Chapter 1: The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here we examine in rodents if reduced motivation to exert effort is controlled by transmission from the lateral habenula (LHb, a nucleus overactive in depressed-like states) to the rostromedial tegmental nucleus (RMTg, a nucleus that inhibits dopaminergic neurons). In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility; driving LHb→RMTg increased immobility; and inhibiting LHb→RMTg produced opposite effects. In an appetitive test, driving LHb→RMTg reduced effort exerted to receive a reward, without affecting the reward’s hedonic property. Notably, LHb→RMTg stimulation had an effect on only specific aspects of motor tasks and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduce effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.

Chapter 2: Co-release of neurotransmitters has been detected in numerous brain regions under physiological and pathological conditions. However, if the opponent neurotransmitters γ-aminobutyric acid (GABA) and glutamate are normally released from single vesicles is not well established. A recent exhaustive study demonstrated that GABA and glutamate are released from individual presynaptic neurons originating at several nuclei targeting the lateral habenula (LHb). Their anatomical techniques indicated that GABA-containing and glutamate containing presynaptic vesicles are segregated. Here we use electrophysiology to characterize a different synaptic projection onto the lateral habenula, and find that the majority of individual quantal events contain a dual glutamate and GABA composition. The lateral habenula may therefore have multiple means to balance excitation and inhibition by co-released GABA and glutamate.