Nature, nurture, and 5-HT4R: Familial predisposition, not parental bonding, is associated with brain 5-HT4R in a sex-specific manner.

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.