The Lateral Habenula Circuitry: Reward Processing and Cognitive Control

Abstract

There has been a growing interest in understanding the role of the lateral habenula (LHb) in reward processing, affect regulation, and goal-directed behaviors. The LHb gets major inputs from the habenula-projecting globus pallidus and the mPFC, sending its efferents to the dopaminergic VTA and SNc, serotonergic dorsal raphe nuclei, and the GABAergic rostromedial tegmental nucleus. Recent studies have made advances in our understanding of the LHb circuit organization, yet the precise mechanisms of its involvement in complex behaviors are largely unknown. To begin to address this unresolved question, we present here emerging cross-species perspectives with a goal to provide a more refined understanding of the role of the LHb circuits in reward and cognition. We begin by highlighting recent findings from rodent experiments using optogenetics, electrophysiology, molecular, pharmacology, and tracing techniques that reveal diverse neural phenotypes in the LHb circuits that may underlie previously undescribed behavioral functions. We then discuss results from electrophysiological studies in macaques that suggest that the LHb cooperates with the anterior cingulate cortex to monitor action outcomes and signal behavioral adjustment. Finally, we provide an integrated summary of cross-species findings and discuss how further research on the connectivity, neural signaling, and physiology of the LHb circuits can deepen our understanding of the role of the LHb in normal and maladaptive behaviors associated with mental illnesses and drug abuse.

Keywords: anterior cingulate cortex; cognition; globus pallidus; lateral habenula; punishment; reward; rostromedial tegmental nucleus.

Figure 1.

The proposed function of the basal ganglia and midbrain evaluation circuits. a, Schematic showing the activity of GPh neurons and the downstream circuitry controlling the midbrain dopaminergic system. Modified from the Allen Mouse Brain Atlas, Allen Institute for Brain Science (available from http://mouse.brain-map.org/). Adapted from Stephenson-Jones et al. (2016). b, Proposed sequence of events by which GPh activity may influence the firing rate in downstream structures. DR, Dorsal raphe; MR, median raphe; pSTN, parasubthalamic nucleus. Upward arrows, increase in firing; downward arrows, decrease in firing; ?, alternative circuits downstream of the LHb, including the serotonergic raphe nuclei, may constitute other key pathways that also process the GPh-LHb PE signals that we demonstrate in Stephenson-Jones et al., 2016.