Dopamine receptor activity participates in hippocampal synaptic plasticity associated with novel object recognition
Open accessAbstract
Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks. To test whether DA-receptor activity influences novelty-detection, we used a novel object recognition (NOR) task where mice remember previously presented objects as an indication of learning. Although DA innervation arises from other sources and the main DA signaling may be from those sources, our molecular approaches verified that midbrain dopaminergic fibers also sparsely innervate the dentate gyrus. During the NOR task, wild-type mice spent significantly more time investigating novel objects rather than previously observed objects. Dentate granule cells in slices cut from those mice showed an increased AMPA/NMDA-receptor current ratio indicative of potentiated synaptic transmission. Post-training injection of a D1-like receptor antagonist not only effectively blocked the preference for the novel objects, but also prevented the increased AMPA/NMDA ratio. Consistent with that finding, neither NOR learning nor the increase in the AMPA/NMDA ratio were observed in DA-receptor KO mice under the same experimental conditions. The results indicate that DA-receptor signaling contributes to the successful completion of the NOR task and to the associated synaptic plasticity of the dentate gyrus that likely contributes to the learning.
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NOP memory elevated the AMPA/NMDA current ratio in the dentate gyrus.
“NOP memory also elevated the AMPA/NMDA current ratio in the dentate gyrus (Yang et al., 2017).”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Yang et al., 2017
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“Using in vivo microdialysis, previous studies reported that novel stimulation increases DA efflux in the medial prefrontal cortex (Feenstra & Botterblom, 1996), the nucleus accumbus shell (De Leonibus et al., 2006), and the insular cortex (Guzman-Ramos et al., 2012), suggesting broad DA influence.”
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MethodDifferential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory
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“DA has a role in learning, memory, and synaptic plasticity via activation of D1/D5 receptors expressed in the hippocampus (Tang & Dani, 2009; Sarinana et al., 2014; Jenson et al., 2015; Broussard et al., 2016).”
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MethodDopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells
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BackgroundAdvances in the behavioural testing and network imaging of rodent recognition memory
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BackgroundGluN3A Promotes Dendritic Spine Pruning and Destabilization during Postnatal Development
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“3C) prior to bath application of 100-lM picrotoxin to prevent the spread of recurrent electrical activity into the CA1 (Kehoe et al., 2014).”
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Self-citationThe projections of the retrorubral field A8 to the hippocampal formation in the rat
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“Other studies, however, also indicate a sparse direct dopaminergic projection from midbrain DA neurons to the CA1 region of the hippocampus (Gasbarri et al., 1994, 1996; McNamara et al., 2014; Rosen et al., 2015; Broussard et al., 2016).”
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Zhao, R. J., Grunke, S. D., Keralapurath, M. M., Yetman, M. J., Lam, A., Lee, T., Sousounis, K., Jiang, Y., Swing, D. A., Tessarollo, L., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.032 · Cited by 34 · cited 2× · see citing works
“Then, DA signaling could be optogenetically (Liu et al., 2014) or chemogenetically (Zhao et al., 2016) manipulated at precise times to determine whether DA influences consolidation of learning pairs or influences the recognition of novel objects.”
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“Altered intracellular zinc signaling spatially restricted to the DG also was sufficient to affect NOR (Tamano et al., 2015).”
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“Evidence supports that substantial dopaminergic signaling in the hippocampus arises from outside the midbrain ventral tegmental area (VTA) and substantia nigra compacta (SNc; Smith & Greene, 2012; Walling et al., 2012).”
BackgroundCocaine effects on behavioral responding to a novel object placed in a familiar environment
Carey, R. J., Damianopoulos, E. N., & Shanahan, A. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2007.08.010 · Cited by 13 · cited 1× · see citing works
“Thus, the NOR task has been routinely applied to evaluate object recognition memory and development of attention processes in rodents and humans (David & Witryol, 1990; Carey et al., 2008; Taglialatela et al., 2009).”
MethodGenetic Approaches to Reveal the Connectivity of Adult-Born Neurons
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“Clones were verified for flex orientation by restriction digest and transfection (Arenkiel & Ehlers, 2009; Arenkiel, 2011).”
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“Thus, the NOR task has been routinely applied to evaluate object recognition memory and development of attention processes in rodents and humans (David & Witryol, 1990; Carey et al., 2008; Taglialatela et al., 2009).”
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“Furthermore, the injection of a dopamine D1-receptor antagonist can block the novel object preference behavior in rodents [32].”
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Dopaminergic innervation and modulation of hippocampal networks
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“Moreover, cholinergic and dopaminergic neurotransmission is important for hippocampal-dependent synaptic plasticity and memory regulation [52, 53].”
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“Dopaminergic centers within the midbrain such as the ventral tegmental area project to the striatum, cortex and even hippocampus and influence learning (35,36), even in aversive contexts (37).”
BackgroundCordella, A., Krashia, P., Nobili, A., Pignataro, A., La Barbera, L., Viscomi, M. T., Valzania, A., Keller, F., Ammassari-Teule, M., Mercuri, N. B., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.006 · Cited by 82 · see citing works
O’Mahony, S. M., Neufeld, K. M., Waworuntu, R. V., Pusceddu, M. M., Manurung, S., Murphy, K., Strain, C., Laguna, M. C., Peterson, V. L., Stanton, C., et al. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14514 · Cited by 79 · see citing works
“Whilst hippocampal dopamine has been related to novel object recognition memory (Yang et al., 2017).”
BackgroundDopaminergic regulation of hippocampal plasticity, learning, and memory
Tsetsenis, T., Broussard, J. I., & Dani, J. A. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.1092420 · Cited by 68 · see citing works
“One common technique is to measure the AMPA/NMDA (A/N) ratio of hippocampal slices extracted ex vivo from mice that had recently undergone a learning procedure, such as the novel object recognition (NOR) task (Yang et al., 2017).”
BackgroundMethodIntegrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease
Chen, A. P. F., Chen, L., Kim, T. A., & Xiong, Q. (2021) · Biomedicines · doi:10.3390/biomedicines9060647 · Cited by 55 · see citing works
Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson's disease model in mice
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Amphetamine sensitization alters hippocampal neuronal morphology and memory and learning behaviors
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Dopamine in the hippocampal dentate gyrus modulates spatial learning via D1-like receptors
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Dopamine D2 receptors in hilar mossy cells regulate excitatory transmission and hippocampal function
Gulfo, M., Lebowitz, J. J., Ramos, C., Hwang, D.-W., Nasrallah, K., & Castillo, P. E. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307509120 · Cited by 14 · see citing works
“To directly address the potential role of MC D2Rs in recognition memory, we tested MC Drd2 cKO and Control mice in the ORM task, which has been used in studies of MC function (5, 8, 36).”
InfluentialSinani, A., Vassi, A., Tsotsokou, G., Νικολακοπούλου, Μ., Kouvelas, E. D., & Mitsacos, A. (2022) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2022.04.008 · Cited by 15 · see citing works
Żurawek, D., Salerno-Kochan, A., Dziedzicka‐Wasylewska, M., Nikiforuk, A., Kos, T., & Popik, P. (2017) · Schizophrenia Research · doi:10.1016/j.schres.2017.04.014 · Cited by 14 · see citing works
“It is worth noting that NMDA receptor blockade can modulate activity of dopaminergic neurons in mesolimbic pathway and that dopamine receptor signaling can modulate hippocampal function (Yang et al., 2016).”
Dopamine activity on the perceptual salience for recognition memory
Osorio‐Gómez, D., Guzmán-Ramos, K. R., & Bermúdez‐Rattoni, F. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.963739 · Cited by 13 · see citing works
Ugalde‐Muñiz, P., Hernández-Luna, M. G., Garcia-Velasco, S., Lugo-Huitrón, R., Murcia-Ramírez, J., Tapia, R., Noriega‐Navarro, R., & Navarro, L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.988167 · Cited by 15 · see citing works
“Recently, a study reported that D1DR activity regulates the synaptic plasticity in the dentate gyrus and significantly contributes to completing the NOR task in mice (Yang et al., 2017).”
BackgroundYang, K., McLaughlin, I., Shaw, J. K., Cardé, N. A. Q., Dani, J. A., & Biasi, M. D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109547 · Cited by 12 · see citing works
Ramírez-Mejía, G., Gil-Lievana, E., Urrego-Morales, O., Gálvez-Márquez, D. K., Hernández-Ortiz, E., Carrillo-Lorenzo, J. A., & Bermúdez‐Rattoni, F. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109464 · Cited by 9 · see citing works
Zhou, Y., Cong, T., Chen, J., Chu, Z., Sun, Y., Zhao, D., Chen, X., Li, L., Liu, Y., Cheng, J., et al. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150128 · Cited by 9 · see citing works
Takahashi, J., Yamada, D., Nagano, W., Sano, Y., Furuichi, T., & Saitoh, A. (2023) · PLoS ONE · doi:10.1371/journal.pone.0294113 · Cited by 8 · see citing works
“Ex vivo electrophysiological experiment demonstrated that the ratio of membrane currents mediated by AMPA receptor to NMDA receptor (AMPA/NMDA ratio), an index of neuronal plasticity, was increased in DG granule cells after NORT [30].”
BackgroundKalkhoran, A. K., Alipour, M. R., Jafarzadehgharehziaaddin, M., Zangbar, H. S., & Shahabi, P. (2022) · BMC Neuroscience · doi:10.1186/s12868-022-00729-5 · Cited by 8 · see citing works
“The activity of hippocampal D1 like receptors, mediates novelty-detection through the NORT, such that, post-training infusion of D1-like receptor antagonist not only significantly weakenes the tendency to explore novel objects, but also decreases the AMPA/NMDA ratio, stater of potentiated synaptic current [67].”
BackgroundDifferential modulatory effects of cocaine on marmoset monkey recognition memory
Melamed, J., de Jesus, F. M., Aquino, J., Vannuchi, C. R. S., Duarte, R. B., Maior, R. S., Tomaz, C. A. B., & Barros, M. (2017) · Progress in brain research · doi:10.1016/bs.pbr.2017.07.005 · Cited by 8 · see citing works
Yamazaki, M., Arai, T., Yarimizu, J., & Matsumoto, M. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac041 · Cited by 7 · see citing works
“The NORT is a model for assessing visual-recognition memory that takes advantage of the natural preference of rodents for novelty: mice that recognize a familiar object have been shown to instinctively spend more time exploring an unfamiliar object (Yang et al., 2017).”
BackgroundKim, H.-H., Lee, S., Ho, W., & Eom, K. (2022) · Experimental Neurobiology · doi:10.5607/en22028 · Cited by 7 · see citing works
“It is known that dopamine receptors, including the D1 and D2 receptors, participate in the synaptic plasticity associated with memory and behavior [25-27], and they are involved in the regulation of the voltage-dependent K channels [28-30].”
BackgroundNeurobiological Mechanisms of Cognitive Decline Correlated with Brain Aging
Zhang, X., An, H., Chen, Y., & Shu, N. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-99-1627-6_10 · Cited by 4 · see citing works
Wang, Q.-N., Wang, Y., Hu, Y., Xie, P.-F., Li, F., Mu, R., Feng, Z.-J., Zhou, F., & Tang, C.-F. (2025) · Nutrition and Metabolism · doi:10.1186/s12986-025-01043-7 · Cited by 3 · see citing works
“Moreover, the absence of external reward or punishment in NOR [45] removes potential motivational influences that could mask mild memory deficits, allowing such impairments to directly manifest as reduced discrimination.”
Wang, H.-X., Deng, Z.-A., Li, Y.-Y., Li, J., Chen, Y., Zhao, Y.-J., Huang, K., Tian, W.-N., Tong, A., & Zhou, L. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00658-5 · Cited by 3 · see citing works
“We performed neurological deficit score, wire-hanging test, tail suspension test and novel object recognition test assessments as previously described, and each was assessed by independent researchers [29, 35–38].”
Urquizu, E., Paratusic, S., Goyenechea, J., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212248 · Cited by 3 · see citing works
A biologically plausible network model for pattern storage and recall inspired by Dentate Gyrus
Janarthanam, V. V., Vishwanath, S., & Shanthi, A. P. (2020) · Neural Computing and Applications · doi:10.1007/s00521-019-04670-3 · Cited by 3 · see citing works
Manara, E., Mele, A., & Migliore, M. (2025) · Scientific Reports · doi:10.1038/s41598-025-17694-8 · Cited by 2 · see citing works
“This phenomenon may be attributed to the amplification of bAPs and have implications for object recognition 66 .”
Nunes, B. B. D. S., Mendonça, J. D. S., de Matos, L. P., Guimarães, A. T. B., Soares, W. R., Rodrigues, A. S. D. L., Govindarajan, M., Gomes, A. R., da Luz, T. M., & Malafaia, G. (2025) · Environmental Science and Pollution Research · doi:10.1007/s11356-024-35840-z · Cited by 2 · see citing works
“…al. 2015; Yamaguchi et al. 2017), which the dopamine levels and its metabolites are associated with anxiety-like behavior (Zarrindast & Khakpai 2015) and that dopaminergic signaling has a significant role in regulating NOR test behavior (Belcher et al. 2008; Camarasa et al. 2010; Yang et al. 2017).”
The common fatty acids have a pheromone-like effect, improving the emotion in micePreprint
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“Hippocampal dopaminergic signaling has been implicated in processes now associated with MCs, such as spatial memory, novelty detection, anxiety-like behavior, and epilepsy (23-31).”
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“Besides its role in reward processing, dopamine is well-known to promote hippocampal synaptic plasticity and is a key determinant of memory encoding [88, 95, 96].”
The Neuropharmacology of What, Where, When
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Dopaminergic Facilitation of Synaptic Transmission in Layer II of the Lateral Entorhinal Cortex
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“It should be noted that NMDAR blockade can regulate dopaminergic signal transduction in the marginal pathway of the mesencephalon (Yang et al. 2017).”
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Intrinsic Excitability of Rat Hippocampal Granule Cells Increases Along the Dorsal‐to‐Ventral Axis
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Voluntary Exercise and Hippocampal Memory Enhancement: Decoding the Molecular Blueprint
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- Authors
- Yang, K., Broussard, J. I., Levine, A. T., Jenson, D., Arenkiel, B. R., & Dani, J. A.
- Affiliations
- University of Pennsylvania (US)
- Baylor College of Medicine (US)
- Corresponding author
- Dani, John A.
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2016-10
- Volume
- 45
- Issue
- 1
- Pages
- 138-146
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC5209255
- OpenAlex
- W2522831505
- Semantic Scholar
- a79563c6e21e65aa2e9a0518e9e73aa61abb598d
- Cited by
- 58
- References
- 58
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 9 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 3
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NS21229, DA09411)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopamine receptors, dentate gyrus, novel object recognition, synaptic plasticity, D1-like receptors, AMPA/NMDA ratio, granule cells, novelty detection, spatial memory, perforant path, hippocampus
- MeSH terms
- Animals, Dopamine, Hippocampus, Synaptic Transmission, Neuronal Plasticity, Receptors, Dopamine, Synapses, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Excitatory Postsynaptic Potentials, Recognition, Psychology
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