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All Publications

  • Cholinergic modulation of dopamine release drives effortful behaviour. Nature Touponse, G. C., Pomrenze, M. B., Yassine, T., Denomme, N., Wang, M., Mehta, V., Zhang, Z., Malenka, R. C., Eshel, N. 2026

    Abstract

    Effort is costly: given a choice, we tend to avoid it1. However, in many cases, effort adds value to the ensuing rewards2. From ants3 to humans4, individuals prefer rewards that had been harder to achieve. This counterintuitive process may promote reward seeking even in resource-poor environments, thus enhancing evolutionary fitness5. Despite its ubiquity, the neural mechanisms supporting this behavioural effect are poorly understood. Here we show that effort amplifies the dopamine response to an otherwise identical reward, and this amplification depends on local modulation of dopamine axons by acetylcholine. High-effort rewards evoke rapid acetylcholine release from local interneurons in the nucleus accumbens. Acetylcholine then binds to nicotinic receptors on dopamine axon terminals to augment dopamine release when reward is delivered. Blocking the cholinergic modulation blunts dopamine release selectively in high-effort contexts, impairing effortful behaviour while leaving low-effort reward consumption intact. These results reconcile in vitro studies, which have long demonstrated that acetylcholine can trigger dopamine release directly through dopamine axons6-11, with in vivo studies that failed to observe such modulation12-14, but did not examine high-effort contexts. Our findings uncover a mechanism that drives effortful behaviour through context-dependent local interactions between acetylcholine and dopamine axons.

    View details for DOI 10.1038/s41586-025-10046-6

    View details for PubMedID 41606339

    View details for PubMedCentralID 6172040

  • Serotonin modulates nucleus accumbens circuits to suppress aggression. bioRxiv : the preprint server for biology Zhang, Z., Touponse, G. C., Alderman, P. J., Yassine, T., Pomrenze, M. B., Harris, T. W., Shank, A. N., Malenka, R. C., Eshel, N. 2025

    Abstract

    Serotonin (5-hydroxytryptamine; 5HT) has long been considered anti-aggressive, but the mechanisms by which 5HT regulates downstream circuits to control aggression remain unclear. Combining fiber photometry, optogenetics, and miniaturized microscope recordings in double-transgenic mice, we find that 5HT levels ramp up in the nucleus accumbens during aggression, inhibiting a subset of D1 medium spiny neurons to suppress attacks. Our results reveal a novel 5HT-mediated neuromodulatory mechanism for limiting aggressive behavior.

    View details for DOI 10.1101/2025.11.26.690732

    View details for PubMedID 41394707

    View details for PubMedCentralID PMC12697279

  • I've got a friend in you: How the brain socializes during opioid withdrawal. Neuron Zhang, Z., Pomrenze, M. B., Eshel, N. 2025; 113 (21): 3498-3500

    Abstract

    Individuals withdrawing from opioids tend to prefer the company of peers who are also withdrawing. In this issue of Neuron, Huo et al.1 reveal that this preference is driven by corticotropin-releasing hormone signaling in the amygdala, uncovering a new mechanism for addiction-related changes in social behavior.

    View details for DOI 10.1016/j.neuron.2025.10.004

    View details for PubMedID 41197607

  • A real-time all-optical interface for dynamic perturbation of neural activity during behavior. Cell reports methods Zhang, Z., Dzialecka, P., Russell, L. E., Ratto, R., Buetfering, C., Gauld, O. M., Selviah, D. R., Häusser, M. 2025: 101180

    Abstract

    We developed a strategy for implementing a dream experiment in systems neuroscience, where circuit manipulation is guided by the real-time readout of neural activity in behaving mice. The system integrates a state-of-the-art calcium imaging analysis package that achieves rapid online activity readout from two-photon calcium imaging, a custom hologram generation program that targets two-photon optogenetic stimulation of specific neuronal ensembles, and software modules that automate essential steps in running complex all-optical experiments. Proof-of-principle experiments demonstrate that neurons can be automatically detected and recruited into a photostimulation ensemble, closed-loop photoinhibition can be implemented immediately after fast mapping of the functional properties of cortical neurons, and targeted activation can be guided by readout of ongoing activity patterns in behaviorally relevant neuronal ensembles during decision-making.

    View details for DOI 10.1016/j.crmeth.2025.101180

    View details for PubMedID 40972568

  • Cholinergic modulation of dopamine release drives effortful behavior. bioRxiv : the preprint server for biology Touponse, G. C., Pomrenze, M. B., Yassine, T., Mehta, V., Denomme, N., Zhang, Z., Malenka, R. C., Eshel, N. 2025

    Abstract

    Effort is costly: given a choice, we tend to avoid it1. But in many cases, effort adds value to the ensuing rewards2. From ants3 to humans4, individuals prefer rewards that had been harder to achieve. This counterintuitive process may promote reward-seeking even in resource-poor environments, thus enhancing evolutionary fitness5. Despite its ubiquity, the neural mechanisms supporting this behavioral effect are poorly understood. Here we show that effort amplifies the dopamine response to an otherwise identical reward, and this amplification depends on local modulation of dopamine axons by acetylcholine. High-effort rewards evoke rapid acetylcholine release from local interneurons in the nucleus accumbens. Acetylcholine then binds to nicotinic receptors on dopamine axon terminals to augment dopamine release when reward is delivered. Blocking the cholinergic modulation blunts dopamine release selectively in high-effort contexts, impairing effortful behavior while leaving low-effort reward consumption intact. These results reconcile in vitro studies, which have long demonstrated that acetylcholine can trigger dopamine release directly through dopamine axons6-11; with in vivo studies that failed to observe such modulation12-14, but did not examine high-effort contexts. Our findings uncover a mechanism that drives effortful behavior through context-dependent local interactions between acetylcholine and dopamine axons.

    View details for DOI 10.1101/2025.06.18.660394

    View details for PubMedID 40667072

    View details for PubMedCentralID PMC12262595

  • CHOLINERGIC INTERNEURONS GATE DOPAMINE RELEASE TO DRIVE EFFORTFUL BEHAVIOR Touponse, G., Pomrenze, M., Yassine, T., Zhang, Z., Malenka, R., Eshel, N. SPRINGERNATURE. 2024: 511

    View details for Web of Science ID 001421429900162

  • Gating of Opioid Withdrawal Aversion by a Unique Class of Neurons in the Nucleus Accumbens Tucciarone, J., Pomrenze, M., Baek, J., Zhang, Z., Touponse, G., Shank, A., Neumann, P., Eshel, N., Malenka, R. SPRINGERNATURE. 2023: 492-493

    View details for Web of Science ID 001126640300497

  • Behaviorally relevant decision coding in primary somatosensory cortex neurons. Nature neuroscience Buetfering, C., Zhang, Z., Pitsiani, M., Smallridge, J., Boven, E., McElligott, S., Häusser, M. 2022

    Abstract

    Primary sensory cortex is thought to process incoming sensory information, while decision variables important for driving behavior are assumed to arise downstream in the processing hierarchy. Here, we used population two-photon calcium imaging and targeted two-photon optogenetic stimulation of neurons in layer 2/3 of mouse primary somatosensory cortex (S1) during a texture discrimination task to test for the presence of decision signals and probe their behavioral relevance. Small but distinct populations of neurons carried information about the stimulus irrespective of the behavioral outcome (stimulus neurons), or about the choice irrespective of the presented stimulus (decision neurons). Decision neurons show categorical coding that develops during learning, and lack a conclusive decision signal in Miss trials. All-optical photostimulation of decision neurons during behavior improves behavioral performance, establishing a causal role in driving behavior. The fact that stimulus and decision neurons are intermingled challenges the idea of S1 as a purely sensory area, and causal perturbation suggests a direct involvement of S1 decision neurons in the decision-making process.

    View details for DOI 10.1038/s41593-022-01151-0

    View details for PubMedID 36042310

  • Closed-loop all-optical interrogation of neural circuits in vivo. Nature methods Zhang, Z., Russell, L. E., Packer, A. M., Gauld, O. M., Häusser, M. 2018; 15 (12): 1037-1040

    Abstract

    Understanding the causal relationship between neural activity and behavior requires the ability to perform rapid and targeted interventions in ongoing activity. Here we describe a closed-loop all-optical strategy for dynamically controlling neuronal activity patterns in awake mice. We rapidly tailored and delivered two-photon optogenetic stimulation based on online readout of activity using simultaneous two-photon imaging, thus enabling the manipulation of neural circuit activity 'on the fly' during behavior.

    View details for DOI 10.1038/s41592-018-0183-z

    View details for PubMedID 30420686

    View details for PubMedCentralID PMC6513754