Significant evidence supports the generally-accepted view that the HPC is critically important for context memories (e.g., Burgess et al., 2002; Howard and Eichenbaum, 2013; Smith et al., 2013; Eichenbaum, 2014; Place et al., 2016; Maurer and Nadel, 2021). Many studies have shown that place cells in the HPC fire strongly when an animal occupies a particular location (a place field; O’Keefe and Nadel, 1978; Gothard et al., 1996). When almost any feature of the context changes, HPC place fields remap or change their spatial and temporal patterns of firing. Additionally, place fields link to represent recent past, present, and future context information (e.g., Muller and Kubie, 1987; Wilson and McNaughton, 1993; Mizumori et al., 1999; Ferbinteanu and Shapiro, 2003; Leutgeb J. K. et al., 2005; Leutgeb S. et al., 2005; Smith and Mizumori, 2006; Nakashiba et al., 2009). In the natural world, it would be unfavorable for an animal to explore an environment similar to one that they have explored in the past that led to danger. Thus, when faced with a new but similar context, the HPC is thought to retrieve information about similar previous experiences (Spiers et al., 2015), then evaluate the extent to which the current context varies from the retrieved (expected) context (Mizumori et al., 1999; Vinogradova, 2001). The degree of similarity between expected and current context information seems reflected in HPC output signals (Mizumori, 2013). Without proper functioning of the HPC, context memory-guided behavior becomes significantly impaired (e.g., Morris et al., 1982; Bradfield et al., 2020; Gridchyn et al., 2020).

The primary motivating factor of a living organism is the need for survival. Thus, an animal’s experiences and actions in the world are highly influenced by recent previous experiences and motivations. For instance, an animal’s willingness to work for food is influenced by whether or not they have eaten recently. There are many outstanding reviews on the neural circuitry underlying motivational systems (e.g., Berridge, 2004; Bromberg-Martin et al., 2010a; Morales and Margolis, 2017; Petrovich, 2018; Burdakov and Peleg-Raibstein, 2020). The distinct and overlapping motivational systems contribute to a specific profile of a motivational state. Motivational systems research has typically focused on relating one’s internal state to specific biologically-motivated behaviors such as hunger and feeding behaviors, as well as reproductive hormones and mate-seeking behaviors. Recent theories postulate that motivation structures such as the lateral hypothalamus serve as an interface between motivation and cognition systems (e.g., Petrovich, 2018; Burdakov and Peleg-Raibstein, 2020), but it is not yet known how motivational state influences the type of response flexibility needed for accurate goal-directed and context-dependent navigation.

If the LHb enables flexible behavioral responses to changing task conditions, one might expect LHb neural activity to somehow reflect this function. Indeed, the LHb has been shown to be a critical part of the neural circuit that generates prediction error signals when task conditions change. The well-known dopamine neural response to prediction errors is driven at least in part by the LHb (Christoph et al., 1986; Matsumoto and Hikosaka, 2007; Ji and Shepard, 2007; Bromberg-Martin and Hikosaka, 2011; Proulx et al., 2014; Baker et al., 2015; Tian and Uchida, 2015; Lalive et al., 2021), even though this occurs indirectly through the rostromedial tegmentum, or RMTg; Li et al., 2019). While these findings illustrate that flexible behavior is likely mediated by more than brain mechanism (e.g., Floresco, 2013), it clearly shows that LHb neural activity is driven by memory-based outcome expectations. Further evidence for the impact of experience on LHb neural responsiveness is the well-documented change in LHb cell firing that occurs during aversive task performance as well as duringstress (e.g., Stamatakis and Stuber, 2012). Is the coding and integration of mnemonic and motivational information sufficient to ensure flexible responding? Recordings of LHb neural activity during a navigation-based foraging task shed new light on this question.

Using a pellet-chasing task that did not require HPC-based context memory, Sharp et al. (2006) described striking velocity-correlated neural activity in rat LHb. A subsequent study by Baker et al. (2015) confirmed the existence of prominent and strong (often r > ± 0.85) velocity-correlated LHb neural activity but this time as rats performed an HPC-dependent spatial working memory task. This result was surprising given the generally accepted view that the LHb contributes to learning and memory by signaling aversive/negative events/consequences/information (see review by Baker et al., 2016). However, Baker et al. (2015) also described another group of LHb neurons that responded to reward encounters, the expectation of rewards, and reward prediction errors in manners similar to the responses of primate LHb reward-responsive neurons described by Matsumoto and Hikosaka (2007). Further, about a third of the recorded LHb neurons showed conjunctive coding of reward and velocity information. During subsequent probe trials in which the reward condition or context was unexpectedly altered, the velocity correlate was retained albeit the overall firing rate was lowered. This pattern of reward and context coding by LHb neurons suggests that the LHb tracks the ongoing behavior of animals, but that the strength of movement state signals may be regulated by reward-related information. Perhaps this behavioral tracking feature is related to the recent report that LHb neurons encode a history of experiences (Andalman et al., 2019). A combination of reward and movement state neural signaling has also been reported for an important efferent structure of the LHb, the VTA (Puryear et al., 2010; Jo et al., 2013), and strong movement state information has been described as a major VTA afferent structure, the lateral dorsal tegmentum (LDTg; Redila et al., 2015). LDTg neurons were postulated to regulate reward responses of DA neurons according to the learned behaviors needed to obtain rewards. What might be the function of LHb movement state signals?

To aid in our understanding of the significance of LHb movement-related neural signals for response flexibility, it is helpful to first consider the finding by Aizawa et al. (2013) that the spiking of LHb neurons is preferentially related in time to the peaks of simultaneously recorded HPC theta rhythms. While a strong argument was made that the LHb spike-HPC theta phase coherence resulted from a common input from the vertical limb of the diagonal band of Broca, this explanation does not address the issue of interest here, and that is how might LHb enable task-specific response flexibility. To shed new light on this issue, we offer the following hypothesis:

Hypothesis: During active navigation, the LHb may track and then relay information about one’s ongoing behaviors to signal at appropriate times when downstream brainstem structures should drive hippocampal theta. In this way, LHb enables flexible responding not because e it selects a particular action, but rather because it enhances a hippocampal neural state that is often associated with greater attention, arousal, and exploration. In freely navigating animals, these are essential conditions that are needed to discover and implement appropriate alternative choices and behaviors.

The HPC theta rhythm is known to encourage exploratory behaviors, increase arousal and attention, and improve learning and memory (e.g., Winson, 1978; Mizumori et al., 1989b; Leutgeb and Mizumori, 1999; Lega et al., 2012; Buzsáki and Moser, 2013). Although the LHb does not have direct anatomical connections with the HPC, functional coupling between LHb and HPC has been demonstrated since LHb spikes exhibit cortical synchrony with the HPC theta phase (Aizawa et al., 2013). Such spike-phase coherence is thought to reflect periodic influences of one structure on another (Singer, 1993; Engel et al., 2001; Buzsáki, 2002). Recent evidence (described below) suggests that a number of prominent LHb efferent targets in the hindbrain area may serve as important nodes for communication from the LHb and HPC. These structures receive substantial input from the LHb, and they are considered to be critical pacemakers for HPC theta. Thus, spiking activity in the LHb may enable response and cognitive flexibility by regulating the HPC theta state to optimize exploration-related neural and memory plasticity. Such regulation could strengthen and/or maintain ongoing memory operations by the HPC during navigation of familiar contexts, as well as enable increased cognitive and response flexibility when task conditions change.

The diverse array of LHb efferent targets is well documented (as reviewed in Kim, 2009; Baker et al., 2016; Mizumori and Baker, 2017). Of particular interest here are those that are considered theta-pacemaker structures for the HPC, such as the nucleus incertus, supramammillary nucleus, the median raphe, and the locus coeruleus (Figure 1). In contrast to the traditional view that hindbrain structures regulate slow processes such as the general state of arousal, recent findings demonstrate temporally and spatially-specific regulation of HPC physiology and behavior by these brain regions.

The Nucleus Incertus (NI) lies in the midline periventricular central gray region of the pontine hindbrain, and it is generally considered to be an essential part of the ascending reticular activating system (Steriade and Glenn, 1982) since it innervates structures known to regulate HPC theta such as the MS (Vanderwolf, 1969; Vertes and Kocsis, 1997; Goto et al., 2001; Olucha-Bordonau et al., 2003; Ma et al., 2013). Also, stimulation or inhibition of the NI up- or down-regulates active locomotion (respectively), as well as modulates physiological indices of arousal and HPC theta (Nuñez et al., 2006; Lu et al., 2020). For example, NI neurons preferentially fire at the initial ascending phase of the HPC theta rhythm (Ma et al., 2013), possibly to reset theta (Martínez-Bellver et al., 2017). Evidence that NI impacts on HPC physiology have consequences for HPC-based memory has been demonstrated using a variety of behavioral tasks (Gil-Miravet et al., 2021), including context fear conditioning (Szönyi et al., 2019), various maze-based tasks (Nategh et al., 2015; Albert-Gascó et al., 2017), as well as spatial working memory operant tasks (Albert-Gascó et al., 2017; Garcia-Diaz et al., 2019).

GABA and glutamate incertus neurons (Lein et al., 2007; Cervera-Ferri et al., 2012) express receptors for stress-related hormones (corticotropin-releasing factor, or CRF) and contain multiple neuropeptide markers for stress and arousal such as neuromedin, relaxin, D2 dopamine receptors, and orexin/hypocretin (e.g., Jennes et al., 1982; Kubota et al., 1983; Ma et al., 2013; Lu et al., 2020). Therefore, the NI had been studied primarily for its role in different physiological states. However, as noted above, more recent emerging evidence clearly shows that especially the relaxin-3 NI neurons likely play a significant role in HPC-based memory (Gil-Miravet et al., 2021). For example, these relaxin-3 neurons are the ones that preferentially fire at the initial ascending phase of the HPCtheta rhythm (Ma et al., 2013). Furthermore, Szönyi et al. (2019) identified an incertus-HPCcircuit that may determine which CA1 pyramidal neurons take part in context memory processing: NI long-range GABAergic neurons project directly and indirectly (via the medial septum) to HPCsomatostatin neurons to regulate the excitatory/inhibitory balance in stratum oriens of CA1, thereby helping to select which cells participate in memory networks and which ones do not. Since the NI receives strong projections from the prefrontal cortex and the LHb (Goto et al., 2001; Lu et al., 2020), one or both of these incertus afferent systems may drive the NI to regulate HPC neural activity in context-specific ways.

The supramammillary nucleus (SUM) is another deep brain structure of interest when considering how LHb neural activity may translate to HPC-mediated response flexibility. The SUM is a hypothalamic structure that provides strong direct and indirect (via the medial septum) theta-rhythmic inputs to the HPC (Haglund et al., 1984; Vertes, 1992, 2015; Kirk and McNaughton, 1993; McNaughton et al., 1995; Kocsis and Vertes, 1997; Vertes and McKenna, 2000; Ito et al., 2018). The overall functional impact of the SUM input is to not only generate HPC theta (Pan and McNaughton, 2004), but SUM afferents amplify neocortical input to the HPC by increasing the responsiveness of dentate gyrus granule cells to input from the entorhinal cortex through disinhibition of inhibitory interneurons (Mizumori et al., 1989a). Such regulation of the excitatory state of granule cells may selectively promote information arriving from the entorhinal cortex. More recently, behaviorally-relevant functional coupling between the SUM and the HPC was shown when SUM spiking became HPC theta phase-modulated particularly before choice points in a continuous alternation task (Ito et al., 2018). Specifically, SUM cells became aligned to the later phases of the CA1 theta cycle, and SUM spiking began close to the time of firing by CA1 interneurons. In the same study, the SUM was demonstrated to be a critical coordinator of communication within the HPC-mPFC-nu. reuniens memory circuit. Thus, it was suggested that the SUM (and by extension, the LHb) dynamically coordinates HPC-related memory circuits by varying spiking relative to HPC theta (Ito et al., 2018).

Not only does the SUM regulate intra- and extra-HPC information processing, but recently it was elegantly demonstrated that the SUM may provide and/or facilitate specific types of information processing in the HPC via its distinct direct inputs to the dentate gyrus and region CA2 (Vertes and McKenna, 2000). The SUM to dentate gyrus input may signal contextual novelty while the SUM to CA2 input may signal social novelty (Chen S. et al., 2020). Thus, the SUM appears to be not only involved in the generation of the HPC theta, but it is also important for gating contextual and social information processing within the HPC. Further, SUM enables HPC to communicate with partnered mnemonic structures such as the mPFC and the nu. reuniens. Given the multiple ways that the SUM impacts HPC processing, it is not surprising that lesion or reversible inactivation of the SUM has been shown to impair different types of HPC-dependent behaviors as shown in spatial working memory and certain avoidance tasks (Shahidi et al., 2004a, b; Aranda et al., 2006, 2008), and to be activated during times of stress (Wirtshafter et al., 1998; Ito et al., 2009; Choi et al., 2012). Given the strong input from the LHb to the SUM (Kiss et al., 2002), the SUM is a strong candidate for linking functions of the LHb and HPC (as noted by Goutagny et al., 2013). Here we hypothesize more specifically that the theta-rhythmic firing of SUM neurons may be regulated by LHb behavioral/movement state signals, and in this way, LHb output can generate the conditions needed for animals to flexibly respond to changes in task conditions.

The median raphe (MR) has long been studied for its role in emotion and stress regulation (e.g., Graeff et al., 1996; Andrade et al., 2013). Recently (Baker et al., 2015), it was suggested that the MR may also play a critical role in the coordination of communication between the LHb and HPC since the MR receives strong input from the LHb (Quina et al., 2015; Metzger et al., 2017), the MR has strong projections to a broad extent of the HPC (Azmitia and Segal, 1978; Vertes et al., 1999) and the MR has been shown to significantly impact HPC-dependent behaviors and theta/ripple oscillations (Vertes and Kocsis, 1997; Wang et al., 2015) Thus, the MR is strategically situated to at least assist in the transformation of LHb signals to regulate HPC theta in a manner that facilitates response flexibility. Indeed, a link between serotonergic function and response flexibility is often discussed given the numerous studies that report alterations of serotonin receptors or neurotransmitter release results in difficulties performing classic response flexibility tasks such as set-shifting and strategy shifting (excellent reviews include Nilsson et al., 2015; Alvarez et al., 2021).

The locus coeruleus (LC) is another hindbrain structure that (in anesthetized and awake rats) is known to project to HPC to impact theta and gamma oscillations (Gray et al., 1975; Walling et al., 2011; Broncel et al., 2021), and to receive at least modest input from the LHb (Mathis et al., 2021). As reviewed by Sara (2009) and Poe et al. (2020), LC neural firing has long been observed to occur in response to novelty, to signal-mismatches events, and to attentional shifts (Aston-Jones and Bloom, 1981a, b; Aston-Jones et al., 1991; Sara and Segal, 1991; Hervè-Minivielle and Sara, 1995; Bouret and Sara, 2005). Our cumulative understanding of the broad impact of the LC across many brain regions as well as the diverse cell types and patterns of LC neural activity have led to theories that especially phasic LC activity enhances the execution of actions in response to unexpected stimuli (Aston-Jones and Cohen, 2005). LC activation, then, effectively resets neural networks to enable rapid switches of cognitive representations or response strategies when needed (Sara and Bouret, 2012). These types of LC responses appear necessary for animals to exhibit adaptive behaviors (Yu and Dayan, 2005). Thus, in addition to the NI, SUM, and MR, the LC is a strong region of interest for its putative role in transmitting LHb signals to the HPC by establishing an HPC theta state that supports response and cognitive flexibility (Figure 2).

Based on our extant knowledge and theories about how the LHb contributes to response flexibility, an important and fundamental question arises: How does one reconcile findings that the LHb signals short duration aversive events (Matsumoto and Hikosaka, 2007), while also signaling longer-duration behavioral/movement states (Baker et al., 2015). One explanation is that while LHb broadly tracks the current sensory/behavioral situation, LHb neurons exhibit different patterns of firing depending on the types of information being tracked. LHb neurons may fire phasically to single, short-duration events such as sensory stimuli or a particular goal outcome, or they may fire tonically during longer-duration behavioral state conditions such as movement through space. This sort of dual-coding is not uncommon in the brain. One example is that the same VTA dopamine neurons fire phasically to rewards, and tonically when moving through space (e.g., Puryear et al., 2010; Jo et al., 2013). Either short- or long-duration firing could impact response flexibility that is enabled by the LHb efferent structures described earlier. For example, encountering an unexpected reward should result in phasic LHb cell firing, which would signal efferent structures to increase HPC theta to resolve a potential conflict between expected and actual context features (Mizumori et al., 1999). When tracking sensory/behavioral information across this relatively short period, the LHb may be serving as a brake signal to halt the initiation of potential inappropriate behaviors thereby allowing other adaptive behaviors to commence (Sleezer et al., 2021). When faced with other aversive situations, LHb output may instead result in the engagement of avoidance behaviors. In either case, LHb activity is considered critical during flexible action selection.

By comparison, tonic LHb neural activity for example during spatially-extended navigation, should signal hindbrain regions to elevate HPC theta for the duration of the translocation in space. Such signaling is postulated (see above) to enable the timely enhancement of neuroplasticity mechanisms needed to evaluate the current context so that memories can be updated in preparation for a future decision. That is, LHb-induced HPC theta may result in greater attention and arousal, along with a stronger neuroplasticity state that provides the basis for more efficient and timely context evaluation. Such context analysis is considered essential in order to then execute adaptive and flexible responses in the future. During real world navigation, the LHb engages in both short (sensory) and intermediate-term (during navigation) behavioral monitoring in the same context as evidenced by LHb neurons that show both reward and velocity-related neural codes (Baker et al., 2015). Such dual time frame coding may not be needed in Pavlovian or operant tasks that do not require animals to move about in a spatially-extended environment, but rather they only require information to be associated over relatively short time scales. Thus, assessing LHb in navigating animals may reveal an extended complement of potential contributions to adaptive responding.

In sum, we propose a) that the LHb contributes to response flexibility by tracking behavior across short (in the tens of ms to seconds range) and intermediate (in the range of seconds to hours or more) time frames. Prolonged disturbances of function in either of these time domains can result in different behavioral disorders and psychopathologies.

LHb responses to short-term aversive or appetitive stimuli are necessary for proper adaptive behavior and do not typically result in behavioral maladaptations (Baker et al., 2015). As shown in many of the experiments described previously, inaccurate stimulus coding results in suboptimal decisions. If LHb encoding of behavioral and movement states are deficient, one would expect impaired and inappropriate activation of HPC theta, which could lead to memory deficits. We also know, based on extensive research on the role of LHb in processing aversive information, the LHb plays a substantial role in fear memories. For instance, in the case of fear conditioning, it is important to learn the association between a specific context and the potential threat. In aversive situations, not only does the LHb respond to the aversive stimulus, but also to the cue predicting the onset of the aversive stimulus (Lecca et al., 2017; Lazaridis et al., 2019; Trusel et al., 2019). It takes merely five trials in order for short-scale synaptic changes to occur in the LHb, likely between the LHb and the RMTg (Wang et al., 2017). Also, inactivation of the LHb following fear conditioning of a context resulted in context memory impairments (Durieux et al., 2020). Furthermore, in the same experiment, the c-fos expression following fear conditioning increased in the HPC, mPFC, as well as the LHb, suggesting an involvement of this circuit in contextual fear memories. Thus, in situations when the LHb does not appropriately function over periods of seconds to minutes to hours, one sees impaired decision making and poor context memory.

Extended and hyperactive LHb aversive signaling can lead to long-lasting plasticity-related changes, resulting in psychiatric disorders such as depression, schizophrenia, and addiction (Metzger et al., 2021). In support of this theory, studies have shown that cocaine exposure induces increased AMPA receptor expression in excitatory LHb neurons, causing long-term potentiation and hyperexcitability (Maroteaux and Mameli, 2012). Similarly, prolonged exposure to an aversive stimulus, such as a foot shock, results in decreased GABAb receptor expression in excitatory LHb neurons, leading to disinhibition and hyperexcitability of LHb neurons (Lecca et al., 2016). Along with synaptic changes, stress and other environmental factors can induce changes in LHb gene expression (Levinstein et al., 2020). Specifically, expression of genes implicated in the RMTg, and not VTA or DRN, pathway is increased in the LHb following stress. These genetic changes alter the strength of the connections between the LHb and downstream structures, resulting in long-lasting changes in plasticity.

Excessive LHb activity can also lead to impaired motivated behavior and result in the pathophysiology of depression. In fact, the LHb is the only brain region that exhibits consistent hyperactivity in depression (Caldecott-Hazard et al., 1988; Andalman et al., 2019). One of the pathways implicated in the expression of depression-like symptoms is the LHb-RMTg pathway that inhibits dopaminergic activity in the VTA and other structures (Proulx et al., 2018). Another pathway underlying this disorder is the LHb’s increased excitation of raphe inhibitory interneuron-based inhibition of serotonergic neurons, which causes a passive coping transition, a marker of depression (Amat et al., 2001; Andalman et al., 2019; Coffey et al., 2020). Ketamine, a common antidepressant medication, has been shown to elevate raphe activity in addition to decreasing the hyperactivity of the LHb, consistent with the role of this pathway in depression (Cui et al., 2018; Yang et al., 2018; López-Gil et al., 2019).

Maladaptive activity in the PFC is frequently tied to the phenotype of schizophrenia (Weinberger et al., 2001). Specifically, the established dopamine hypothesis of schizophrenia posits that schizophrenia arises as a result of dopaminergic hyperactivity in subcortical areas due to cortical dysfunction (Winterer and Weinberger, 2004). In a rat model of schizophrenia, Li et al. (2019) found that there was significant hypofunctionality in the LHb, potentially disinhibiting subcortical dopamine activity. In the same experiment, lesioning the LHb of schizophrenic rats resulted in a significant decrease in cortical activity. Interestingly, functional connectivity between the habenula and cortex increases in schizophrenic patients, suggesting that the habenula may be contributing to the cortical dysfunction seen in schizophrenia (Zhang et al., 2017). Moreover, serotonergic activity in the DRN increases in the pathophysiological profile of schizophrenia. Typically, in healthy brains, the LHb functions to inhibit serotonergic activity in the DRN. However, in schizophrenia, LHb activity is hypoactive, disinhibiting serotonergic activity in the DRN. When the LHb is lesioned in schizophrenic rats, serotonin levels in the DRN, as well as in the mPFC, increased (Li et al., 2019). Owing to these findings, hypofunction in the LHb may contribute to the pathophysiology of schizophrenia.

Likely as a consequence of its critical role in reward valuation and processing, the LHb plays a large role in addiction. Repeated drug exposure results in addiction, or excessive drug-seeking behavior, and is tied to increases in LHb activity (Zhang et al., 2005). Although the LHb processes both aversive and rewarding properties of stimuli (Matsumoto and Hikosaka, 2009b), it appears that the LHb primarily responds to the aversive properties of drug exposure (Zhang et al., 2013). In particular, LHb activity is thought to underlie the negative effects of drug-seeking behavior through its projection to the RMTg (Meye et al., 2015). In support of this finding, Maroteaux and Mameli (2012) showed that cocaine exposure results in increased AMPA receptor expression in LHb neurons selectively projecting to the RMTg. Lastly, chronic drug exposure causes neurodegeneration in the main output fiber bundle of the LHb, the fasciculus retroflexus, disrupting the LHb’s communication with and modulation of downstream monoaminergic structures (Lax et al., 2013).

Reasoning that long-term LHb function underlies maladaptive behavior, clinicians recently target the LHb in an attempt to correct LHb dysfunction as a therapeutic approach. Deep brain stimulation (DBS) of the LHb has been one such therapeutic procedure that is producing encouraging results (Sartorius et al., 2010). Interestingly, DBS frequency parameters exhibit differential therapeutic outcomes in distinct disorders such as depression and addiction (Ferraro et al., 1996). For an in-depth discussion of DBS in the LHb, see the excellent review by Germann et al. (2021). Relatedly, ketamine has proven to be a successful therapeutic treatment that inhibits the LHb and disinhibits reward centers such as dopamine and serotonin (Yang et al., 2018).

Another emerging therapeutic approach for the development of treatments for LHb-related psychopathology focuses on the serotonergic system. Evidence suggests that serotonergic dysfunction results in the inability to adapt to changing environmental conditions, as seen in depression and addiction. Interestingly, the effects of serotonin depletion or overexpression do not always resemble one another across studies. For instance, Lapiz-Bluhm et al. (2009) showed that chronically stressed rats that were serotonin-depleted using para-chlorophenylalanine showed significant deficits in reversal learning which was rescued with a serotonin reuptake inhibitor. In a separate study, humans were exposed to a rapid tryptophan depletion paradigm on a reversal-learning task and exhibited slightly improved decision-making (Talbot et al., 2006). Such discrepancy in the literature may be attributed to inter-species differences, as well as the reliability of the drug cocktail protocol. Recent evidence has exposed distinct functions of serotonin subtypes as the main culprit (Alvarez et al., 2021). Importantly, Morris et al. (1999) showed that selective serotonin depletion causes significant increases in LHb activity, mimicking the neural correlate of depression, compared to other structures. Furthermore, tryptophan depletion causes a significant impairment in context memory in mice, implicating the serotonergic system in both motivation and context memory (Uchida et al., 2007). Serotonin 2A receptors subtype has been extensively studied in relation to its influence on behavioral flexibility. A selective serotonin 2A receptor blockade significantly impaired performance on a spatial reversal learning task (Boulougouris et al., 2008). In the same study, a selective serotonin 2C receptor blockade improved performance on a spatial reversal learning task. Interestingly, serotonin 2C and serotonin 2A receptors are found on GABAergic dorsal raphe neurons (Serrats et al., 2005). Psilocybin, being studied as an antidepressant, is a strong serotonin 2A receptor agonist and serotonin 2A receptors are highly expressed in the LHb. This raises the question as to whether psilocybin has modulatory effects on LHb activity. Indeed, activation of serotonin 2A receptors inhibits excitatory LHb neurons, likely through the facilitation of GABAergic transmission, suggesting that psilocybin mimics a neuromodulator and works to rescue LHb dysfunction (Figure 3; Shabel et al., 2012; Metzger et al., 2017). In support of this, psilocybin administration has proven effective in drug-resistant depression (Carhart-Harris et al., 2018), and addiction (Johnson et al., 2014). Whether the therapeutic effects of psilocybin result from the direct action on LHb activity, however, is not yet clear and is in need of further study.

The diversity of LHb inputs from cortical and subcortical areas makes the LHb a prime region for integrating information related to context memory and motivation. Likewise, the LHb’s downstream control of monoaminergic centers, as well as the HPC, implicates it in a number of psychiatric disorders, such as those described above. The reviewed data provide a compelling argument that the LHb should be one of the primary targets of therapeutic intervention, such as with psilocybin, for psychiatric disorders that manifest in context memory, motivational impairments, and certain disorders of behavioral control.