The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH+) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH+ neurons project more profusely than ventral tegmental area TH+ neurons to the hippocampus, optogenetic activation of locus coeruleus TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.
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We thank M. Evans for Th-Cre mice; H. Rowe and D. Tse for pilot studies; M. Lo, H-C. Tsai and C. Ramakrishnan for optogenetics training; UNC Viral Cores for producing AAVs; J. Cala, R. Fitzpatrick, J. Tulloch and T. Thai for technical support; R. Watson for animal care; N. Uchida and J. Cohen for assistance with optogenetic identification of TH+ neurons; P. Pedarzani, S. Canals, L. Genzel, M. Kroes, J. Lisman, D. Manahan-Vaughan, M. Munoz, T. Spires-Jones, S.-H. Wang, O. Eschenko and E. Wood for scientific discussion. The study was funded by the European Research Council (G.F., R.G.M.M.: ERC-2010-AdG-268800-NEUROSCHEMA), UK Medical Research Council (A.J.D., R.G.M.M.), the European Commission’s 7th Framework 2011 ICT Programme for Future Emerging Technologies (A.J.D., R.G.M.M.: 600725-GRIDMAP), Department Veterans Affairs, National Institutes of Health grant 5R01MH080297 (R.W.G.), and NIDA-T32-DA7290 Basic Science Training Program in Drug Abuse (principal investigator A. Eisch (A.S.)). The Instituto de Neurociencias at Alicante is ‘Centre of Excellence Severo Ochoa’.
The authors declare no competing financial interests.
Reviewer Information Nature thanks S. Thompson and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
a, Example sandwell locations (black circles) and starting positions (black arrows) used during regular training and non-rewarded probe tests (probe tests). Sixteen different sandwell configurations were used throughout experiments, with daily rewarded sandwell positions counterbalanced between animals. b, Latency to dig in correct sandwell during choice test decreased as initial training progressed (Fig. 1a; Th-Cre mice, n = 13). Grey bars mark acquisition probe test sessions. c, Ten-minute probe tests conducted at different stages of initial training illustrate the learning curve (F2,24 = 9.35, P < 0.001), with animals performing above chance on probe test 3 (one-sample t-test versus chance, t12 = 4.76, P < 0.001). d, Increased reward during the sample trial resulted in persistent memory at 24 h (1 h versus 24 h: t12 < 1; 1 h: t12 = 4.16, P < 0.01; 24 h: t12 = 4.70, P < 0.001). e, Impact of intra-hippocampal infusion of propranolol (Prop) or SCH23390 (SCH) on animals’ performance in 24-h probe test (Fig. 1c). Infusion of Prop or SCH in dorsal hippocampus 20 min before novelty exploration had no impact on the total time that mice spent digging in sandwells (F2,24 < 1). **P < 0.01, ***P < 0.001 versus chance. Dashed line indicates the chance level. Data are means ± s.e.m.
Extended Data Figure 2 Specificity and expression rate of Cre-inducible AAV in VTA and LC of Th-Cre mice.
a, Schematic of viral injection. b–e, Double immunofluorescence for eYFP (green) and TH (red). In VTA (b, c) and LC (d, e), most eYFP-expressing cells are positive for TH (asterisks), and eYFP expression in TH– cells (arrows) is only occasionally observed. f, g, Quantification of specificity (f) and expression rate (g) of the Cre-inducible AAV in VTA and LC of Th-Cre mice. VTA-TH+ neurons are defined as TH+ cells located in the parabrachial pigmented area (PBP), paranigral (PN), interfascicular (IF) and rostral linear (RLi) nuclei. Measurements were made from the VTA in the left hemisphere, and three coronal sections (AP: –2.9, –3.5 and –3.9 from Bregma) from each mouse. LC-TH+ neurons are defined as TH+ cells located in the lateral floor of the fourth ventricle. Measurements were made from the LC in the left hemisphere, and five coronal sections (AP: –5.3 to –5.7 from Bregma) from each mouse. Total numbers of neurons measured were 2,500 and 1,520 in VTA and LC, respectively. Data are presented as mean ± s.e.m. (n = 3 mice in each). IPN, interpeduncular nucleus; LC, locus coeruleus; SNc, Substantia nigra pars compacta; SNr, Substantia nigra pars reticulata; VTA, ventral tegmental area. Scale bars: 200 μm (b, d); 20 μm (c, e). The mouse brain in this figure has been reproduced with permission from Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd ed, 691 (Academic, 2007).
a, b, Average spontaneous (black) and light-evoked (blue) waveforms of all identified VTA-TH+ neurons in Th-Cre mice expressing ChR2–eYFP in VTA (a, n = 15 neurons from 5 mice) and LC-TH+ neurons in Th-Cre mice expressing ChR2–eYFP in LC (b, n = 10 neurons from 3 mice) show nearly perfect overlap. c, Comparison of the novelty response dynamics of VTA-TH+ and LC-TH+ neurons. When z-scored to their average firing rates in the familiar environment, LC-TH+ neurons showed stronger modulation by novelty than VTA-TH+ neurons (two-way ANOVA: brain area × time interaction, F29,667 = 2.60, P < 0.001). Additionally, LC-TH+ neurons but not VTA-TH+ neurons displayed habituation in a manner consistent with a novelty signal (one-way ANOVA: main effect of time for LC novel, F29,261 = 2.04, P < 0.01; no effect of time for VTA novel: F29,406 = 1.18, P > 0.05). d, VTA-TH+ and LC-TH+ neurons fire more bursts in novel than in familiar environments (5 min of exploration) (VTA-TH+: two-tailed paired t-test, t14 = 3.70, P < 0.01; LC-TH+: t9 = 2.48, P < 0.05). Dashed line indicates the baseline burst set rate. e, Firing properties of VTA-TH+ and LC-TH+ neurons in novel environments used to choose physiologically relevant optogenetic stimulation protocols. The average firing rate and within-burst firing rate of our optogenetic stimulation protocols for both in vivo and extracellular ex vivo experiments are within the physiological range of both VTA-TH+ and LC-TH+ neurons. In addition, several recorded neurons fired most of their spikes in bursts. *P < 0.05, **P < 0.01, paired t-test. Data are means ± s.e.m.
a, Immunofluorescence showing overall distribution of TH (red) and NET (green) immunoreactivity in the mouse hippocampus. b, Representative high magnification images of double immunofluorescence for TH (red) and NET (green). Note that most TH+ axons are co-labelled for NET, and TH+-NET– axons (arrows) are only occasionally observed. c–e, Double-labelling fluorescence in situ hybridization showing distinct expression pattern of TH (red) and NET (green) mRNAs in VTA (c, d) and LC (e). Note that mRNA for NET is detected in virtually all TH-positive neurons in LC, whereas it is not in any of TH+ neurons in VTA. CA1 and CA3, hippocampal subregions CA1 and CA3; DG, dentate gyrus; HPC, hippocampus; LC, locus coeruleus; SNc, Substantia nigra pars compacta; SNr, Substantia nigra pars reticulate; VTA, ventral tegmental area. Scale bars: 200 μm (a); 5 μm (b); 100 μm (c); 10 μm (d); 50 μm (e).
Representative images of coronal sections containing VTA (a, b) and LC (c, d) showing TH+ (green) neurons labelled with retrobeads (red) in LC, but not in VTA. CA1 and CA3, hippocampal subregions CA1 and CA3; DG, dentate gyrus; LC, locus coeruleus; MPB, medial parabrachial nucleus; SNc, Substantia nigra pars compacta; SNr, Substantia nigra pars reticulata; SuM, supramammillary nucleus; VTA, ventral tegmental area. Scale bars: 200 μm (a); 50 μm (b–d). The mouse brain in this figure has been reproduced with permission from Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd ed, 691 (Academic, 2007).
Extended Data Figure 6 Performance during training and probe tests in the optogenetic activation experiment.
a, ChR2-expressing LC-TH+ and VTA-TH+ neurons reliably follow 25-Hz blue light stimulation in awake mice. b, ChR2+ mice (n = 8) and ChR2– controls (n = 6) both acquired the task over several weeks of training and maintained exceptionally stable performance from session (S) 46 until the end of training (S46 to S125: group × session interaction, F15,180 = 1.14, P > 0.05; group effect, F1,12 = 4.63, P > 0.05). After 15 training sessions, Th-Cre mice were allocated into ChR2+ and ChR2– groups based on their performance (average performance index in S1–S15: 75% in both groups). Vertical grey bar denotes the break in training due to implantation surgery. Pre, pre-training. c, Ten-minute probe test conducted before the implantation surgery, showing good memory (correct digging: one-sample t-test versus chance, t13 = 3.17, P < 0.01; ChR2+ versus ChR2–: two-tailed paired t-test, t12 < 1, P > 0.05). d, Infusion of propranolol (Prop) or SCH23390 (SCH) in dorsal hippocampus 20 min before LC photoactivation had no impact on the total digging time in either group (ChR2+: F3,21 < 1, P > 0.05; ChR2–: F3,15 = 1.44, P > 0.05) (see Fig. 4f). **P < 0.01 versus chance. Dashed lines indicate the chance level. Data are means ± s.e.m.
Extended Data Figure 7 ChR2–eYFP expression in LC-TH+ neurons of Th-Cre mice and optogenetic stimulation protocols for ex vivo hippocampal electrophysiology.
a, Representative images of double immunofluorescence for eYFP (green) and TH (red) in LC cell bodies (top) and LC axons in CA1 (bottom) in the strain of Th-Cre mice used for ex vivo hippocampal electrophysiology. b, c, Photostimulation protocols used in intracellular (b) and extracellular (c) ex vivo hippocampal electrophysiology.
a, In vivo optrode recordings of eArch3.0-expressing LC-TH+ neurons in anaesthetized Th-Cre mice. Left, complete inhibition of multi-unit activity in LC during the 5 min ‘532-nm light on’ period (example trace and population data (n = 9 traces from 5 mice)), followed by pronounced rebound activation. Grey shading represents ± s.e.m. Right, mean multi-unit activity in LC (Pre versus LC-on: t8 = 35.6, P < 0.001; Pre versus rebound: t8 = 3.98, P < 0.01; Pre versus Post: t8 < 1, P > 0.05). NS, not significant. **P < 0.01, ***P < 0.001. b, Single traces showing rebound excitation of eArch3.0-expressing LC-TH+ neurons after incomplete inhibition. Rebound excitation could not be reduced by low-power illumination (10 mW, left), even when light intensity was decreased monotonically over 3 min (right). c, Rebound excitation of the membrane trafficking-enhanced variants of halorhodopsin (eNpHR3.0)-expressing LC-TH+ neurons of Th-Cre mouse. Green shading indicates ‘light on’ periods. The mouse brain in this figure has been reproduced with permission from Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd ed, 691 (Academic, 2007).
Extended Data Figure 9 Performance during training and probe tests in the pharmacological inactivation experiment.
a, Th-Cre mice (n = 15) acquired the task over several weeks of training and maintained stable performance from session (S) 36 until the end of training (S36–S90: F10,140 < 1, P > 0.05). Pre, pre-training. b, Mice showed effective memory when tested 1 h after weak encoding (one-sample t-test versus chance, t14 = 5.68, P < 0.001). c, Intra-VTA infusion of lidocaine (Lid, left) or intraperitoneal injection of clonidine (Clo, right) before novelty exploration had no impact on the total digging time (see Fig. 6b, c) (lidocaine: t14 < 1, P > 0.05; clonidine: F2,28 = 1.01, P > 0.05). ***P < 0.001 versus chance. Dashed lines indicate the chance level. Data are means ± s.e.m.
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Takeuchi, T., Duszkiewicz, A., Sonneborn, A. et al. Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537, 357–362 (2016). https://doi.org/10.1038/nature19325
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