Nicotinic modulation of behaviors motivated by natural rewards – NIMONAR

The ventral tegmental area (VTA) is a critical brain region involved in processing reward-related stimuli and plays a pivotal role in various neuropsychiatric disorders, including addiction. VTA dopaminergic neurons transition from tonic to burst firing mode in response to sensory cues predicting rewards, triggering phasic dopamine release in the nucleus accumbens, a crucial signal for the expression of reward-related behaviors. Excitatory drive, notably from cholinergic inputs originating from hindbrain pontin nuclei, prompts this firing mode switch. Furthermore, nicotine, by acting through nicotinic acetylcholine receptors (nAChRs), directly activates VTA dopamine neurons, inducing bursts of action potentials and reinforcing effects central to tobacco addiction. VTA nAChRs are thus key modulators of dopaminergic circuits and are central to the reinforcing effects of nicotine. However, the brain likely evolved to respond not to drugs but to natural rewards, such as food and social interactions, which are evolutionarily important for survival and reproduction. Surprisingly, the involvement of acetylcholine (ACh) and associated nicotinic receptors in the encoding of natural rewards remains largely unexplored.

This research grant proposal aims to investigate the role of midbrain ACh and its nicotinic receptors in natural reward processing (food and social interactions), as well as the neurophysiological and behavioral adaptations following nicotine exposure. The project will employ innovative home-made tools, including intelligent cages specifically designed for continuous behavioral monitoring related to natural rewards, and opto-chemo-genetic methods for precise nAChR manipulation in discrete brain regions. We will combine these custom tools with electrophysiology, fiber photometry and optogenetics, to elucidate the dynamics of ACh release, identify VTA subcircuits modulated by ACh, and causally link VTA ACh to natural reward-seeking behavior.

This proposal is organized into three aims. In aim 1, we will explore how VTA neurons integrate information from different cholinergic afferents and how this affects natural reward encoding. The goal is to unveil the source of ACh participating in the encoding of natural rewards, the dynamics of its release in the VTA, and its functional impact on VTA subcircuits and on reward-seeking behavior. A custom ethological environment will be used to study food and social reward in a “natural” setting. Aim 2 will focus on causally linking midbrain ACh to natural reward seeking behavior, by employing a combination of optogenetic as well as home-made chemogenetic and photochemical tools to manipulate nicotinic neurotransmission in the VTA with high precision. We aim to link modulation of the different VTA subcircuits by endogenous ACh with natural reward seeking behavior. Finally, in Aim 3, the project will investigate how repeated overactivation of the cholinergic system by nicotine leads to alterations in the sensitivity of VTA circuits to natural rewards, thus resulting in behavioral adaptations. The outcomes are expected to contribute significantly to understanding the neurobiology of nicotine addiction and its impact on natural reward processing.