Flexibility & Adaptability: The Role of the Lateral Habenula & Medial Prefrontal Cortex

Abstract

The ability to make appropriate decisions that result in an optimal outcome is critical for survival, yet the same processes that support flexibility can also give rise to maladaptive choices when they break down. Identifying the neural circuits that mediate flexible behavior, and how those circuits are affected in maladaptive states, is invaluable to our understanding and subsequent treatment of psychiatric conditions. The lateral habenula (LHb) plays a well-known role in reward and aversive processing, but accumulating evidence from our laboratory and others has implicated the LHb in flexible decision-making more broadly (Baker et al., 2015; Mizumori & Baker, 2017; Hones & Mizumori, 2022; Ahmadlou et al, 2025). Flexible behavior recruits a number of cognitive processes including contextual memory and motivational state information that the LHb does not directly mediate, raising the question of which broader circuits work together with the LHb to support adaptive choices. Converging evidence points toward a circuit in which contextual information from the hippocampus (HPC) reaches the LHb via the medial prefrontal cortex (mPFC), where the LHb integrates that information with motivational state signals to enable strategy switching when goals or contexts change (Hones & Mizumori, 2022). This same HPC–mPFC–LHb circuit is implicated across a variety of psychiatric conditions characterized by maladaptive decision-making, including opioid use disorder, where morphine withdrawal disrupts mPFC function at least in part through serotonin depletion and pyramidal cell hyperactivity (Goeldner et al., 2011; Piao et al., 2017). Serotonergic agonists such as psilocybin have the potential to act on this circuit by promoting dendritic growth and other markers of plasticity (Shao et al., 2021; Pacheco et al., 2023), offering a potential therapeutic avenue for restoring flexibility in maladaptive states.To test the role of this circuit in flexible and adaptive behavior, we approached the problem from two complementary directions. First, we asked how disrupting a key node of the circuit, the LHb, shapes flexible and adaptive behavior on a spatial set-shifting task. Pharmacologically inactivating the LHb with muscimol did not abolish flexibility per se: rats still readily changed their choice patterns from trial to trial, even at more elevated levels than saline controls. Inactivation did, however, impair their ability to direct that flexibility toward a new, correct strategy after uncued shifts in reward contingencies, indicating that the LHb specifically supports the adaptive use of negative outcome information to guide subsequent decisions. As such, without an intact LHb, flexibility manifests as maladaptive choice rather than effective strategy switching. Next, we approached the same circuit from the opposite direction by inducing a maladaptive state, morphine withdrawal, and asking how that state alters circuit function, focusing on the mPFC. We combined a spatial set-shifting task with a novel object recognition test (NORT) and recorded prelimbic neurons in the mPFC in vivo using calcium imaging. Morphine-withdrawn rats showed impairments across several aspects of flexible behavior on the set-shifting task, as well as deficits in novel object recognition. At the neural level, prelimbic neurons in morphine-withdrawn rats were hyperactive, but less active in response to novel objects, and this inhibited neural response was consistent with their behavioral NORT impairment. Functional clustering of prelimbic responses showed that distinct subpopulations of neurons changed their activity selectively depending on the drug condition, indicating that maladaptive states reshape the intrinsic activity patterns of subpopulations of prelimbic neurons. A single therapeutic dose of psilocybin (1 mg/kg) alleviated some aspects of the morphine-related impairments on both the set-shifting task and the NORT, and further improved set-shifting performance in saline-treated control rats. The behavioral effect of psilocybin treatment was paired with improved neural activity in prelimbic neurons across testing conditions, as well as during the NORT. This suggested that serotonergic plasticity has a broader, positive effect on cognition that may extend beyond pathological states. Together, these findings contribute to our understanding of the HPC–mPFC–LHb circuit as a coordinated system that uses context, outcome, and internal state information to guide flexible and adaptive behavior. Importantly, our results highlight a broader issue in the flexibility literature, where flexibility is often inferred from task outcomes alone. As Searle’s Chinese Room illustrates, observing the output of a process does not reveal the process itself. When we examined trial-to-trial strategy use rather than just the outcome alone, we found that disrupting different nodes of this circuit produced hyperflexible, maladaptive states rather than the hypoflexibility that outcome-based measures alone would suggest. We also identify psilocybin as a potential intervention that can restore, and potentially enhance, the behavioral flexibility and adaptability this circuit typically supports.