Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin

The lateral habenula (LHb) is a critical brain region that inhibits dopaminergic centers, functioning as an 'anti-reward' signal. While the basal ganglia are a major input to the LHb, they are traditionally considered inhibitory. This study investigates the nature of this connection, specifically examining whether it transmits excitatory signals that could contribute to aversive, anti-reward responses.

The researchers used a combination of optogenetics, immunohistochemistry, and electrophysiology in rats. They injected a light-sensitive ion channel (ChR2) into the entopeduncular nucleus (EP)—the rodent homologue of the primate globus pallidus internus—and stimulated these axons within the LHb. They recorded synaptic responses to confirm the nature of the neurotransmission and used a directed place preference behavioral assay to determine if activating this pathway is perceived as rewarding or aversive. They also examined how neuromodulators like serotonin affect this specific synaptic transmission.

The team demonstrated that transmission from the EP to the LHb is predominantly excitatory and glutamatergic, relying on AMPA-type receptors. This finding challenges the conventional view that basal ganglia output to the LHb is solely inhibitory. Behaviorally, optogenetic stimulation of these axons in the LHb resulted in significant place avoidance, identifying the pathway as an aversive signal. Furthermore, the researchers found that this excitatory transmission is presynaptically inhibited by serotonin. This interaction provides a potential neurobiological link between serotonergic function and the coding of negative reward outcomes, which is highly relevant to the study of depression.

By identifying an excitatory, aversive pathway from the basal ganglia to the LHb, this study clarifies how 'anti-reward' signals are generated in the brain. The discovery that serotonin suppresses these synapses offers a mechanistic bridge between the known involvement of serotonin in mood disorders and the brain's reward-processing circuits, suggesting that serotonin might modulate an individual's sensitivity to negative life events.