Laterodorsal tegmentum–ventral tegmental area projections encode positive reinforcement signals

• Published in: Journal of neuroscience research 2021-11, Vol.99 (11), p.3084-3100
• Main Authors: Coimbra, Bárbara, Domingues, Ana Verónica, Soares‐Cunha, Carina, Correia, Raquel, Pinto, Luísa, Sousa, Nuno, Rodrigues, Ana João
• Format: Article
• Language: English
• Subjects: Animals; Aversion; Behavior; Brain stem; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dopaminergic Neurons - physiology; Immunofluorescence; LDT; Male; Motivation; neuronal circuits; Neurons; Nucleus Accumbens; optogenetics; Place preference conditioning; Positive reinforcement; Rats; Reinforcement; REM sleep; Reward; Stimulation; Tegmentum; Tegmentum Mesencephali; Ventral Tegmental Area - physiology; Ventral tegmentum
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.24931

The laterodorsal tegmentum (LDT) is a brainstem nucleus classically involved in REM sleep and attention, and that has recently been associated with reward‐related behaviors, as it controls the activity of ventral tegmental area (VTA) dopaminergic neurons, modulating dopamine release in the nucleus accumbens. To further understand the role of LDT–VTA inputs in reinforcement, we optogenetically manipulated these inputs during different behavioral paradigms in male rats. We found that in a two‐choice instrumental task, optical activation of LDT–VTA projections shifts and amplifies preference to the laser‐paired reward in comparison to an otherwise equal reward; the opposite was observed with inhibition experiments. In a progressive ratio task, LDT–VTA activation boosts motivation, that is, enhances the willingness to work to get the reward associated with LDT–VTA stimulation; and the reverse occurs when inhibiting these inputs. Animals abolished preference if the reward was omitted, suggesting that LDT–VTA stimulation adds/decreases value to the stimulation‐paired reward. In addition, we show that LDT–VTA optical activation induces robust preference in the conditioned and real‐time place preference tests, while optical inhibition induces aversion. The behavioral findings are supported by electrophysiological recordings and c‐fos immunofluorescence correlates in downstream target regions. In LDT–VTA ChR2 animals, we observed an increase in the recruitment of lateral VTA dopamine neurons and D1 neurons from nucleus accumbens core and shell; whereas in LDT–VTA NpHR animals, D2 neurons appear to be preferentially recruited. Collectively, these data show that the LDT–VTA inputs encode positive reinforcement signals and are important for different dimensions of reward‐related behaviors. LDT–VTA inputs optogenetic manipulation changes motivational drive and modifies preference.