Hcar1

Hydroxycarboxylic acid receptor 1 (G protein-coupled receptor 81)

Spatial tier: REGION_BIASED · Class: GPCR · Top region: LM (Lateral mammillary nucleus) · Positive regions: 42/554

50.6Discovery Score
39.0Targetability Score
CEvidence grade C
What this means: Hcar1: fine CCF profile is region-biased toward LM (top regions: LM, NLOT1, MMd, ENTl1, AUDd1); this is a discovery lead, not direct proof.

Function in LM: evidence, prediction, innovation

Gene function
Hcar1 encodes HCA1 (GPR81), a Gi/o-coupled receptor activated by L-lactate at millimolar concentrations. Activation lowers cAMP and, in adipocytes, suppresses lipolysis; in brain it links glycolytic and exercise-driven lactate to receptor signalling rather than to fuel use. It is expressed by neurons, by perivascular and pial fibroblast-like cells, and at the blood-brain interface.
Region function
The lateral mammillary nucleus generates the head-direction signal, relaying vestibular and tegmental input through the mammillothalamic tract to anterodorsal thalamus and presubiculum for spatial orientation.
Published in this region
inferred No region-specific literature found. The closest evidence is from elsewhere in brain: Lauritzen et al. 2014 localised HCAR1 to neurons and the blood-brain interface and linked it to neurovascular coupling; Briquet et al. 2022 showed HCAR1 activation down-modulates neuronal activity in rodent and human tissue; Jorwal et al. 2019 showed lactate suppresses subicular epileptiform activity via HCA1 and GIRK channels; Morland et al. 2017 showed exercise drives cerebral VEGFA and angiogenesis through HCAR1; Ordenes et al. 2021 showed lactate activates hypothalamic POMC neurons.
Predicted function
Prediction: here HCA1 most plausibly acts as a Gi brake coupling local glycolytic lactate to reduced excitability of head-direction cells, probably via GIRK opening as in subiculum, with a parallel perivascular pool driving activity-dependent angiogenesis in this heavily vascularised nucleus. Because the gene is also enriched at the blood-brain interface, part of the regional signal is likely vascular. Hcar1 knockout or local agonist infusion should shift head-direction cell gain and tuning stability during demanding navigation and blunt exercise-induced mammillary capillary growth.
Innovation
★★★★☆ 4/5 Lactate-receptor signalling is well studied in cortex and hippocampus but never in the head-direction system, where metabolic demand during navigation is high.
Tools
Hcar1 knockout mice; selective agonists 3,5-dihydroxybenzoic acid (3,5-DHBA) and 3-chloro-5-hydroxybenzoic acid; L-lactate; anti-HCAR1 antibodies; lateral mammillary access by stereotaxic AAV and retrograde targeting from anterodorsal thalamus.
References

Direct evidence located at the region

Hcar1 Allen ISH at the CCF centroid of LM

Allen ISH experiment 77464856, section image 77469822 (section 152): the section that contains the CCF centroid of Lateral mammillary nucleus according to the Allen image-to-atlas alignment (reference_to_image), with a 2 mm window around that point. Left: whole section, red box = window. Middle: ISH signal. Right: Allen's expression-mask view of the same window. open this image in the Allen viewer

Look it up yourself: Allen Mouse Brain ISH for Hcar1Allen reference atlas: LM (structure 210)ABC Atlas MERFISH viewer(in the ABC Atlas choose dataset MERFISH-C57BL6J-638850-CCF, colour cells by gene "Hcar1" or by parcellation_substructure "LM")All genes confined to LM + 3-D brain

Direct spatial evidence

MERFISH REGION LOCATOR
LM MERFISH region locator
Real single-cell MERFISH coordinates for the LM (Lateral mammillary nucleus) section -- our own ground-truth data, showing exactly where this region sits, independent of whether the Allen ISH section below is easy to read.

Regional expression figure

Hcar1 regional expression profile

Predicted WMB × fine-CCF profile; not direct full-transcriptome spatial measurement.

Spatial profile

LM
1.21
NLOT1
1.02
MMd
0.937
ENTl1
0.626
AUDd1
0.6
TTv
0.595
VISpor1
0.586
ENTm1
0.546
SSp-m1
0.529
SCzo
0.491
SSs1
0.466
ORBm1
0.445
SSp-bfd1
0.438
IG
0.42
VISp1
0.417
SSp-un1
0.417
SSp-n1
0.409
AUDp1
0.407
ME
0.398
SSp-ul1
0.395

Evidence and specificity

Evidence status
PREDICTED_FINE
Direct sources
None; predicted localization only
Exclusive threshold
12 positive regions out of 554
Spatial specificity
0.308
Top-region fraction
0.049
Filter status
PASS

Interpretation limits