Elsevier

Biological Psychiatry

Volume 60, Issue 10, 15 November 2006, Pages 1155-1162
Biological Psychiatry

Original article
Human Choline Transporter Gene Variation Is Associated with Corticolimbic Reactivity and Autonomic-Cholinergic Function

https://doi.org/10.1016/j.biopsych.2006.03.059Get rights and content

Background

Our previous work has shown genetic variation in the human choline transporter gene (CHT1) to be associated with depressive symptoms and autonomic cardiac (cholinergic) dysregulation. Here, functional magnetic resonance imaging (fMRI) was used to examine the relation between a single nucleotide polymorphism (SNP) in CHT1 on regional brain reactivity relevant to autonomic (cholinergic) function.

Methods

Thirty-two participants of European ancestry (18 men, 14 women; age: 33–54 years) completed an fMRI protocol using corticolimbic reactivity and prefrontal inhibitory control paradigms. Resting cholinergic function, as measured by heart rate variability (HRV), was quantified from electrocardiogram Subjects were genotyped for a CHT1 G/T SNP.

Results

GG homozygotes had greater right (R) dorsal amygdala (p < .008), bilateral anterior cingulate (p < .009), and R caudate reactivity (p < .015) than T-allele carriers. Heart rate variability was related to R frontal cortex (Brodmann Areas 6, 9, and 46), R hippocampal formation, bilateral caudate, and bilateral anterior cingulate reactivity (p’s < .007).

Conclusions

CHT1 variation is related to differences in a distributed corticolimbic circuitry mediating behavioral and physiologic arousal. These relations may contribute to a biological mechanism by which genetic variation in cholinergic neurotransmission affects cognition, mood, and autonomic cardiac function.

Section snippets

Participants

Thirty-two healthy men (n = 18) and women (n = 14) of European ancestry aged 33–54 years (mean ± SD: 41.13 ± 5.77 years) were included in the sample. These participants were derived from an ongoing study of cardiovascular disease risk factor covariation in a community sample recruited by mass-mail solicitation from Southwestern Pennsylvania (principally Allegheny County). No participants had a history of myocardial infarction or coronary revascularization, cerebrovascular events or disease,

Main Task Effects

For the corticolimbic reactivity paradigm, analysis of the fMRI data showed significant activation of the bilateral amygdala as well as bilateral posterior fusiform and parahippocampal gyri, prefrontal and parietal cortices in all subjects. During the inhibitory control paradigm, response inhibition (no-go) was associated with engagement of several ventral prefrontal cortex areas (BA 9), the anterior cingulate gyrus (BA 32), and the caudate.

No significant effects of gender were noted on either

Discussion

To our knowledge, this is the first study to investigate the potential relation of a choline transporter gene polymorphism, previously shown to be associated with individual variation in peripheral cholinergic activity (as measured by HRV components) and negative mood (Neumann et al 2005a, Neumann et al 2005b), to regional brain activity in middle-aged adults. As anticipated, our findings suggest that CHT1 GG homozygosity is related to right dorsal amygdala, right caudate nucleus, and anterior

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      Both cortical and subcortical cholinergic systems are also known to be involved in facilitating sensory motor-gating and in mediating arousal and attentional processing (Kobayashi and Isa, 2002; Sarter and Bruno, 1999). Interestingly, the Ile89Val variant showed significant association with depression severity in a cohort of 110 patients with major depressive disorder and subjects carrying the 3′SNP polymorphism associated with enhanced CHT function showed reduced depressive symptoms, indicating that cholinergic signaling deficits may also be implicated in the disorder (Hahn et al., 2008; Neumann et al., 2006). One possibility is that hypofunctional CHT leads to decreased cholinergic tone in the central nervous system, which in turn alters receptor sensitivity and impacts risk for depression.

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