Nature, nurture, and 5‐HT4R: Familial predisposition, not parental bonding, is associated with brain 5‐HT4R in a sex‐specific manner
- 1Neurobiology Research Unit Rigshospitalet Copenhagen Denmark
- 2Bispebjerg‐Frederiksberg Hospital Psychiatric Centre Copenhagen Copenhagen Denmark
- 3Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
Abstract
Background: Major depressive disorder (MDD) aggregates in families. The neostriatum, key to reward and attachment circuits, has the highest density of serotonin 4 receptors (5‐HT4R). Striatal 5‐HT4R is low in MDD and linked to familial depression risk. Poor parental bonding increases depression risk, yet whether nature and nurture converge on 5‐HT4R is unknown. We investigated whether parental bonding quality is associated with adult neostriatal 5‐HT4R levels and could replicate prior findings on familial predisposition.
Methods: Familial predisposition, parental bonding instrument, and positron emission tomography data with [11C]SB207145 were available from 70 unmedicated MDD patients and 95 healthy controls (64% female; aged 18–57 years). 5‐HT4R binding was quantified in the neostriatum and, secondarily, the amygdala, ACC, and neocortex. Linear regression models examined associations among 5‐HT4R binding, familial predisposition to depression, and parental bonding, adjusting for sex, age, depression, and tracer mass. Sensitivity analyses were conducted with adjustments for hormonal contraceptives and within the healthy subsample only.
Results: Familial predisposition linked to neostriatal 5‐HT4R differently by sex (sex interaction, P = 0.037): predisposed females had 6.8% higher binding than non‐predisposed females (P = 0.024); males showed no significant difference in association. This was consistent across sensitivity analyses and secondary regions. Parental bonding was not associated with 5‐HT4R in any region.
Conclusion: Familial predisposition to depression is associated with neostriatal 5‐HT4R in a sexually dimorphic manner, suggesting that inherited depression risk influences the serotonergic system through sex‐specific mechanisms. The absence of parental bonding effects suggests that the impact on the serotonergic system may be subtle or compensated for.
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BibTeX
@article{kjær2026nature,
title = {{Nature, nurture, and 5‐HT4R: Familial predisposition, not parental bonding, is associated with brain 5‐HT4R in a sex‐specific manner}},
author = {Randi T. Kjær and Martin B. Jørgensen and Kristian H. R. Jensen},
journal = {Psychiatry and Clinical Neurosciences},
year = {2026},
month = aug,
doi = {10.1111/pcn.70112},
url = {https://doi.org/10.1111/pcn.70112},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Nature, nurture, and 5‐HT4R: Familial predisposition, not parental bonding, is associated with brain 5‐HT4R in a sex‐specific manner
AU - Randi T. Kjær
AU - Martin B. Jørgensen
AU - Kristian H. R. Jensen
PY - 2026
DA - 2026/08/01
JO - Psychiatry and Clinical Neurosciences
DO - 10.1111/pcn.70112
UR - https://doi.org/10.1111/pcn.70112
AB - Background: Major depressive disorder (MDD) aggregates in families. The neostriatum, key to reward and attachment circuits, has the highest density of serotonin 4 receptors (5‐HT4R). Striatal 5‐HT4R is low in MDD and linked to familial depression risk. Poor parental bonding increases depression risk, yet whether nature and nurture converge on 5‐HT4R is unknown. We investigated whether parental bonding quality is associated with adult neostriatal 5‐HT4R levels and could replicate prior findings on familial predisposition. Methods: Familial predisposition, parental bonding instrument, and positron emission tomography data with [11C]SB207145 were available from 70 unmedicated MDD patients and 95 healthy controls (64% female; aged 18–57 years). 5‐HT4R binding was quantified in the neostriatum and, secondarily, the amygdala, ACC, and neocortex. Linear regression models examined associations among 5‐HT4R binding, familial predisposition to depression, and parental bonding, adjusting for sex, age, depression, and tracer mass. Sensitivity analyses were conducted with adjustments for hormonal contraceptives and within the healthy subsample only. Results: Familial predisposition linked to neostriatal 5‐HT4R differently by sex (sex interaction, P = 0.037): predisposed females had 6.8% higher binding than non‐predisposed females (P = 0.024); males showed no significant difference in association. This was consistent across sensitivity analyses and secondary regions. Parental bonding was not associated with 5‐HT4R in any region. Conclusion: Familial predisposition to depression is associated with neostriatal 5‐HT4R in a sexually dimorphic manner, suggesting that inherited depression risk influences the serotonergic system through sex‐specific mechanisms. The absence of parental bonding effects suggests that the impact on the serotonergic system may be subtle or compensated for.
SN - 1323-1316
SN - 1440-1819
ER -