The Journal of Neuroscience, January 10, 2018 • 38(2):257–259 • 257

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Cognitive Control, the Anterior Cingulate, and Nicotinic Receptors: A Case of Heterozygote Advantage

X Jason Smucny Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, California 95817 Review of Sadaghiani et al.

The cholinergic neurotransmitter system, as attention (Parasuraman et al., 2005; Re- was analyzed during a Stop-Signal task. In via diffuse projections emanating from invang et al., 2009; Espeseth et al., 2010)as this task, subjects were asked to respond the basal forebrain and synapsing onto well as nicotine addiction (Breitling et al., to left or right-pointing arrows with a left numerous cortical targets, modulates sev- 2009; Rocha Santos et al., 2015). The rela- or right button press (respectively), but eral neurocognitive functions, including tionships between its allelic combinations were told to withhold the response when attention, working memory, and cogni- (T/T, T/C, and C/C) and cognition, how- the arrow was followed by a “stop” signal tive control (Picciotto et al., 2012). Con- ever, are unclear. Some studies have dem- (up arrow). Cognitive control-associated cordantly, loss-of-function in this system onstrated an advantage (e.g., increased activity was defined as brain activity dur- is associated with cognitive impairment in attentional load capacity) with the T allele ing all “stop” trials and during errors on numerous psychiatric and neurological (Greenwood et al., 2005, 2012; Espeseth et “go” trials. Activity during “stop” trials disorders such as Alzheimer’s disease al., 2010) and others an advantage (e.g., measures the response inhibition aspect (Francis et al., 1999), epilepsy (Ghasemi decreased reaction times) with the C allele of control, and activity during errors-only and Hadipour-Niktarash, 2015), and schi- (Parasuraman et al., 2005; Reinvang et al., “go” trials measures the response conflict- zophrenia (Sarter et al., 2012; Smucny and 2009). Heterozygotes, furthermore, have driven, task adjustment aspect of control Tregellas, 2013), making it an attractive tar- not been well characterized. (Verbruggen and Logan, 2008). For the get for therapeutic intervention. To clarify the effects of these alleles, PNC dataset, network activity was analyzed The most abundantly expressed cho- Sadaghiani et al. (2017) recently exam- during a visual n-back working memory linergic receptor in the mammalian brain ined functional activation (using fMRI) task. For this task, subjects were asked to ␣ ␤ is the ionotropic nicotinic 4 2 receptor. and performance during cognitive control- determine whether an abstract geometric Interestingly, behavioral phenotypes may associated tasks in healthy young adults with image matched a target image (0-back con- be modulated at the level of single-nuc- the T/T, T/C, or C/C rs1044396 genotype. dition), the image shown previously (1-back ␣ ␤ leotide polymorphisms (SNPs) of 4 2 The authors focused on activation of the condition), or the image shown two trials receptor-encoding genes. A striking ex- cingulo-opercular network because of its previously (2-back condition). Cognitive ample of this phenomenon is demon- ␣ demonstrated importance in cognitive control-associated activity was defined as strated by the rs1044396 SNP of the 4 control-associated functions (Lesh et al., brain activity across all conditions. subunit encoding gene CHRNA4, which 2011; Sheffield et al., 2015) and robust nic- Under this framework, Sadaghiani et al. influences neurocognitive processes such otinic receptor expression (Paterson and (2017) found that heterozygotes (T/C sub- Nordberg, 2000). jects) showed greater task-associated activ- To maximize statistical power, Sad- ity in the cingulo-opercular network than Received Sept. 26, 2017; revised Nov. 6, 2017; accepted Nov. 9, 2017. This work was supported in part by a fellowship from the National In- aghiani et al. (2017) used large datasets either T/T or C/C homozygotes. This effect stitutes of Mental Health (F32 MH114325-01). from two publicly available databases: the was specific to the cingulo-opercular net- The author declares no competing financial interests. IMAGEN dataset (Schumann et al., 2010; work: group differences were not observed Correspondence should be addressed to Dr. Jason Smucny, Imaging ϭ nfMRI 1358) and the Philadelphia Neu- in the default, dorsal attention, or frontopa- ResearchCenter,UniversityofCalifornia,Davis,4701XStreet,Sacramento, rodevelopmental Cohort (PNC; Satterth- rietal networks. Heterozygotes also showed CA 95817. E-mail: [email protected]. ϭ DOI:10.1523/JNEUROSCI.2775-17.2017 waite et al., 2014; nfMRI 228). For the greater accuracy during other visual Copyright © 2018 the authors 0270-6474/18/380257-03$15.00/0 IMAGEN dataset, brain network activity continuous performance tasks relative 258 • J. Neurosci., January 10, 2018 • 38(2):257–259 Smucny • Journal Club to homozygotes. These results suggest that dopamine (Cools and D’Esposito, 2011) found differential effects depending on ␣ heterozygotes show both increased activa- and serotonin (Cano-Colino et al., 2014), CHRNA7 (the 7 nicotinic receptor gene) tion of neuronal circuits during cognitive are also due to the influence of these sys- genotype (Tregellas et al., 2011). control-related tasks as well as improved tems on E/I balance. By demonstrating heterozygote advan- overall performance relative to either ho- Regardless of the mechanism, the results tage in human nicotinic receptor SNPs, the mozygous genotype. of Sadaghiani et al. (2017) have important work by Sadaghiani et al. (2017) makes To further understand the mechanism implications for the understanding and an important contribution to our under- underlying this difference, Sadaghiani et treatment of diseases with nicotinic associa- standing of how genes can shape the al. (2017) analyzed gene expression data tions. Schizophrenia, for example, is associ- neuronal mechanisms of cognition. This from the Genotype-Tissue expression project ated with high rates of nicotine dependence study is also one of the first neuroimaging database (GTEx Consortium, 2015). They that have been hypothesized to be a form of genetics studies to take advantage of large found that T/T homozygotes had the self-medication to normalize deficient levels public databases. To this point, reproduc- greatest CHRNA4 expression levels, with of nicotinic signaling (Winterer, 2010). ibility has been an issue in neuroimaging T/C heterozygotes showing intermediate Supporting this view, previous neuroimag- genetics studies due to low power associ- levels and C/C homozygotes the lowest ing studies have observed reduced expres- ated with small sample sizes (Carter et al., levels. This finding suggests that the sion of nicotinic receptors in schizophrenia 2017). This challenge has been difficult rs1044396 SNP may affect cognition by (Freedman et al., 1995;D’Souza et al., 2012). to overcome because of the high costs ␣ affecting 4 subunit expression. Tying this result to the Sadaghiani et al. ($500–1000 per MRI scan; Paulus and These results have important implica- (2017) paper, schizophrenia patients also Stein, 2007) and long study durations nec- tions for our understanding of the rela- show behavioral and functional deficits in essary to conduct large-scale functional tionships between receptor expression cognitive control (including reduced ante- imaging studies. Publicly available data- and neurotransmitter signaling by sug- rior cingulate activation; Lesh et al., 2011, bases such as IMAGEN and the PNC will gesting that intermediate expression of the 2013; Culbreth et al., 2016; Smucny et al., help overcome this hurdle by freely enabling CHRNA4 gene may confer an optimal level 2017). Although no known relationship ex- neuroscience researchers to analyze data of nicotinic signaling for cognitive control. ists between risk for schizophrenia and the collected in parallel across numerous sites, Why might such an “inverted U” shaped ef- rs1044396 SNP, it is possible that the exponentially increasing overall efficiency fect occur? One possibility may lie in how rs1044396 SNP may influence endophe- and reproducibility in the search for genetic the nicotinic system influences the balance notypic traits associated with the illness, mechanisms that underlie dysfunctional between excitation and inhibition (i.e., E/I e.g., deficits in cognitive control. Indeed, neurocognitive processes in neurological balance) in the brain. Healthy brain func- it has been suggested that the effects of and psychiatric disease. tion depends upon homeostatic control of single gene mutations may be better iso- cortical excitability allowing for dynamic lated in polygenic disorders such as schi- control of plasticity and information trans- zophrenia on an endophenotypic level References Breitling LP, Dahmen N, Mittelstrass K, Rujescu fer to optimize efficiency according to task (as demonstrated by the nicotinic ␣7 D, Gallinat J, Fehr C, Giegling I, Lamina C, demands (Krause et al., 2013). 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