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A hypothalamic novelty signal modulates hippocampal memory - Nature.com

A hypothalamic novelty signal modulates hippocampal memory - Nature.com

A hypothalamic novelty signal modulates hippocampal memory - Nature.com
Sep 30, 2020 9 mins, 48 secs

Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus6.

Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM–CA2 circuit is preferentially activated by novel social encounters.

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Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence.

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Placement in a novel environment induces fos-like immunoreactivity in supramammillary cells projecting to the hippocampus and midbrain.

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Three-dimensional distribution of Fos-positive neurons in the supramammillary nucleus of the rat exposed to novel environment.

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Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice.

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Supramammillary glutamate neurons are a key node of the arousal system.

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Supramammillary nucleus afferents to the dentate gyrus co-release glutamate and GABA and potentiate granule cell output.

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Social stimuli induce activation of oxytocin neurons within the paraventricular nucleus of the hypothalamus to promote social behavior in male mice.

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Galanin neurons in the medial preoptic area govern parental behaviour.

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a, Counts of FOS+ cells in hypothalamic regions that show response to contextual and social novelty.

Two-way ANOVA with Tukey’s post-hoc test, n = 4 mice for all groups.

Open circles are values from individual mice.

b, Example FOS immunostaining (red) in the hypothalamus of one mouse from a total of 4 replicates at various distances from bregma along the rostrocaudal axis of mice 1.5 h after exposure to a familiar context, a novel context or a novel mouse.

AHN, anterior hypothalamic nucleus; DMH, dorsal medial hypothalamic nucleus; LHA, lateral hypothalamic area; LPO, lateral preoptic area; MM, medial mammillary nucleus; MPN, medial preoptic nucleus; MPO, medial preoptic area; PH, posterior hypothalamic nucleus; PVH, paraventricular hypothalamic nucleus; SuM, supramammillary nucleus; VMH, ventromedial hypothalamic nucleus.

b, An example coronal section of the SuM from one of 17 mice used for recording with tetrode locations indicated by arrows.

c, Reconstructed tetrode tip locations (71 in target and 14 off target) from 17 mice overlaid onto schematic mouse brain slices.

e, Mean firing rate of all putative interneuron (pIN; n = 22 from 17 mice) units during different exposures.

BLA, basolateral amygdala; LHA, lateral hypothalamic area; PAG, periaqueductal grey; PF, parafascicular thalamic nucleus; PH, posterior hypothalamic nucleus; RL, rostral linear nucleus raphe; SuM, supramammillary nucleus.

AcbSh, accumbens nucleus, shell; AHN, anterior hypothalamic nucleus; CM, central medial thalamic nucleus; DG, dentate gyrus; DP, dorsal peduncular cortex; fi, fimbria of hippocampus; IAM, interanteromedial thalamic nucleus; IG, induseum griseum; LHA, lateral hypothalamic area; LHb, lateral habenular nucleus; LPO, lateral preoptic area; LS, lateral septal nucleus; MD, mediodorsal thalamic nucleus; MDl, mediodorsal thalamic nucleus, lateral part; MPO, medial preoptic area; MS, medial septal nucleus; PH, posterior hypothalamic nucleus; RE, nucleus of reuniens; SFi, septofimbrial nucleus; SHi, septohippocampal nucleus; SuM, supramammillary nucleus; vhc, ventral hippocampal commissure.

AAV-DIO-eYFP was injected into the SuM of SuM-Cre mice to label SuM projections by Cre-dependent eYFP expression.

Acb, accumbens nucleus; DG, dentate gyrus; EC, entorhinal cortex; SuM, supramammillary nucleus.

d, AbScale shows eYFP+/FOS+ neurons in the SuM after exposure to contextual (left, mouse #252-1263) or social novelty (right, mouse #252-1265).

a, Collateral projections of DG- and CA2-projecting SuM neurons.

Dual-colour Cre-dependent retrograde AAVs were used to label the cell bodies and axons of SuM neurons projecting to the DG (mCherry, red) and CA2 (eYFP, green) (see also Fig. 2d, e).

Weak collateral projections from DG- and CA2-projecting SuM neurons could be seen in the medial (MS) and lateral septal nucleus (LS) and lateral hypothalamic area (LHA).

b, Dual-colour CTB labelling was used to trace the cell bodies of SuM neurons projecting to DG (CTB 488, green) and CA2 (CTB 594, red).

The majority of the identified SuM cell bodies were found to project solely either to the DG or CA2 with only 2.6 ± 0.5% (n = 3 mice, n = 708 neurons) projecting to both.

c, d, Strategy for multiplex fluorescent in situ hybridization (RNAscope) to identify Vglut2 and Vgat mRNAs present in the cell bodies of DG- and CA2-projecting SuM neurons.

Cre-dependent retrograde AAV was used to label the cell bodies and axons of SuM neurons projecting to the DG (c) and CA2 (d).

e, f, DG-projecting (e) and CA2-projecting (f) SuM neurons were stained by antisense probes directed against Vglut2 (570 nm), Vgat (690 nm) and eYFP (520 nm) mRNAs.

g, h, Quantification of eYFP+Vglut2+Vgat+ and eYFP+Vglut2+Vgat− neurons in the DG-projecting (g) and CA2-projecting (h) SuM neurons.

n = 2 mice for each group.

All the DG- and CA2-projecting neurons are Vglut2+.

The majority (average: 71.3%, mouse 1: 72.2%, mouse 2: 70.3%) of DG-projecting neurons are Vgat+, whereas only a small portion (average: 13.1%, mouse 1: 12.3%, mouse 2: 13.8%) of CA2-projecting neurons are Vgat+.

Retrograde AAV-DIO-ChR2-eYFP was bilaterally injected into the DG (a) or CA2 (b) of SuM-Cre mice to infect DG-projecting (a) or CA2-projecting (b) SuM cells.

Two weeks later, acute transverse hippocampal slices were prepared and whole-cell voltage clamp recordings were performed in CA2 pyramidal neurons (PNs, a) or DG granule cells (GCs, b) to determine whether the DG-projecting SuM neurons also innervated CA2 cells (a), and vice versa (b).

No inhibitory or excitatory light-evoked current was detected for any of the 17 CA2 PNs from 6 mice and 19 DG GCs from 7 mice, suggesting that DG-projecting SuM cells do not innervate CA2, and vice versa.

RetroAAV-DIO-ChR2 was bilaterally injected into the DG (e) or CA2 (f) of SuM-Cre mice to infect DG-projecting (e) or CA2-projecting (f) SuM cells.

Two-way ANOVA with Bonferroni post-hoc test, n = 8 mice (DG–ChR2) versus n = 8 (DG–eYFP) in g, n = 8 mice (CA2–ChR2) versus n = 8 (CA2–eYFP) in h

Two-tailed unpaired t-tests, n = 8 mice (DG–ChR2) versus n = 8 (DG–eYFP) in i, n = 8 mice (CA2–ChR2) versus n = 8 (CA2–eYFP) in j

b, d, Strategy to label DG-projecting (b) or CA2-projecting (d) SuM cells using retroAAV-DIO-eYFP with the SuM-Cre mice

DG-projecting SuM neurons were preferentially activated by contextual novelty (DG-projecting: 53.3 ± 6.1% versus CA2-projecting: 37.1 ± 0.4%, *P = 0.0429, one-way ANOVA with Tukey’s post-hoc test, n = 3 mice for both groups), whereas CA2-projecting neurons responded more to social novelty (CA2-projecting: 50.2 ± 1.8% versus DG-projecting: 25.4 ± 2.7%, **P = 0.0042, one-way ANOVA with Tukey’s post-hoc test, n = 3 mice for both groups)

Open circles are values from individual mice

g, j, Strategies for optogenetic identification and recording DG-projecting (g) and CA2-projecting (j) neurons in the SuM

i, l, Histology of recorded mice for circuit-specific optogenetic identification and recording

Thirty-five tetrodes were in target and 8 out of target from 8 mice for recording DG-projecting neurons, and 49 tetrodes were in target and 9 out of target from 11 mice for recording CA2-projecting neurons

c–e, Example travelling trajectories of mice during each contextual exposure described in b under different optogenetic manipulations of the SuM–DG circuit

Two-way ANOVA with Bonferroni post-hoc test, n = 11 mice (DG–ChR2–light) versus n = 11 (DG–ChR2–no light) in f (**P = 0.0013, F (20, 100) = 2.882), n = 11 (DG–eNpHR–light) versus n = 11 (DG–eNpHR–no light) in g (****P < 0.0001, F (20, 100) = 2.402), n = 11 (CA2–ChR2–light) versus n = 11 (CA2–ChR2–no light) in h, n = 10 (CA2–eNpHR–light) versus n = 10 (CA2–eNpHR–no light) in i

Left, diagram illustrating the whole-cell recordings of hippocampal pyramidal neurons (PNs) and SuM fibre stimulation in acute slice preparation

Data for a–c were collected from 156 slices from 92 mice

f, Diagram illustrating the local circuitry and whole-cell recording configuration of DG GCs in acute brain slices prepared from SuM-Cre mice injected with AAV-DIO-ChR2-eYFP

i, j, Sample traces (i) and time course of amplitudes (j, IPSCs only, n = 22 GCs from 8 mice) of light-evoked EPSCs (black) and IPSCs (red) recorded in DG GCs before and after application of 10 μM NBQX and 50 μM APV (grey), and further application of 1 μM SR95531 and 2 μM CGP55845A (green)

AMPA and NMDA receptor blockers completely blocked EPSCs (13 ± 3.1 pA, n = 20 GCs), but only partially blocked IPSCs (by 36%, 86 ± 21 pA before, 31 ± 7.2 pA following NBQX and APV addition, **P = 0.0037, Wilcoxon signed-rank test, n = 22 GCs from 8 mice), indicating that there is feed-forward inhibition recruited by SuM inputs, accompanied by a larger amount of direct inhibitory transmission

The remaining light-evoked IPSCs were entirely blocked by the subsequent addition of GABAA and GABAB receptor blockers, suggesting that DG-projecting neurons in the SuM are capable of simultaneously releasing both glutamate and GABA

IPSCs displayed significantly different response latencies from the EPSCs, with a longer IPSC response latency consistent with bi-synaptic feed-forward inhibition (2.9 ± 0.1 ms for EPSCs, n = 166 PNs; 6.2 ± 0.4 ms for IPSCs, n = 69 PNs; ****P < 0.0001, Mann–Whitney U test; Kolmogorov–Smirnov test, ****P < 0.0001, data from 92 mice)

n, o, Sample traces (n) and time course of amplitudes (o, IPSCs only, n = 7 from 4 mice) of light-evoked EPSCs (black) and IPSCs (red) recorded in CA2 PNs before and after application of 10 μM NBQX and 50 μM APV (grey)

Both the EPSCs (16 ± 4.8 pA, n = 6 PNs from 4 mice) and IPSCs (167 ± 40 pA, n = 7 PNs from 4 mice) were completely blocked by the application of AMPA and NMDA receptor blockers, indicating that the synaptic transmission from the SuM is entirely glutamatergic in CA2

Application of TTX and 4-AP abolishes IPSCs and spares EPSCs in CA2 pyramidal neurons (PNs), consistent with mono-synaptic excitation and di-synaptic inhibition

P = 0.22 for EPSCs, P = 0.016 for IPSCs, Wilcoxon signed-rank test, n = 7 PNs from 3 mice

a, b, Strategies of projection-specific retrograde tracing to map the upstream inputs to the DG-projecting (a) and CA2-projecting (b) neurons

This allows for the retrograde labelling of upstream neurons that send efferent axons to DG- or CA2-projecting SuM cells by the rabies virus

c, d, Coronal sections showing DG-projecting (c) and CA2-projecting (d) starter cells in the SuM

Cells in red (mCherry) are TVA+ cells that express rabies virus (one example of four mice for DG injections, one example of five mice for CA2 injections)

e, f, Coronal sections with trans-synaptically labelled input cells upstream to the DG-projecting (e) and CA2-projecting (f) SuM neurons

g, h, Quantification of inputs from various brain regions to the DG-projecting (g, n = 4 mice) and CA2-projecting (h, n = 5 mice) SuM neurons

Both populations received extensive inputs from subcortical regions including the hypothalamus, brainstem, septum and nucleus accumbens

However, the inputs to the DG-projecting population were comparatively biased to brain regions in the reward and motor systems, such as the VTA, SI, AcbSh, LS and MS, whereas the CA2 projectors received proportionally greater inputs from neurons in socially engaged regions, particularly the PVH (*P = 0.0159, Mann–Whitney U test) and MPO

LS, lateral septal nucleus; MS, medial septal nucleus; SI, substantia innominata; AcbSh, accumbens nucleus, shell; ZI, zona incerta; LHA, lateral hypothalamic area; MPO, medial preoptic area; LPO, lateral preoptic area; PVH, paraventricular hypothalamic nucleus; PH, posterior hypothalamic nucleus; PAG, periaqueductal grey; MRN, midbrain reticular nucleus; VTA, ventral tegmental area; Raphe: DR, dorsal raphe nucleus and MnR, median raphe nucleus

A hypothalamic novelty signal modulates hippocampal memory

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