Drug addiction is a chronic relapsing disorder which blights the lives of millions worldwide. A central component of the addictive cycle is the emergence of an aversive withdrawal state, which starts developing during abstinence from all drugs of abuse. In general, this withdrawal state is characterized by acute physical symptoms and persistent psychological symptoms, many of which are reminiscent of depression. The withdrawal state undermines attempts to abstain from drug use, as it is frequently cited as a major contributing factor for relapse to drug intake. The majority of neuroscience research to date has focused its resources on elucidating the neurobiology underlying the motivational drive to continually seek the euphoric high experienced during drug intake. Comparatively less is known regarding the neural substrates of withdrawal, and of the drive to terminate such an aversive experience. It is clear that to establish a fuller picture of the neural adaptations occurring during addiction in order to support development of more effective therapy, we must uncover the substrates of drug withdrawal.

One key brain node implicated in mediating the aversive state emerging in withdrawal is the epithalamic lateral habenula (LHb). LHb neurons encode aversive external stimuli through their increase in neuronal activity. Additionally, adaptations in the LHb underlie the development of depressive-like symptoms following exposure to stress and during drug withdrawal. Through its output projections, the LHb exerts control over the activity of neurons located in the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) respectively. Both these nuclei fundamentally regulate motivated behaviors and their maladaptation underlie aspects of drug addiction. Whilst several studies have demonstrated the link between LHb adaptations and the aversive state emerging during drug withdrawal, less is known concerning the downstream repercussions of such adaptations. In particular, whether drug withdrawal could influence segregated populations of LHb neurons that provide direct innervation to the VTA and DRN is currently unclear. Like the LHb, both the VTA and DRN exhibit functional diversity that is in part, due to segregated output-specific projections. This thesis aims to unravel this complex circuitry to provide a clearer, and further developed picture, of how drug withdrawal-driven adaptations in LHb circuits may contribute to the aversive state.

To this end I present in this thesis manuscript two studies examining how withdrawal from different drugs drives independent forms of synaptic plasticity in output-specific LHb circuits using a combination of electrophysiological, anatomical and behavioral techniques. We find that morphine withdrawal drives a postsynaptic depression of excitatory transmission in DRN- projecting neurons – a circuit we show to regulate social behavior. This plasticity is mediated by an elevation of inflammatory cytokines and collectively these adaptations underlie social deficits emerging in morphine withdrawal. Concerning the LHb projection to the VTA, we first provide a precise anatomical characterization of this projection and its targets in the VTA. We observe that cocaine withdrawal drives opposing plasticity of glutamate release probability from LHb axons on to VTA neurons projecting to the medial Prefrontal Cortex (mPFC) and Nucleus Accumbens (NAc), adaptations that are not visible when globally examining total LHb innervation of the VTA. These VTA circuits are considered to represent functionally distinct populations that principally regulate processing of aversion and reward respectively.

In light of these results I propose a framework of how adaptations in the LHb may contribute to the aversive state emerging during drug withdrawal. The observation that drug withdrawal drives precise forms of LHb circuit plasticity represents an overall nuanced adaptation of this important brain nucleus’ regulation of downstream targets. These plastic processes may represent a substrate for the control the LHb has over many aspects of motivated behavior that can be hijacked during addiction. Altogether these studies expand our knowledge of the neural- circuit basis of drug withdrawal.
—
L’addiction aux drogues d’abus est un trouble chronique rĂ©current qui affecte la vie de millions de personnes dans le monde. Un Ă©lĂ©ment central du cycle de la dĂ©pendance aux drogues est l’apparition d’un Ă©tat de manque aversif. En gĂ©nĂ©ral, cet Ă©tat de manque se caractĂ©rise par des symptĂ´mes physiques aigus et psychologiques persistants, dont beaucoup rappellent la dĂ©pression. L’Ă©tat de manque participent aux Ă©checs de tentative de sevrage, car c’est un facteur majeur de rechute dans la consommation de drogues. La majoritĂ© des recherches en neurosciences se sont focalisĂ©es sur l’Ă©lucidation de la neurobiologie qui sous- tend la motivation Ă  rechercher l’euphorie lors de la prise de drogue, mais on en sait relativement peu sur les substrats neuronaux du sevrage. Pour obtenir une image plus complète des adaptations neuronales qui se produisent au cours de la dĂ©pendance, nous devons dĂ©couvrir les substrats du sevrage afin de soutenir le dĂ©veloppement d’une thĂ©rapie plus efficace.

L’un des structures neuronales impliquĂ©s dans la mĂ©diation d’un Ă©tat aversive induit par les drogues est la latĂ©rale habenula (LHb). Les neurones de la LHb encodent les stimuli aversifs en augmentant leurs activitĂ©s neuronales. Après une exposition au stress ou pendant le sevrage d’une drogue, les adaptations de la LHb sont Ă  l’origine des symptĂ´mes de type dĂ©pressif. De par ces projections, la LHb exerce un contrĂ´le de l’activitĂ© des neurones de l’aire tegmentale ventrale (VTA) et du raphĂ© dorsal (DRN). Ces deux noyaux rĂ©gulent les comportements motivĂ©s tandis que leurs dysfonctionnements sous-tendent certains aspects de la toxicomanie. Alors que plusieurs Ă©tudes ont dĂ©montrĂ© le lien entre les adaptations de la VTA, du DRN et l’Ă©tat aversif du sevrage, on en sait moins sur les rĂ©percussions en aval de ces adaptations. En particulier, on ne sait pas encore si le sevrage de la drogue peut influencer des populations distinctes de neurones de la LHb qui projettent sur la VTA et le DRN. Comme la LHb, la VTA et le DRN prĂ©sentent une diversitĂ© fonctionnelle qui est en partie due Ă  leurs projections spĂ©cifiques sur des noyaux distincts. Cette thèse a pour but de dissĂ©quer ces circuits complexes afin de fournir une image plus claire et dĂ©veloppĂ©e de la manière dont les adaptations des circuits de la LHb, induites par le sevrage, contribuent Ă  l’Ă©tat aversif.

Je prĂ©sente dans ce manuscrit de thèse deux Ă©tudes examinant comment le sevrage de diffĂ©rentes drogues entraĂ®ne des formes de plasticitĂ© synaptique dans les circuits de spĂ©cifiques des effĂ©rences de la LHb en utilisant une combinaison de techniques Ă©lectrophysiologiques, anatomiques et comportementales. Nous avons constatĂ© que le sevrage de la morphine entraĂ®ne une dĂ©pression post-synaptique de la transmission excitatrice des neurones qui projettent sur le raphĂ© qui en retour rĂ©gule le comportement social. Cette plasticitĂ© est mĂ©diĂ©e par une Ă©lĂ©vation des cytokines inflammatoires et, collectivement, ces adaptations sous-tendent les dĂ©ficits sociaux qui apparaissent lors du sevrage de la morphine. Concernant les projections de la LHb vers la VTA, nous avons dĂ©crits dans un premier temps les connexions spĂ©cifiques au sein de la VTA. Nous avons observĂ© que le sevrage de la cocaĂŻne entraĂ®ne un effet opposĂ© sur la probabilitĂ© de libĂ©ration du glutamate sur les neurones de la VTA qui projettent vers le cortex prĂ©frontal mĂ©dian (mPFC) et le noyau Accumbens (NAc). Ces sous-circuits de la VTA reprĂ©sentent des populations fonctionnellement distinctes qui rĂ©gulent principalement le traitement de l’aversion et de la rĂ©compense respectivement.

En dernière partie, je propose un cadre pour expliquer comment ces adaptations de la LHb peuvent contribuer Ă  l’Ă©tat d’aversion qui Ă©merge pendant le sevrage des drogues. L’observation selon laquelle le sevrage de la drogue entraĂ®ne des formes prĂ©cises de plasticitĂ© du circuit de la LHb, reprĂ©sente une adaptation nuancĂ©e globale de la rĂ©gulation des cibles en aval de cet important noyau cĂ©rĂ©bral. Ces processus plastiques peuvent reprĂ©senter un substrat pour le contrĂ´le que la LHb exerce sur de nombreux aspects de comportement motivĂ© qui peuvent ĂŞtre dĂ©tournĂ©s lors la dĂ©pendance. Dans l’ensemble, ces Ă©tude Ă©largissent nos connaissances sur les circuits neuronaux Ă  la base du sevrage des drogues.