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Synaptic plasticity in the lateral habenula controls neuronal output : implications in physiology and drug addiction

Abstract : The capacity of the brain to anticipate and seek future rewards or alternatively escape aversive events allows individuals to adapt to their environment. A considerable research effort has focused on unraveling the cellular and synaptic mechanisms within the meso-cortico-limbic system underlying motivational processing both in physiological conditions and in pathologies such as addiction and depression. However, only recently we begin to understand the circuit substrates capable to control midbrain monoaminergic nuclei and their contribution to motivated behaviors. The Lateral Habenula (LHb) has emerged in the last decade, as a major player encoding stimuli with motivational value and in controlling monoaminergic systems. The wiring of this epithalamic structure subserves discrete features of motivated behaviors, including preference and avoidance. Recent advances have also demonstrated that aberrant modifications in LHb function trigger negative emotional states in disorders including depression and addiction, highlighting the LHb as an important brain target for therapeutic intervention for these pathological states. In my thesis work I first sought to investigate how modulation of synaptic transmission in the LHb controls neuronal activity, especially focusing on the role of metabotropic glutamate receptors. In a second study, I expanded my work examining how drug experience changes synaptic transmission in a precise habenular circuit that we discovered to be crucial for depressive states during cocaine withdrawal. In an initial data set, we found that, in the LHb, metabotropic glutamate receptor 1 activation drives a PKC-dependent long term depression of excitatory (eLTD) and inhibitory (iLTD) synaptic transmission. Despite the common induction, eLTD and iLTD diverged in their expression mechanism. While eLTD required endocannabinoid-dependent reduction of glutamate release, iLTD expressed postsynaptically through a decrease of β2-containing GABAA receptors function. Further, eLTD and iLTD bidirectionally controlled LHb neuronal output. In a second study, we showed that chronic cocaine exposure leads to a persistent and projection-specific increase of excitatory synaptic transmission onto LHb neurons. This form of synaptic potentiation required membrane insertion of GluA1-containing AMPA receptors and a reduction in potassium channels function ultimately leading to increased LHb neuronal excitability both in vitro and in vivo. These cocaine-driven adaptations within the LHb were instrumental for depressive-like states emerging after drug withdrawal. Altogether this work demonstrates how synaptic plasticity in the LHb affects neuronal output and thereby contributes to behaviors associated with the pathology of motivation.
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Kristina Valentinova. Synaptic plasticity in the lateral habenula controls neuronal output : implications in physiology and drug addiction. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2016. English. ⟨NNT : 2016PA066743⟩. ⟨tel-01927180⟩

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