Tonic activity in lateral habenula neurons acts as a neutral valence brake on reward-seeking behavior

Post, Ryan J; Bulkin, David A.; Ebitz, R. Becket; Lee, Vladlena; Han, Kasey J; Warden, Melissa R.

doi:10.1016/j.cub.2022.08.016

Cited by 7 publications

(3 citation statements)

References 115 publications

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“…This aspect of DA release was not mirrored in the tonic firing of identified lateral VTA DA neurons (Mohebi et al 2019). However, prolonged states of reward expectation can be reflected in the tonic firing of other cell populations, including in lateral habenula (Post et al, 2022) and dorsal raphe (Cohen et al, 2015). We therefore examined whether reward expectation changes the tonic firing of CINs, as this could conceivably be responsible for the relationship between VS DA and reward rate.…”

Section: Resultsmentioning

confidence: 99%

A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors

Duhne,

Mohebi,

Kim

et al. 2024

Preprint

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Movement, motivation and reward-related learning depend strongly on striatal dopamine and acetylcholine. These neuromodulators each regulate the other, and disturbances to their coordinated signals contribute to human disorders ranging from Parkinson's Disease to depression and addiction. Pauses in the firing of cholinergic interneurons (CINs) are thought to coincide with pulses in dopamine release that encode reward prediction errors (RPEs), together shaping synaptic plasticity and thereby learning. However, such models are based upon recordings from unidentified neurons, and do not incorporate the distinct characteristics of striatal subregions. Here we compare the firing of identified, individual CINs to dopamine release as unrestrained rats performed a probabilistic decision-making task. The relationships between CIN spiking, dopamine release, and behavior varied strongly by subregion. In dorsal-lateral striatum a Go! cue evoked burst-pause CIN spiking, quickly followed by a very brief (~150ms) dopamine pulse that was unrelated to RPE. In dorsal-medial striatum the same cue evoked only a CIN pause; this pause was curtailed by a movement-selective rebound in firing. Finally in ventral striatum a reward cue evoked slower, RPE-coding increases in both dopamine and CIN firing, without any distinct pause. Our results demonstrate a spatial and temporal dissociation between CIN pauses and dopamine RPE signals, and will inform new models of striatal microcircuits and their contributions to behavior.

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Section: Resultsmentioning

confidence: 99%

A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors

Duhne,

Mohebi,

Kim

et al. 2024

Preprint

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“…To measure the effect of optogenetic stimulation on task engagement, we used a previously described nose poke-reward association task 3 . After three days of water restriction, mice with expression of an optogenetic opsin (ChR2, stGtACR2 or eNpHR3.0) or tdTomato (control) were trained to enter their nose into a nose-poke port on one wall of a custom-made operant chamber (25 cm × 20 cm × 30 cm (l × w × h); in a sound-attenuating box) in order to receive a water reward from a lick spout on the wall opposite to the nose-poke port.…”

Section: Methodsmentioning

confidence: 99%

A subcortical switchboard for exploratory, exploitatory, and disengaged states

Ahmadlou,

Shirazi,

Zhang

et al. 2023

Preprint

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To survive in evolving environments with uncertain resources, animals need to dynamically adapt their behavior and exhibit flexibility in choosing appropriate behavioral strategies, for example, to exploit familiar choices, to explore and acquire novel information, or to disengage altogether. Previous studies have mainly investigated how forebrain regions represent choice costs and values as well as optimal decision strategies during explore/exploit trade-offs. However, the neural mechanisms by which the brain implements alternative behavioral strategies such as exploiting, exploring or disengaging from the environment, remains poorly understood. Here we identify a neural hub critical for flexible switching between behavioral strategies, the median raphe nucleus (MRN). Using cell-type specific optogenetic manipulations, calcium fiber photometry and circuit tracing in mice performing diverse instinctive and learnt behavioral tasks, we found that the MRN’s main cell types, GABAergic, glutamatergic (VGluT2-positive), and serotonergic neurons, have complementary functions and drive exploitation, exploration and disengagement, respectively. Suppression of MRN GABAergic neurons, for instance through inhibitory input from lateral hypothalamus which conveys strong positive valence to the MRN, leads to perseverance in current actions and goals, and thus promotes exploitatory behavior. In contrast, activation of MRN VGluT2+ neurons drives exploratory behavior. Activity of serotonergic MRN neurons is necessary for general task engagement. Input from the lateral habenula conveying negative valence suppresses serotonergic MRN neurons, leading to disengagement. These findings establish the MRN as a central behavioral switchboard, uniquely positioned to flexibly control behavioral strategies. These circuits thus may also play an important role in the etiology and possible treatment of major mental pathologies such as depressive or obsessive-compulsive disorders.

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“…LHb neurons inhibit VTA dopamine neurons 35,[76][77][78][79][80][81] , and the two populations are thought to have roughly opposite response profiles and functions 32,35 . Consistent with these opposing roles, activation of NAc-projecting DA neurons during defeat biases towards resilience 26 , whereas here we show activation of LHb neurons during defeat biases towards susceptibility (Figure 5).…”

Section: Separate Roles For Lhb and Vta Dopamine During Defeat In The...mentioning

confidence: 99%

Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility

Zhukovskaya,

Christopher,

Willmore

et al. 2023

Preprint

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Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between stress susceptible and resilient mice during stress to produce different outcomes. After but not before chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and stimulation of the LHb during stress biases mice towards susceptibility. This stimulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity that closely mimics the brainwide correlates of susceptibility. Taken together, our results indicate that a stronger aversive teaching signal in the LHb during stress produces brainwide and behavioral substrates of susceptibility.

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Tonic activity in lateral habenula neurons acts as a neutral valence brake on reward-seeking behavior

Cited by 7 publications

References 115 publications

A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors

A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors

A subcortical switchboard for exploratory, exploitatory, and disengaged states

Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility

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