The Lateral Habenula and Adaptive Behaviors

Abstract

The evolutionarily conserved lateral habenula (LHb) enables dynamic responses to continually changing contexts and environmental conditions. A model is proposed to account for greater mnemonic and contextual control over LHb-mediated response flexibility as vertebrate brains became more complex. The medial prefrontal cortex (mPFC) provides instructions for context-specific responses to LHb, which assesses the extent to which this response information matches the motivation or internal state of the individual. LHb output either maintains a prior response (match) or leads to alternative responses (mismatch). It may also maintain current spatial and temporal processing in hippocampus (match), or alter such activity to reflect updated trajectory and sequenced information (mismatch). A response flexibility function of the LHb is consistent with poor behavioral control following its disruption (e.g., in depression).

Keywords: adaptive behavior; cognitive flexibility; lateral habenula.

Figure 1. Illustration of the Many Afferent and Efferent Connections of the Lateral Habenula (LHb)

The structures shaded dark green (prefrontal cortex, PFC; entopeduncular nucleus, EPN; suprachiasmatic nucleus, SCN; vertical limb of the diagonal band of Broca, vDBB; and the lateral preoptic area, LPO) comprise major inputs of sensory, response, and internal state information to both medial (red) and lateral (blue) sectors of the LHb. The lateral hypothalamus (LH) also provides strong input regarding internal state and motivation, but primarily to the medial LHb. The medial and lateral LHb have overlapping and separate projections to mostly midbrain regions (ventral tegmental area, VTA; rostromedial tegmentum, RMTg; median raphe, MnR; dorsal raphe, DR; interpeduncular nucleus, IPN; and the periacqueductal grey, PAG). Of these, the MnR and IPN provide direct feedback to the hippocampus, which in turn directly connects with PFC, thereby completing the information loop across the hippocampus, PFC, and the LHb.

Figure 2. Maze-Based Tasks Reveal a Role for the Lateral Habenula (LHb) in Adaptive Decision Making

(A) The LHb determines whether the ongoing strategy should continue to be employed based on currently available internal and external information, or whether the strategy should be replaced by an alternative. Current information can include the presence of danger such as the possibility of shock or predator odors, information cues such as tones or lights to guide choices, or the reward history of the ongoing strategy. In a maze-based context, many of these task conditions have been utilized to clarify the role of the LHb in adaptive decision-making [21,23,110,111]. (B) One such example is the utilization of tones to guide choice behaviors [23]. Using a trained rat, a low tone was played when the rat was in the stem arm of a T-maze, indicating that it should turn left to receive reinforcement. This tone choice pairing was repeated for three to six trials. (C) When the auditory cue was switched to a high tone, the opposite arm choice resulted in reinforcement. Over the course of a single training session a rat experienced 16 switches in tones, requiring a high level of adaptive choice behavior. (D) Inactivation of the LHb with baclofen/muscimol (Bac/Mus) resulted in chance-level performance in this task. (E) This impairment was characterized by an increased likelihood of rats to ignore the auditory cues and continue to make the same arm choice as measured by a choice-bias score (the number of errors for a single arm choice over the total number of choice errors). Data in (D,E) are adapted from [23].

Figure 3. A Working Hypothesis Describing the Hippocampus, Medial Prefrontal Cortex (mPFC), and Lateral Habenula (LHb) as a Core Neural Circuit That Enables Animals To Respond Adaptively as Task Conditions and the External and Internal Contexts Change

The mPFC integrates information about recent action sequences and response outcomes to determine whether the current strategy or responses should continue. If the response outcomes are not as expected, the next response may need to be adjusted to achieve a desired goal. Instructions about whether to stay the course or adjust the response are fed forward to the LHb, which ultimately maintains a current response or enables a changed response depending on the extent to which information about current internal state (e.g., motivation or stress levels) warrants a behavioral switch. For example, an animal may have knowledge of what behaviors are necessary to achieve a goal such as food, but the degree of hunger or level of stress may determine whether the optimal choice is worth the perceived risks. LHb indirect (dashed line) innervation of dopaminergic and/or serotonergic systems could bias responses to stay the course or engage new behaviors. The LHb may also (via indirect connections; dashed line) inform hippocampus of the extent to which responses, recent outcomes, and internal state information occur as expected (i.e., match), which in turn can help to define the current and expected context for subsequent mnemonic processing. Abbreviations: DA, dopamine; EPN, entopeduncular nucleus; 5HT, serotonin; OFC, orbitofrontal cortex; SCN, suprachiasmatic nucleus.

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