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, 15 (1), e0227575
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The Interoceptive Hippocampus: Mouse Brain Endocrine Receptor Expression Highlights a Dentate Gyrus (DG)-cornu Ammonis (CA) Challenge-Sufficiency Axis

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The Interoceptive Hippocampus: Mouse Brain Endocrine Receptor Expression Highlights a Dentate Gyrus (DG)-cornu Ammonis (CA) Challenge-Sufficiency Axis

Richard Lathe et al. PLoS One.

Abstract

The primeval function of the mammalian hippocampus (HPC) remains uncertain. Implicated in learning and memory, spatial navigation, and neuropsychological disorders, evolutionary theory suggests that the HPC evolved from a primeval chemosensory epithelium. Deficits in sensing of internal body status ('interoception') in patients with HPC lesions argue that internal sensing may be conserved in higher vertebrates. We studied the expression patterns in mouse brain of 250 endocrine receptors that respond to blood-borne ligands. Key findings are (i) the proportions and levels of endocrine receptor expression in the HPC are significantly higher than in all other comparable brain regions. (ii) Surprisingly, the distribution of endocrine receptor expression within mouse HPC was found to be highly structured: receptors signaling 'challenge' are segregated in dentate gyrus (DG), whereas those signaling 'sufficiency' are principally found in cornu ammonis (CA) regions. Selective expression of endocrine receptors in the HPC argues that interoception remains a core feature of hippocampal function. Further, we report that ligands of DG receptors predominantly inhibit both synaptic potentiation and neurogenesis, whereas CA receptor ligands conversely promote both synaptic potentiation and neurogenesis. These findings suggest that the hippocampus acts as an integrator of body status, extending its role in context-dependent memory encoding from 'where' and 'when' to 'how I feel'. Implications for anxiety and depression are discussed.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Endocrine receptor gene expression in mouse brain and enrichment in the hippocampus (HPC).
More than one third of all endocrine receptors were detectably expressed in brain, where they are likely to modulate brain function and cognition. Expression was restricted to specific brain regions: other than hippocampus (HPC), cerebellum (CB), and cortex (CX), there was little evidence for specific gene expression in other comparable regions (~4%; see text). (A) Mouse brain section highlighting the three regions studied in detail: HPC, CB, and CX. (B) (Left) Heatmap of 'raw' (unnormalized expression data, see Methods) for HPC versus CB and CX. (Right) Scatterplots of unnormalized expression levels; horizontal lines are medians and quartiles showing that the mean expression level of all receptors in HPC is significantly higher than in either CB or CX. (C) Normalized (maximum expression level = 100%) gene expression data. On three counts, the HPC (red), versus CB (green) and CX (blue), is the major site of expression of endocrine receptors (253 receptors examined) as further evidenced by the inset showing (i) exclusive expression in HPC, (ii) most prominent expression in HPC, (iii) overall number of receptors expressed. *Receptors showing no detectable expression or low-level/punctate/irreproducible expression are classified as expression absent. Note that the dendrograms (generated by heatmap.2), depicted in A and B, are not supported by statistical analysis versus alternative, competing dendrograms. Genes that are expressed exclusively in HPC, CB, or CB were not distributed among these three regions with equal probability, and ‘exclusive genes’ were expressed most often in HPC; the same result emerges when considering genes that are expressed most prominently in one brain region. Thus, the HPC expresses both a greater number and level of endocrine receptor genes than any other brain region analyzed.
Fig 2
Fig 2. Subregional representation of 86 receptors expressed in mouse hippocampus (HPC).
Data are normalized to the maximum expression level. *The data indicate that some receptors are somewhat restricted in their expression pattern to one subregion, whereas others are expressed in combinations of regions. Note: the depicted dendrograms (generated by heatmap.2) are not supported by statistical analysis versus alternative, competing dendrograms. There were significant positive correlations between CA2 and CA3, and significant negative correlations between CA1 and DG (Table D in S1 Appendix).
Fig 3
Fig 3. Expression of 'informative' endocrine receptors in subregions of the mouse hippocampus (HPC).
(Above) Principal neuroatomical subdivisions of the rodent HPC (adapted from the model of [15]). (Below) Informative (see main text) receptors sorted according to regional expression (heatmap, normalized data) with CA1 and DG at the two extremes (Methods) showing expression clustering of receptor types in different regions (e.g., 'sufficiency'–FGF receptors FGFR1, FGFR3, and KL in CA regions; and 'challenge'–interleukin and TNF receptors IL1R1, IL17RD, IL10RB, IL2RB, TNFRSRF 25, TNFRSF21, TNFRSF19 in DG).
Fig 4
Fig 4. Ratios of CA versus DG expression for informative receptors.
(A) Group A (DG/challenge). (B) Group B (CA/sufficiency). Individual genes are ordered as in Fig 3. The differential DG versus CA pattern of expression was highly significant.
Fig 5
Fig 5. Differential effects of receptor activation on long-term potentiation (LTP) and neurogenesis.
(A) Group A (DG/challenge). (B) Group B (CA/sufficiency). Individual genes are ordered as in Figs 3 and 4. (C) Mean scores for the two groups, demonstrating that group A receptors tend to suppress both LTP and neurogenesis, whereas group B receptors tend to promote both parameters. The differential patterns of stimulation/inhibition of LTP and neurogenesis were highly significant between the two groups.

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Grant support

The authors received no specific funding for this work.
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