Chrna5

Neuronal acetylcholine receptor subunit alpha-5

Spatial tier: RESTRICTED · Class: ION_CHANNEL · Top region: IPR (Interpeduncular nucleus, rostral) · Positive regions: 17/554

45.2Discovery Score
40.6Targetability Score
CEvidence grade C
What this means: Chrna5: fine CCF profile is restricted toward IPR (top regions: IPR, IPC, IPI, IPDL, CA1sp; 17 positive regions); direct spatial validation is still required.

Function in IPR: evidence, prediction, innovation

Gene function
CHRNA5 encodes the alpha-5 subunit of neuronal nicotinic acetylcholine receptors. Alpha-5 is an accessory subunit: it cannot form a binding site itself but occupies the fifth position in alpha4beta2 or alpha3beta4 pentamers, where it strongly increases calcium permeability and alters desensitisation. The human D398N coding variant in the CHRNA5-A3-B4 cluster is one of the strongest common genetic risk factors for heavy smoking and lung cancer.
Region function
The rostral interpeduncular nucleus is the principal target of the medial habenula, receiving cholinergic, glutamatergic and substance-P input via the fasciculus retroflexus; it mediates nicotine aversion, withdrawal and anxiety-like behaviour.
Published in this region
direct Direct. Morton et al. 2018 showed that Chrna5-expressing neurons in the interpeduncular nucleus mediate aversion primed by prior stimulation or nicotine exposure, using a Chrna5-Cre line to identify and manipulate the cells. Fowler et al. 2011 established that alpha-5 signalling in the habenulo-interpeduncular pathway sets the aversive brake that limits nicotine intake, and Antolin-Fontes et al. 2015 reviewed how this pathway drives nicotine aversion and withdrawal.
Predicted function
Prediction: alpha-5 in the rostral interpeduncular nucleus should turn out to be a state-dependent amplifier rather than a constitutive brake - it is predicted to raise the calcium permeability of alpha3beta4 receptors specifically after prior nicotine exposure, converting a modest cholinergic input into a strong aversive signal and thereby setting the ceiling on nicotine self-administration. IPN-restricted Chrna5 knockdown is predicted to increase nicotine intake at high unit doses and reduce somatic and affective withdrawal signs, while lentiviral re-expression of wild-type but not D398N alpha-5 in IPN of knockouts should restore the aversive ceiling.
Innovation
★★☆☆☆ 2/5 Chrna5 in the interpeduncular nucleus has a clear primary paper and an active literature, though the rostral subdivision specifically and the D398N variant's local effects remain open.
Tools
Chrna5-Cre mice (Morton et al. 2018), Chrna5 knockout and the humanised D398N knock-in; lentiviral alpha-5 re-expression constructs; nicotine, mecamylamine and the alpha3beta4-preferring antagonist AT-1001; Chat-Cre and Tac1-Cre for the medial habenular inputs; anti-alpha5 antibodies.
References

Direct evidence located at the region

Chrna5 Allen ISH at the CCF centroid of IPR

Allen ISH experiment 75826567, section image 75708081 (section 214): the section that contains the CCF centroid of Interpeduncular nucleus, rostral 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 Chrna5Allen reference atlas: IPR (structure 607344834)ABC Atlas MERFISH viewer(in the ABC Atlas choose dataset MERFISH-C57BL6J-638850-CCF, colour cells by gene "Chrna5" or by parcellation_substructure "IPR")All genes confined to IPR + 3-D brain

Direct spatial evidence

MERFISH REGION LOCATOR
IPR MERFISH region locator
Real single-cell MERFISH coordinates for the IPR (Interpeduncular nucleus, rostral) 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

Chrna5 regional expression profile

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

Spatial profile

IPR
3.47
IPC
2.64
IPI
1.52
IPDL
1.27
CA1sp
1.04
SSp-tr6b
1.03
ACAv6b
0.998
ACAd6a
0.947
VISa6b
0.928
VISam6b
0.928
VTA
0.899
SSp-ll6b
0.885
ACAv6a
0.882
MOs6a
0.874
SNc
0.872
PL6a
0.867
TEa6b
0.834
ECT6a
0.816
VISli6b
0.804
MOp6a
0.799

Evidence and specificity

Evidence status
PREDICTED_FINE
Direct sources
None; predicted localization only
Exclusive threshold
12 positive regions out of 554
Spatial specificity
0.278
Top-region fraction
0.060
Filter status
PASS

Interpretation limits