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Hypothalamic melanin-concentrating hormone regulates hippocampus-dorsolateral septum activity

Nature Neuroscience volume 25, pages 61–71 (2022)Cite this article

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Abstract

Hypothalamic melanin-concentrating hormone (MCH) polypeptide contributes to regulating energy homeostasis, sleep and memory, although the mechanistic bases of its effects are unknown. In this study, in mice, we uncovered the physiological mechanism underlying the functional role of MCH signaling in projections to the dorsolateral septum (dLS), a region involved in routing hippocampal firing rhythms and encoding spatial memory based on such rhythms. Firing activity within the dLS in response to dorsal CA3 (dCA3) excitation is limited by strong feed-forward inhibition (FFI). We found that MCH synchronizes dLS neuronal firing with its dCA3 inputs by enhancing GABA release, which subsequently reduces the FFI and augments dCA3 excitatory input strength, both via pre-synaptic mechanisms. At the functional level, our data reveal a role for MCH signaling in the dLS in facilitating spatial memory. These findings support a model in which peptidergic signaling within the dLS modulates dorsal hippocampal output and supports memory encoding.

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Fig. 1: Endogenous MCH suppresses spontaneous neural activity in the dLS.
Fig. 2: MCH enhances excitatory synaptic transmission in the dLS .
Fig. 3: MCH enhances excitatory synaptic transmission in the dHP-to-dLS pathway.
Fig. 4: Augmentation of inhibitory synaptic transmission by MCH accounts for the suppressive effect on dLS neuronal activity and excitability.
Fig. 5: MCH enables high-frequency-coded information flow in the HP-dLS-LHA circuit.
Fig. 6: MCH is required for HP-dependent spatial learning and memory consolidation.

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Data availability

All data are contained in the main text, extended data or supplementary information. Source data can be downloaded at https://figshare.com/s/608dcd5f1a9d5a1d60df. Source data are provided with this paper.

Code availability

No custom code was used in this study.

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Acknowledgements

We would like to thank G. Buzsáki and members of the Tsien laboratory, especially X. Wang and E. McCurdy, for their critical reading and constructive suggestions. We would like to thank A. Kusnecov, C. Manzini, B. Xia, A. Chang and Y. Zhang for their generous help in the behavioral tests and analyses. We would also like to thank A. Rabson and N. Francis of Rutgers for their input on the manuscript. We especially would like to thank B. Mensh, G. Edgerton and S. Aamodt for their critical input and suggestions on the manuscript. We also thank Z.-R. Xu, V. Li and J. Salvatore for suggestions on statistical analyses. The Pang laboratory is supported by NIH R01AA023797, NIH RF1MH120144 and, in part, by the Robert Wood Johnson Foundation (grant no. 74260) to the Child Health Institute of New Jersey.

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Authors and Affiliations

  1. Child Health Institute of New Jersey, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Jing-Jing Liu & Zhiping P. Pang

  2. Department of Neuroscience and Cell Biology, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Jing-Jing Liu & Zhiping P. Pang

  3. NYU Neuroscience Institute, New York University School of Medicine, New York, NY, USA

    Jing-Jing Liu & Richard W. Tsien

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J.-J.L. and Z.P.P. conceived the study. J.-J.L. performed the experiments and analyzed the data. R.W.T. provided constructive intellectual input to the overall study. All authors contributed to the final manuscript.

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Correspondence to Zhiping P. Pang.

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Extended data

Extended Data Fig. 1 Optogenetic stimulation of LHA MCH-dLS may induce immediate impact on spontaneous dLS neuronal firing.

a, Wiring diagram of possible dLS neurocircuitry. b, Sample traces of optogenetically-induced oEPSCs and feed-forward-inhibitory oIPSCs. c, Representative traces of dLS neuronal spontaneous action potentials (sAPs) before, during, and after 10 s optogenetic stimulation of MCH fibers. d. Raster plot of sAPs. e-h, Normalized and pooled data of dLS neuronal firing under 10 s or 80 s, 10 Hz or 20 Hz stimulation. Data are mean ± SEM; numbers of neurons/animals analyzed are indicated. Paired two-tailed Student’s t-tests were used, e, before vs. during p = 0.622758; before vs. after p = 0.109378; f, before vs. during p = 0.01251; before vs. after p = 0.575929; g, before vs. during p = 0.0.875236; before vs. after p = 0.000832; h, before vs. during p = 0.000201; before vs. after p = 1.25×10−9. * p < 0.05, ** p < 0.01, ***p < 0.001.

Source data

Extended Data Fig. 2 MCH enhances excitatory transmission in dLS-to-LHA projecting neurons via a presynaptic mechanism.

a, Quantification of mRNAs of MCHR1 or vGAT in the dLS.n = 10. b, Sample traces of sEPSCs before and after trains of optogenetic activation of MCH fibers (left panel); right panel, Pooled data of the comparisons of frequencies and amplitudes of sEPSCs. n = 15 cells/8 animals and 16/9 cells/animals, at 5 Hz and 20 Hz, respectively. Paired Student’s t-tests were used: sEPSC frequency: Control vs. Post 5 Hz p = 0.0053; Control vs. Post 20 Hz p = 0.0051; sEPSC amplitude: Control vs. Post 5 Hz p = 0.0533; Control vs. Post 20 Hz p = 0.047. c, Sample traces of sEPSCs before and after optogenetic activation of MCH fibers in the presence of SNAP94847; right panel, Pooled data of the comparisons of frequencies and amplitudes of sEPSCs. n = 7 cells/3 animals and 10/4, at 5 Hz and 20 Hz, respectively. Student’s t-tests were used: sEPSC frequency: Control vs. Post 5 Hz p = 0.3281; Control vs. Post 20 Hz p = 0.5684; sEPSC amplitude: Control vs. Post 5 Hz p = 0.6994; Control vs. Post 20 Hz p = 0.8967. d&e, In the presence of Tc-MCH7c, no changes in spontaneous (d) or evoked EPSCs (e) were observed post 20 Hz optogenetic stimulation of MCH fibers.n = 9 cells /4 animals (d), 12/4 (e). Student’s t-tests were used: d, sEPSC frequency, Control vs. Post 20 Hz p = 0.584; sEPSC amplitude, Control vs. Post 20 Hz p = 0.9283; e, eEPSC amplitude, Control vs. Post 20 Hz p = 0.2007; PPR, Control vs. Post 20 Hz p = 0.4978. Data are mean ± SEM, * p < 0.05, ** p < 0.01, ***p < 0.001.

Source data

Extended Data Fig. 3 MCH regulates excitatory transmission in dLS neurons.

a-e, Impact of exogenously applied MCH and [Ala17]-MCH on sEPSCs, showing representative traces (a) and pooled data (b-e). n = 11 cells/6 animals for b&c; and 10/3 for d&e. Paired two-tailed Student’s t-tests were used: b, frequency p = 0.0006, amplitude p = 0.936; c, frequency p = 0.0025, amplitude p = 0.021.d-f, Expression of eYFP in MCH neurons after optogenetic stimulation does not impact synaptic transmission. d, Sample traces of PSCs and sEPSCs before and after trains of optogenetic stimulation (20 Hz 1 min x 2) of MCH fibers expressing eYFP. e&f, Pooled data of the normalized frequency or amplitude of PSCs (e) and sEPSCs (f). Data are mean ± SEM; n = 6 cells/3 animals for e; n = 11/3 for f. Paired two-tailed Student’s t-tests were used, no statistical significances were found. For PSCs, Frequency p = 0.8676, Amplitude p = 0.8205; for sEPSCs, Frequency p = 0.0717, Amplitude p = 0.4319. g-l, Knockdown of MCH abolish the regulatory effects after optogenetic activation of MCH neuronal fibers in the dLS. g, Sample images of tissue following unilateral injections of shRNA AAVs shRNA-scramble or shRNA-Pmch viruses. h&i Quantification of MCH neurons and MCH immunofluorescent signal in the hypothalamic area after shRNA knockdown of pMch. n = 7, 15, 7, in contralateral, scrambled and shRNA-pMch groups, respectively. h, Welch’s AN OVA tests were used, F(2,11.45)=109.8, p < 0.0001. Contralateral vs. shRNA scramble p = 0.9845, Contralateral vs. shRNA-pMch p < 0.0001, shRNA-scramble vs. shRNA-pMch p < 0.0001. I, Welch’s ANOVA tests were used, F(2,11.27)= 18.22, p = 0.0008, Contralateral vs. shRNA scramble p = 0.3187, Contralateral vs. shRNA-pMch p = 0.0133, shRNA-scramble vs. shRNA-pMch p = 0.0016. j, Quantification of MCH immunofluorescent signal in cells with expression of C1V1-mCherry. n = 8,6, in Scrambled shRNA and shRNA-pMch groups. Unpaired Student’s t-test, p = 0.0266 k-l, Impact of MCH shRNA AAV (or control scrambled shRNAs) on the modulatory effect of post-optogenetic stimulation of sEPSCs, showing representative traces (k) and pooled data (l). n = 12, 14 for l in shRNA-scramble and shRNA-pMch groups, respectively. Paired Student’s t-tests were used, shRNA-scramble: Control vs. post 20 Hz, Frequency p = 0.003531; Amplitude p = 0.001719; shRNA-pMch; Control vs. post 20 Hz, Frequency, p = 0.0.998361, Amplitude, p = 0.95653. Data are mean ± SEM; * p < 0.05, ** p < 0.01, ***p < 0.001.

Source data

Extended Data Fig. 4 MCH facilitates hippocampal excitatory inputs to dLS neurons.

a, Sample images of retrograde labeled CA2/3 neurons after microfluorescent RetroBeads were injected into the dLS region. b, Retrograde labelled LHA neurons (green) with immunoreactivity for MCH (blue). c, Quantification of mRNA of MCHR1 and vGAT in the dorsal hippocampal CA3 region. n = 7, unpaired Student’s t-test, p < 0.0001. d, Sample oEPSCs evoked by paired-pulse protocols at different intervals before (control) and after the application of MCH. e&f, Quantification of oEPSCs originating from hippocampus in dLS neurons before and after the application of MCH. Data are mean ± SEM; n = 7 cells/3 animals for e & f. Paired two-tailed Student’s t-tests were used: e, p = 0.0031; f, p = 0.0033 ** p < 0.01. g&h, Sample images of injection sites. i&j Endogenous MCH facilitates HP-to-dLS EPSCs via MCHR1 signaling. i, Representative superimposed traces of optogenetically-induced EPSCs in the dLS, in the presence of TC-MCH7c (10 µM) or SNAP94847 (20 µM), pre- (black trace) and post- (red trace) prolonged 590 nm light activation on C1V1-positive MCH axons. j, Pooled single oEPSC amplitude data. Paired two-tailed Student’s t-tests were used but no statistical differences were found, p = 0.0907 in TC-MCH7c and p = 0.6607 in SNAP94847.

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Extended Data Fig. 5 Endogenous MCH increases GABA tone in the dLS.

a, Pooled data for amplitude. n = 11 cells/9 animals and 14/9 for 5 Hz and 20 Hz, respectively. Paired two-tailed Student’s t-tests were used: 5 Hz, p = 0.2905 and 20 Hz, p = 0.132. AAV-DIO-ChR2-eYFP was injected into the lateral hypothalamic region of MCH-Cre mice, sIPSCs (isolated pharmacologically in the presence of CNQX and APV) were recorded in dLS neurons. MCH fibers were optogenetically activated using two different paradigms (5 Hz 5 second x 5 or 20 Hz 2 min). sIPSCs were recorded before optogenetic stimulation (Control) and 2–3 min after optogenetic stimulation (indicated as 5 Hz or 20 Hz). b, Sample traces showing the impact of optogenetic stimulation of MCH fibers on sIPSCs in dLS neurons, as described above, in the presence of Tc-MCH7c. c, Pooled data show that in the presence of TC-MCH7c, the facilitatory effects induced post-prolonged optogenetic stimulation of MCH fibers were abolished, suggesting the involvement of MCH signaling. n = 14/7 and 13/7 for 5 Hz and 20 Hz, respectively. Paired two-tailed Student’s t-tests were used: 5 Hz, p = 0.4489 and 20 Hz, p = 0.9195. d, Sample traces of sIPSCs in the absence (Control) or presence of MCH. f, Pooled data for e. n = 8/4 neurons/animals. Paired two-tailed Student’s t-tests were used, p = 0.0198. f-h MCH suppresses collateral transmission in the dLS. g, Diagram of experimental setup and sample images showing AAV-ChR2-eYFP infection in the dLS. Whole-cell patch clamp recordings were made from cells without ChR2-eYFP infection in the dLS; fibers and neuronal cell bodies expressing ChR2 were activated by 470 nm LED light (each pulse at 1 ms duration at 1, 5 and 10 Hz); collateral optogenetically-induced IPSCs were recorded. g, Sample traces showing the GABAAR-mediated inhibitory collateral synaptic transmission before (black traces) and after (green traces) administration of exogenous MCH (600 nM) through perfusion chamber. h, Pooled data from b. n = 12 cells/5 animals. Paired two-tailed Student’s t-tests were used, p = 0.0006. i, GABAB receptor-mediated inhibition suppresses spontaneous firing of dLS neurons. Sample traces showing that GABAB receptor-mediated inhibitory synaptic transmission is sufficient to suppress dLS spontaneous action potential firing. AAV-ChR2-eYFP was injected into the dLS. Whole-cell patch clamp recordings under current clamp mode were made from cells without ChR2-eYFP infection in the dLS; fibers and neuronal cell bodies expressing ChR2 were activated by 470 nm LED light (each pulse was 1 ms duration delivered at 1, 5 or 10 Hz). In the presence of GABAAR blocker PTX, optogenetic stimulation delivered at varying frequencies (1 Hz, 5 Hz and 10 Hz) to activate dLS neurons suppressed spontaneous firing. Higher frequencies produce prolonged hyperpolarization in dLS neurons. In the presence of CGP55845, a GABABR blocker, the suppression of firing and hyperpolarization of membrane potential were both blocked, suggesting the involvement of GABAB receptor signaling. Data are mean ± SEM * p < 0.05, ** p < 0.01, ***p < 0.001.

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Extended Data Fig. 6 GABABR-mediated FFI functions as a low-pass filter.

The FFI acts as a gate to block high-frequency-encoded information generated in the hippocampus from passing through to downstream targets through the dLS neural network. a, Sample traces of dLS neuron firing in response to optogenetically-evoked oEPSCs from the dHP. b&c, Pooled data from a. d, Sample traces of neurons firing spontaneous APs interferes with 1 Hz dHP excitatory inputs induced AP generations. n = 38 cells/ 9 animals. Data are presented as mean ± SEM.

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Extended Data Fig. 7 Hippocampal inputs induced postsynaptic action potentials.

a, Sample traces of neuronal oAPs induced by 1 Hz dHP excitatory inputs. b, Superimposed postsynaptic potentials (upper panel) and postsynaptic currents (lower panel) under different conditions (indicated by different color as indicted in a). c, Diagram of possible wiring of HP-dLS-LHA neurocircuitry.

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Extended Data Fig. 8 Behavioral impacts of MCH signaling in the dLS.

a, Light microscope image of sample coronal brain slices illustrating the guide and internal cannula tracks. Tracks of injector tips are labeled by stars. b-e, RotaRod Motor learning task data. b&d, pooled data for the first 10 trials, in which speed accelerated from 4–40 revolutions/min in 300 s. Two-way ANOVA test was used. b, animals x treatment p = 0.9602, treatment p = 0.464. d, animals x treatment p = 0.9509, treatment p = 0.5329. c&e, Pooled data from the last 2 trials, in which speed accelerated from 4–40 revolutions/min in150s. Two-way ANOVA test was used. c, animals x treatment p = 0.1222, treatment p = 0.2944. e, animals x treatment p = 0.0776, treatment p = 0.4157. f-k, Performance on the locomotor open field test with patterned wall. n = 6,7,7 in control, MCH and Tc-MCH7c groups. One-way ANOVA test with posthoc Tukey’s multiple comparison were used for all analysis. f, Schematic of the testing arena. g, Distance traveled under each treatment condition. F(2,17)=0.1059,p = 0.9001. h, Time spent in center time under each treatment condition. Treatment F(2,17)=2.124, p = 0.1501. i,Time spent active under each treatment condition. Treatment F(2,17)=0.2081, p = 0.8142. j, Movement velocity under each treatment condition. treatment F(2,17)=0.1037, p = 0.902. k, Time spent near patterned walls under each treatment condition. Treatment F(2,17)=4.522, *p = 0.0.0266; Control vs. Ala17]MCH, p = 0.0477, [Ala17]MCH vs. TC-MCH7c, p = 0.0482. l-n Social recognition behavior with or without MCHR1 agonist. Metric=time (%) spent in the side of each chamber (Chamber 1: familiar mouse; Chamber 2: novel mouse). m, Preference for chamber 1: Two-way ANOVA test was used for statistics, F(1,11)=8.459, p = 0.0142. n, Data showing a shifted preference, n = 7 and 6 in control and MCH groups, respectively. Unpaired Two-tailed Student’s t-test was used: p = 0.04. o&p, Nesting behavioral analyses. Metric = arbitrary nesting scores. o, Two-way ANOVA test with posthoc Tukey’s multiple comparison were used for statistics, treatment x day F(6,44)=0.7998, p = 0.5754, treatment F(1.985, 43.68)=67.51, p < 0.0001; Control vs. [Ala17]MCH p = 0.0106, Control vs. TC-MCH7c p < 0.0001, [Ala17]MCH vs. TC-MCH7c, p < 0.0001. p, Average nesting score over 4 days. F(2,19)=30.36, p < 0.0001. Posthoc Tukey’s multiple comparison, Control vs. MCH: p=0.0096; Control vs. TC-MCH7c, p < 0.0001; MCH vs. TC-MCH7c, p < 0.0001. Data are presented as mean ± SEM, * p < 0.05; ** p < 0.01, *** p < 0.001.

Extended Data Fig. 9 Summary of inferred mechanism through which MCH regulates hippocampo-septal neurocircuits.

a, Diagram of hippocampo-septal circuit, including the role of MCH releasing neurons (green). b, Diagram showing presynaptic regulation of both excitatory and inhibitory synaptic inputs onto a dLS neuron. Synaptic release of GABA activates both GABAA and GABAB receptors. c, Downstream impact of MCH release on dLS neurons. Left: in the absence of MCH, strong collateral inhibition limits the hippocampal-dLS excitatory synaptic inputs induced dLS neuronal firing. Right: In the presence of MCH, dLS neurons are silenced by MCH-induced enhancement of GABAergic inhibition. This in turn reduces the collateral inhibition. However, MCH also enhances dHP-dLS excitatory synaptic inputs, thus enabling the postsynaptic dLS neuron to fire in high fidelity with HP neuronal firing. d, Plot depicts that MCH enhances dLS neuronal firing fidelity in response to HP inputs and thus increased the dynamic range of firing capacity.

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Liu, JJ., Tsien, R.W. & Pang, Z.P. Hypothalamic melanin-concentrating hormone regulates hippocampus-dorsolateral septum activity. Nat Neurosci 25, 61–71 (2022). https://doi.org/10.1038/s41593-021-00984-5

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