NICADO

Nicotine and the brain : from adaptation to pathology

Nicotine addiction is a chronic relapsing disorder associated with psychiatric comorbidities. The prognosis is notably bleak for most of adult smokers who began in adolescence, as early onset of nicotine use is associated with an increased risk of dependence throughout the lifetime. Vaping has emerged as an alternative nicotine delivery method immensely popular especially amongst adolescents. These increases in adolescent nicotine use stress the need for effective evidence-based interventions.

In this project, we dissect the mechanisms and the sequence of events underlying the impact of protracted nicotine exposure on the adolescent and adult brains

We have 4 major aims focusing on changes that affect dopamine (DA) neurons of the reward system and their modulation by acetylcholine, the endogenous ligand for nicotinic acetylcholine receptors (nAChRs).<br />1- To determine how adolescent nicotine exposure shapes VTA DA neuron maturation.<br />2- To examine the state of VTA DA subnetworks following chronic nicotine exposure in adulthood, and characterize the impact of its withdrawal at both the cellular and behavioral levels.<br />3- To investigate how nicotine exposure reshuffles the laterodorsal tegmental nucleus, a key source of endogenous acetylcholine to VTA DA neurons.<br />4- To assess how nicotine exposure in adolescence orients behavior in adult animals and promotes a vulnerable phenotype.<br />NICADO should help to develop and optimize novel aids for smoking cessation treatment.

This project displays strong foundations in behavior and electrophysiological recordings. It builds on previous expertise and breakthroughs of the teams in order to achieve a further qualitative leap in understanding the function and mechanisms of the modulation of DA dynamics by nicotine. The innovative aspect of this project lies mainly in a systematic and complete circuit-based analyses of the brain allostatic overload triggered by chronic nicotine exposure during adolescence and adulthood, taking sex differences into account. We will focus on emotional, decision making and motivation behavioral domains. These domains are affected by nicotine and known to be altered in many psychiatric conditions. These broad behavioral analyses will allow to link individual behavioral variability with current state of the DA system, which will be monitored using ex vivo patch-clamp recordings, in vivo electrophysiology and fiber-photometry.

We here present the main results gathered by the consortium on the 2 main axes:

(i) The impact of adolescent nicotine exposure on adult physiology
We analyzed the evolution of VTA DA cells activity with ages. VTA DA neurons are spontaneously active, and alterations in their spontaneous activity are linked to behavioral changes relevant to mental health. Typically, DA neurons exhibit either regular or short bursts of action potential discharge activity, with this burst activity being present only in intact brains. By recording mice at different stages between early adolescence (postnatal day (PND) 21) and early adulthood (PND 60), we found clear changes in the development of these discharge properties during adolescence in male mice. This development is affected when nicotine is solely given for one week during adolescence. Furthermore, our preliminary data suggest that the trajectory in females peaks at a different age. These results demonstrate an adaption of VTA DA cells physiology with age.

(ii) The outcomes of its exposure during adulthood.
We have been parsing the effects of nicotine exposure (6 weeks) in adulthood on the cellular responsiveness of the LDTg->VTA axis and its behavioral impact onto motivational processes. In brief we demonstrate marked changes in nicotine-elicited currents when puffed onto VTA dopamine (DA) neurons as well as an increased in presynaptic adaptations. This suggests adaptations at nicotinic receptors signaling and likely changes in cholinergic neurotransmission from the LDTg. Using optogenetics, we ruled out adaptations at glutamatergic and GABAergic LDTg terminals within the VTA. At the LDTg level, we found increases in the excitability profile of cholinergic, but not GABAergic neither Glutamatergic, neurons projecting to the VTA. At the morphological levels, we found increases in the density of immature spines onto cholinergic LDTg->VTA neurons. This reveals a discrete impact of nicotine on cholinergic/nicotinic system arising from the LDTg and targeting the VTA. To identify the inputs shaping adaptations on the LDTg->VTA axis, we probed the connectivity from 3 brain regions relevant for nicotine’s reinforcing properties, namely the Insular Cortex, the Prefrontal Cortex and the lateral habenula. In naive conditions, we primarily found stronger connectivity of cholinergic LDTg->VTA neurons with habenular inputs rather than cortical ones.
In a separate study, we have shown that chronic nicotine exposure modifies decision making (Dongelmans et al 2021). We are now testing whether a similar pattern is observed following adolescent exposure.

The two partners have already generated compelling data to address the 2 major aspects of this project: (i) the impact of adolescent nicotine exposure on adult physiology and (ii) the outcomes of its exposure during adulthood. One paper is already in press (Dongelmans et al., 2021 Nature Communications). Two other papers are in preparation (Reynolds et al.; Costa Campos et al.) and should be submitted by the end of this year.

We are currently assessing the changes at habenular->LDTg terminals following chronic nicotine exposure; preliminary data indicates a decrease in synaptic strength, which goes in line with an increased numbers in immature spines on cholinergic neurons. At the behavioral level, nicotine exposure in adults results in increased motivational properties for natural reward. We will seek causality by counteracting these cellular maladaptations with DREADD systems.

In the near future we aim to develop interventions to restore circuit activity and behavior, first through direct optogenetic manipulations to isolate the affected circuits, and then through «positive« environmental influences with the goal of one day translating them into public health interventions. Overall we hope to be able to publish three articles with this work.

• Article in press
Chronic nicotine increases midbrain dopamine neuron activity and biases individual strategies towards reduced exploration in mice.
Dongelmans M, Durand-de Cuttoli R, Nguyen C, Come M, Duranté EK, Lemoine D, Brito R, Ahmed Yahia T, Mondoloni S, Didienne S, Bousseyrol E, Hannesse B, Reynolds LM, Torquet N, Dalkara D, Marti F, Mourot A, Naudé J, Faure P. Nat Commun. 2021. 12:6945. doi: 10.1038/s41467-021-27268-7

• We attended and presented posters at the FENS forum 2022:
1. Adolescent nicotine exposure disrupts its anxiogenic properties
Reynolds LM, Fayad SL, Nguyen C, Topilko T, Gulmez A, Marti F, Heck N, Renier N, Mourot A and Faure P.
2. Chronic nicotine alters motivational value of natural rewards through circuit-based alterations of VTA DA neurons.
Campos R, Ortiz V, Fofo H, Heck N, Pousinha P, Fernandez S, Barik J.

• P1and P2 met several times since the beginning of the project:
11/01/2021: Meeting via Zoom, Kick-Off meeting.
29/04/2021/: Meeting via Zoom, Planning of behavioral experiments and experimental details for nicotine administration in both adolescents and adults.
30/03/2022: Meeting via Zoom, Presentations of ex-vivo results obtained by P1 and in-vivo data generated by P2
10/07/2022 Paris during FENS 2022, discussion of the missing experiments in order to finalize the scientific articles in preparation.

Smoking, regardless of gender, is one of the leading causes of preventable deaths. Nicotine addiction is a chronic relapsing disorder associated with many psychiatric comorbidities. The prognosis is notably bleak for most of adult smokers who began in adolescence as early onset of nicotine use is associated with an increased risk of dependence throughout the lifetime. Vaping has emerged as an alternative nicotine delivery method immensely popular especially amongst adolescents. Although e-cigarettes spare exposure to toxic chemical constituents of conventional cigarettes, vapers are still chronically exposed to nicotine. These increases in adolescent nicotine use stress the need for effective evidence-based interventions. Yet, only few effective interventions currently exist to curb nicotine addiction. We believe that this heightened adolescent vulnerability reflects the impact of nicotine on the ongoing synaptic remodeling of the brain, which builds specific networks necessary for the gradual emergence of adult behaviors in cognitive, emotional and motivational domains. We propose to dissect the mechanisms and the sequence of events underlying the impact of protracted nicotine exposure in order to help developing and optimizing novel aids for smoking cessation treatment.
Ventral tegmental area (VTA) dopamine (DA) neurons, whose anatomical connectivity dynamically develops during adolescence, are directly affected by nicotine, which acts on distinct VTA nicotinic acetylcholine receptors (nAChR). Aberrant changes in DA neurons’ activity have been associated with many psychiatric conditions. Thus, alterations of the input and output connectivity of VTA DA neurons is likely to sustain the enduring impact of nicotine exposure on the adolescent and adult brains. We propose a preclinical approach to comprehensively study in adult male and female mice the effects of chronic exposure to nicotine during adolescence or adulthood. We will tackle the impact of nicotine from the perspective of a dysfunction of well-delineated brain networks using state of the art approaches: including pharmaco- and opto-genetics and viral tracers combined with electrophysiology, fiber photometry, and relevant behavioral paradigms. We will address 4 major aims:
1- To determine how adolescent nicotine exposure shapes VTA DA neurons maturation.
2- To examine the state of VTA DA subnetworks following chronic nicotine exposure in adulthood, and characterize the impact of its withdrawal at both the cellular and behavioral levels.
3- To investigate how nicotine exposure reshuffles the laterodorsal tegmental nucleus, a key source of endogenous acetylcholine to VTA DA neurons.
4- To assess how nicotine exposure in adolescent orients animal’s behavior in adulthood and define a vulnerable phenotype.
NICADO focuses on 3 behavioral domains (emotional states, decision making and motivation) that are affected by nicotine and known to be altered in many psychiatric conditions. These broad behavioral analyses will also allow to link individual behavioral variability with current state of the DA system. Last, we will employ virus-based interventions to intervene, in a projection- and cell-specific manner, when nicotine-induced maladaptations have already occurred. Thus, the results gathered will have greater translational value.
The innovative aspect of NICADO lies mainly in a systematic and complete circuit-based analyses of the brain allostatic overload triggered by chronic nicotine exposure during adolescence and adulthood, taking sex differences into account. This project clearly falls within the aims of the ANR. Most tools and paradigms have been set-up, and solid preliminary data supporting each task ensure the feasibility of NICADO with low risks.

Project coordination

Jacques BARIK (Institut de pharmacologie moléculaire et cellulaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

NPS Neurosciences Paris-Seine
IPMC Institut de pharmacologie moléculaire et cellulaire

Help of the ANR 508,517 euros
Beginning and duration of the scientific project: December 2020 - 42 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter