Dopamine in the ventral and dorsal striatum shapes reward-related behaviors (Markowitz et al., 2023; de Jong et al., 2022; Yang et al., 2018; Keiflin and Janak, 2015; Tsai et al., 2009); its dysregulation has been associated with several psychiatric disorders, including addiction (Lüscher and Janak, 2021; Lüscher et al., 2020; Pascoli et al., 2023) and depression (Nestler and Carlezon, 2006; Krishnan et al., 2007; Deguchi et al., 2016). It is known that rewarding stimuli evoke dopamine transients both in the ventral (Kim et al., 2020; Patriarchi et al., 2018) and dorsal striatum Howe et al., 2013, and that the stimulation of dopaminergic neurons (Harada et al., 2021; Pascoli et al., 2018) or terminals (Yang et al., 2018) in the striatum is sufficient to trigger operant or Pavlovian conditioning (Saunders et al., 2018), as well as conditioned place preference. Instead, aversive stimuli or omission of expected reward delivery cause a decrease in dopamine in the ventral striatum, resulting in negative reinforcement learning (Tan et al., 2012; van Zessen et al., 2012) via D2 receptors (Iino et al., 2020; Lüscher and Pascoli, 2021).

Although the role of the dopaminergic projections to the striatum or mesolimbic dopamine pathway has been investigated extensively (Kim et al., 2020; Cohen et al., 2012) – their role in encoding reward prediction errors (RPEs) in particular has been a point of focus (Kim et al., 2020; Schultz et al., 1997) – the role of dopamine in other brain regions is relatively understudied (Hasegawa et al., 2022; Vander Weele et al., 2018; Gyawali et al., 2023; Chen et al., 2014). The lateral hypothalamus (LH) plays a pivotal role in reward-seeking behavior (Gibson et al., 2018; Harris et al., 2005; Otis et al., 2019; Sharpe et al., 2017; James et al., 2019) and feeding (O’Connor et al., 2015; Jennings et al., 2015; Jennings et al., 2013; Marino et al., 2020), and several dopamine receptors are reported to be expressed in the LH (Yang et al., 2019). The mechanism through which dopamine modulates neuronal activity in the LH, resulting in the modulation of behaviors, has not been established. To the best of our knowledge, there have been no measurements of dopamine transients in the LH during reward-associated behaviors.

The LH is a heterogeneous structure containing glutamatergic and GABAergic neurons, as well as several neuropeptidergic neurons, such as melanin-concentrating hormone-positive and orexin-positive neurons (Mickelsen et al., 2019; González et al., 2016a). Like dopamine, orexins (also known as hypocretins) are reported to play a pivotal role in reward-seeking behavior (Harris et al., 2005; Borgland et al., 2006; Bubser et al., 2005). Orexinergic and dopaminergic systems are known to have reciprocal connections with each other, and some orexinergic neurons project to dopaminergic neurons in the ventral tegmental area (VTA), positively modulating their activity (Thomas et al., 2022; Baimel et al., 2017). While there has been extensive investigation into how dopamine modulates orexinergic neuronal activity ex vivo (i.e., acute brain slices) (Yamanaka et al., 2006; Li and van den Pol, 2005; Linehan et al., 2015; Linehan et al., 2019), it remains unclear whether and how dopamine transients modulate orexin neuronal activity in vivo (Linehan et al., 2019). Advancements in optical tools, such as optogenetics for manipulating dopamine neurons and genetically encoded dopamine sensors for monitoring dopamine transients, have made it possible to precisely control and observe the dynamics of dopamine in neural systems (Patriarchi et al., 2018; Feng et al., 2019; Sun et al., 2020; Zhuo et al., 2023; Wu et al., 2022; Patriarchi et al., 2020). Here, we implemented an ‘opto-Pavlovian task’ (Saunders et al., 2018), in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation. Using this task we measured dopamine transients in the nucleus accumbens (NAc), finding that dopamine activity patterns are consistent with previous reports of RPE-encoding dopaminergic neuron activity (Cohen et al., 2012). Using the same paradigm, we found that optical stimulation of dopaminergic neurons in the VTA evokes an increase in extrasynaptic dopamine in the LH, where the delivery of a cue preceding a reward also triggers dopamine transients in a way that is consistent with RPEs (Schultz et al., 1997). Furthermore, we investigated the regulation of LH orexinergic neurons by VTA dopaminergic neurons and observed a dopamine transient in the LH and an increase in orexinergic neuronal activity during both predictive cue and the delivery of laser stimulation, indicating that the concentration of extrasynaptic dopamine in the LH and orexinergic neuronal activity are positively correlated. Finally, by stimulating dopaminergic terminals in the LH combined with pharmacological intervention, we found that dopamine in the LH positively modulates orexinergic neurons via the type 2 dopamine receptor (D2).

Overall, our study sheds light on the meso-hypothalamic dopaminergic pathway and its impact on orexinergic neurons.

The mesolimbic dopamine system has been proposed to encode RPEs (Kim et al., 2020; Cohen et al., 2012; Schultz et al., 1997), which signal a discrepancy between expected and experienced rewards. Recently, it has been demonstrated that the optical stimulation of midbrain dopamine neurons is sufficient to create Pavlovian conditioning (Saunders et al., 2018). While it is known that cells within the LH express several different dopamine receptor subtypes (Yang et al., 2019), and microinjection of D1 and D2 receptor agonists have been shown to decrease food intake in rodents (Yonemochi et al., 2019), before our study, dopamine transients in the LH during reward-associated tasks had not been reported. Here, we used an opto-Pavlovian task that echoed, with NAc dopamine measurements, already reported findings on the midbrain dopamine neurons’ RPE-encoding role (Saunders et al., 2018). Then, we determined that VTA dopaminergic neurons release dopamine in the LH and found that dopamine transients in the LH in response to the same opto-Pavlovian task were qualitatively similar to those observed in the mesolimbic dopamine system.

Recent findings suggest that dopaminergic transients in the dorsal bed nucleus of the stria terminalis encode RPE (Gyawali et al., 2023), indicating qualitative similarities in dopamine activity within this brain region compared to what we observed in the LH and NAc. Conversely, dopamine responses in other brain regions, such as the medial prefrontal cortex (Vander Weele et al., 2018; Verharen et al., 2020) and amygdala (Zhuo et al., 2023; Lutas et al., 2019), predominantly react to aversive stimuli. Furthermore, we have found that dopamine in the LH also encodes RPE. However, the specific response of dopamine in the LH to aversive stimuli has not been fully explored, despite existing reports of significant orexinergic activity in response to such stimuli (Yamashita et al., 2021). This gap highlights the need for a detailed examination of how dopamine behaves in the LH when faced with aversive stimuli.

Indeed, during the opto-Pavlovian task, in which we stimulated VTA dopamine neurons and measured dopamine, we observed dopamine transients around a Pavlovian laser-paired cue presentation. We also observed a dip in dLight signal during omission trials, suggesting that a detectable concentration of dopamine is at extrasynaptic space in the LH at basal condition and that at the moment of omission the concentration of extrasynaptic dopamine decreases. These data indicate that dopamine transients in the LH, as in the NAc, could be encoding RPE.

While smaller than the response to the laser-paired cue, we observed modulation of the dLight signal in the NAc during the presentation of the non-laser-paired cue. In session 1, the cue presentation immediately triggered a dip, whereas in session 10, it evoked a slight increase in the signal, followed by a dip. Our hypothesis suggests that two components contribute to the dip in the signal. The first is the aversiveness of the cue; the relatively loud sound (90 dB) used for the cue could be mildly aversive to the experimental animals. Previous studies have shown that aversive stimuli induce a dip in dopamine levels in the NAc, although this effect varies across subregions (Yang et al., 2018; Verharen et al., 2020). The second component is related to RPE. While the non-laser-paired cue never elicited the laser stimulation, it shares similarities with the laser-paired cue in terms of a loud tone and the same color of the visual cue (albeit spatially different). We posit that it is possible that the reward-related neuronal circuit was slightly activated by the non-laser-paired cue. Indeed, a small increase in the signal was observed on day 10 but not on day 1. If our hypothesis holds true, as this signal is induced by two components, further analysis unfortunately becomes challenging.

While dopaminergic transients in the NAc and LH share qualitative similarities, the kinetics of dopamine differs between these two brain regions. Under optical stimulation, the dLight signal in the NAc exhibited a continuous increase, never reaching a plateau until the laser was turned off. In contrast, in the LH, the dLight signal reached a plateau shortly after the initiation of the laser stimulation. The distinction in dopamine kinetics was also evident during omission trials, where the dopamine kinetics in the LH were faster than those in the NAc. The molecular mechanisms underlying this difference in kinetics and its impact on behavior remain to be elucidated. Due to this kinetic difference, we employed distinct time windows to capture the dip in the dLight signal during omission trials.

Previous work indicates that orexin neurons project to VTA dopamine neurons (Borgland et al., 2006; Thomas et al., 2022; Baimel et al., 2017), facilitating dopamine release in the NAc and promoting reward-seeking behavior. However, while it has been demonstrated that systemic injection of dopamine receptor agonists activates orexin neurons (Bubser et al., 2005), their reciprocal connection with dopaminergic neurons had not yet been investigated in vivo (Linehan et al., 2019). Here, we studied the relationship between orexinergic and dopaminergic activity in the LH and found that LH dopamine transients and orexinergic neuronal activities are positively correlated. Seeing as dopamine-related orexinergic activity was reduced by systemic injections of raclopride, we postulate that dopamine in the LH activates orexin neurons via D2R. D2R couples to Gi proteins (Ford, 2014), so it is unlikely that dopamine directly activates orexin neurons. Our testable hypothesis is that dopamine modulates orexin neuron activation via a disinhibitory mechanism; for example, GABA interneurons could be inhibited by the activation of D2R, consequently disinhibiting orexin neurons (Ferrari et al., 2018; Burt et al., 2011). It has been established that D1 receptor expressing medium spiny neurons (D1-MSNs) in the NAc densely project to the LH, especially to GABAergic neurons (O’Connor et al., 2015; Thoeni et al., 2020), raising a possibility that dopamine in the LH modulates the presynaptic terminals of D1-MSNs. However, administration of D1R antagonist (SCH 23390) did not block the calcium transient in orexin neurons evoked by the dopaminergic terminal stimulation in the LH, implying that the contribution of D1-MSNs to orexin neuronal activity is minimal in our experimental design. While systemic injections of raclopride effectively reduced dopaminergic terminal stimulation-evoked orexinergic activity, the long-lasting calcium signal remained unaltered (Figure 6E). This discrepancy could arise from an insufficient blockade of dopamine receptors. For D1R blockade, we administered 1 mg/kg of SCH-23390 5 min before recordings. This dose is adequate to induce behavioral phenotypes (Womer et al., 1994) and block D1R-based dopamine sensors (Patriarchi et al., 2018), although higher doses have been used in some studies (Zhuo et al., 2023). To block D2R, we injected 1 mg/kg of raclopride, a dose known to induce hypo-locomotion (Simón et al., 2000), indicating effective modification of the neuronal circuit. However, these data do not guarantee complete receptor blockade, and it is possible that optical stimulation resulted in high extrasynaptic dopamine concentration, leading to partial receptor binding. Alternatively, this component might be mediated by other neurotransmitters, such as glutamate (Mingote et al., 2017; Zell et al., 2020; Dal Bo et al., 2004) or GABA (Melani and Tritsch, 2022), which are known to be co-released from dopaminergic terminals.

Several ex vivo experiments suggest that dopamine, particularly at high concentrations (50 μM or higher), reduces the firing rate of orexin neurons, albeit with a potency significantly lower than that of norepinephrine (Yamanaka et al., 2006; Li and van den Pol, 2005) through both direct and indirect mechanisms (Linehan et al., 2015; Linehan et al., 2019). This apparent discrepancy with our results could be attributed to a different time course of dopamine transients. In slice experiments, the concentration of exogenous dopamine or dopamine agonists is determined by the experimenter and often maintained at high levels for minutes. In contrast, in our experimental setup, dopamine evoked by laser stimulation is degraded/reuptaken as soon as the laser is turned off. This variation in the time course of dopamine transients could contribute to the observed differences in responses to dopamine. Another plausible explanation for this discrepancy is the difference in dopamine concentration. Modulations of synaptic transmission to orexinergic neurons by dopamine are reported to be concentration-dependent (Linehan et al., 2015). Despite the brightness of the genetically encoded dopamine sensor following a sigmoidal curve in response to changes in dopamine concentration (Patriarchi et al., 2018), estimating dopamine concentration in vivo based on the sensor’s brightness is not technically feasible. Therefore, it is challenging to determine the exact dopamine concentration achieved by laser stimulation, and it is possible that this concentration differs from the one that triggers the reduction in the firing rate of orexin neurons.

Although presentation of laser-paired cue and laser stimulation of VTA dopamine neurons evoked dopamine transient in the LH and an increase in calcium signals of orexin neurons, we did not observe a dip in calcium signal of orexin neurons during omission trials. This lack of a dip could be due to (1) slow sensor kinetics (Zhang et al., 2023) – since the pre-omission cue triggers LH dopamine release, and increases the calcium transient in orexin neurons, if the kinetics of GCaMP6s expressed in orexin neurons were too slow, we would not be able to observe an omission-related orexin activity dip – and (2) dopamine signaling properties. Dopamine receptors couple to G proteins (Baik, 2013), which act relatively slowly, potentially preventing us from seeing an omission-related signaling dip. Both theories are compatible with our observation that orexinergic activity increases over time during the presentation of our laser-paired cue, as our observed increases are not sporadic but developed over time. Recent studies indicate that orexin neurons respond to cues associated with reward delivery. However, unlike dopaminergic responses, which linearly correlate with the probability of reward delivery, the orexin response plateaus at around 50% probability of reward delivery (Bracey et al., 2022). This observation indicates that orexin neurons encode multiplexed cognitive information rather than merely signaling RPE. Our data indicate a direct conveyance of dopaminergic information, specifically RPE, to orexinergic neurons. However, the mechanism by which orexinergic neurons process and convey this information to downstream pathways remains an open question.

The silencing of orexinergic neurons induces conditioned place preference (Garau et al., 2020), suggesting that the silencing of orexin neurons is positively reinforcing. Considering that the stimulation of VTA dopamine neurons (Harada et al., 2021; Pascoli et al., 2018) and dopaminergic terminals in the LH (Hoang et al., 2023) is generally considered to be positively reinforcing, the activation of orexin neurons by dopaminergic activity might be competing with dopamine’s own positive reinforcing effect. At the moment of omission, we observed a dopamine dip both in the NAc and LH, while orexin neurons were still activated. These data suggest that there is a dissociation between dopamine concentration and orexin neuronal activity at the moment of omission. This raises the intriguing possibility that this dissociation – the activation of orexin neurons during a quiet state of dopamine neurons – could be highly aversive to the mice, therefore could be playing a role in negative reinforcement (Iino et al., 2020; Cohen et al., 2012; González et al., 2016a).

It has been demonstrated that the orexin system plays a critical role in motivated learning (Sakurai, 2014). Blocking orexin receptors impairs Pavlovian conditioning (Keefer et al., 2016), operant behavior (Sharf et al., 2010), and synaptic plasticity induced by cocaine administration (Borgland et al., 2006). Additionally, dopamine in the LH is essential for model-based learning, and the stimulation of dopaminergic terminals in the LH is sufficient to trigger reinforcement learning (Hoang et al., 2023). These collective findings strongly suggest that the activation of orexin neurons, evoked by dopamine transients, is crucial for reinforcement learning. Our data indicate that dopamine in both the NAc and LH encodes RPE. One open question is the existence of such a redundant mechanism. We hypothesize that dopamine in the LH boosts dopamine release via a positive feedback loop between the orexin and dopamine systems. It has already been established that some orexin neurons project to dopaminergic neurons in the VTA, positively modulating firing (Thomas et al., 2022). On the other hand, our data indicate that dopamine in the LH stimulates orexinergic neurons. These collective findings suggest that when either the orexin or dopamine system is activated, the other system is also activated consequently, followed by further activation of those systems. Although the current findings align with this idea, the hypothesis should be carefully challenged and scrutinized.

In summary, by implementing an opto-Pavlovian task combined with fiber photometry recordings, we found evidence that the meso-hypothalamic dopamine system exhibits features qualitatively similar to those observed in the mesolimbic dopamine system – where dopamine is thought to encode RPEs. Furthermore, our findings show that dopamine in the LH positively modulates the neuronal activities of orexin neurons via D2 receptors. These findings give us new insights into the reciprocal connections between the orexin and dopamine systems and shed light on the previously overlooked direction of dopamine to orexin signaling, which might be key for understanding negative reinforcement and its dysregulation.

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 1, 2, 3, 4, 5, 6.

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Author details

1. Masaya Harada

   Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2958-2772

2. Laia Serratosa Capdevila

   Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

   Contribution

   Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

3. Maria Wilhelm

   Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

   Contribution

   Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

4. Denis Burdakov

   1. Neuroscience Center Zürich, University and ETH Zürich, Zürich, Switzerland
   2. Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland

   Contribution

   Resources, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

5. Tommaso Patriarchi

   1. Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
   2. Neuroscience Center Zürich, University and ETH Zürich, Zürich, Switzerland

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Visualization, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   patriarchi@pharma.uzh.ch

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9351-3734

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