The human brain receives input from the outside world and converts it to internal psychological activity to control individual behaviors; this is the cognitive process [1]. Cognition, which is the most basic human psychological process, refers to acquiring knowledge, applying knowledge, or processing information. Cognition is critical to normal psychological function and cognitive impairment is the core symptom of many disorders, including neurodegenerative (e.g., Alzheimer’s disease (AD)) [2, 3, 4] and psychiatric diseases (e.g., schizophrenia and affective disorders) [4, 5]. Therefore, it is important to investigate the factors that contribute to cognition.

Intelligence is a general cognitive ability and a quantitative trait that accounts for much of the variation in diverse cognitive abilities. Previous studies demonstrated that general cognitive ability is approximately 50%–70% heritable [6, 7], meaning that genetic differences account for more than 50% of individual variation in performance on tests of cognitive ability. In contrast, the influence of the environment on general cognitive ability is less significant and unstable [8]. Twin studies and molecular genetic studies of unrelated persons have both converged on similar heritability estimates [9, 10]. Cognitive functions other than intelligence include diverse abilities, such as reasoning, memory, selective attention, processing speed, mental rotation, knowledge, and executive function. However, less research has been conducted on factors related to cognitive functions beyond intelligence.

In recent decades, the assessment of cognitive functions has gained increasing widespread attention. Previous studies focused on the effect of Stathmin1 (Stmn1) polymorphisms on individual emotion regulation, whereas the present study planned to evaluate an individual’s ability to inhibit a habitual response and react selectively to information, as well as complicated verbal learning and memory, which is different from and more multifaceted than previous studies. The Stroop Color-Word Test (SCWT) is a frequently used test that measures an individual’s ability to inhibit the normal response in favor of an unexpected response [11]. Previous studies have revealed the functions of the SCWT to assess cognitive abilities including selective attention, processing speed, working memory, and cognitive flexibility [12, 13]. In the present study, the SCWT was used to evaluate the participants’ ability to inhibit a habitual response and react selectively to information. The Hopkins Verbal Learning Test-Revised (HVLT-R) is a multicomponent wordlist learning task developed to assess verbal learning and memory [14], which are important aspects of cognitive function. The utility and validity of the HVLT-R have been demonstrated in individuals with a wide range of different races and ethnicities with significant cognitive impairments, such as AD [15, 16, 17] and Huntington’s disease [18]. It also has high ability of classification accuracy for distinguishing individuals with dementia from those without dementia [15, 19] and patients with AD from those with vascular dementia [17, 20]. Therefore, the HVLT-R was used to evaluate verbal learning and memory function for the participants in the present study.

Stmn1 is highly expressed in central nervous system brain regions, such as the amygdala, prefrontal cortex, and nucleus accumbens, in both mice and humans [4, 21, 22]. It is involved in microtubule (MT) dynamics and neuronal growth and, thus, plays a vital part in neurite outgrowth and synaptic plasticity [23]. Synaptic plasticity refers to the property that the connection strength and functional properties of synapses can change. This plasticity is the basis for the ability of the nervous system to adapt to environmental changes and to execute cognitive functions such as learning and memory. Synaptic plasticity mainly includes short-term and long-term types. Long-term potentiation (LTP) is an important manifestation of long-term synaptic plasticity, which refers to the phenomenon of persistent enhancement of synaptic transmission efficiency and strength that occurs when synapses between two neurons are subjected to a certain form of stimulation. Currently, memory is thought to be encoded by changes in synaptic strength. Thus, LTP plays a crucial role in the process of learning to remember. However, the biological mechanism of LTP has not been fully elucidated. Animal studies found that Stmn1 gene knockout mice showed deficits in spike-timing-dependent LTP, and exhibited deficient memory related to fear conditioning and the recognition of danger in innately aversive environments, relative to wildtype controls [21].

Based on the involvement of Stmn1 in LTP and memory, it was hypothesized that Stmn1 variation primarily impacts human cognition. Brocke et al. [24] demonstrated the significant impact of two single nucleotide polymorphisms (SNPs) of the Stmn1 gene (rs182455 and rs213641) on fear and anxiety responses in healthy German volunteers. Ehlis et al. [23] demonstrated the effect of the rs182455 SNP on cognitive-affective processing in healthy German volunteers. Previous research results on the effect of Stmn1 on human emotion regulation and executive function indicated that Stmn1 genes and proteins may influence human cognitive function. However, no study has reported a correlation between Stmn1 gene polymorphisms and cognitive function assessed by the SCWT or HVLT-R. SNP rs182455 is located within or close to the putative transcriptional control region and affects the Stmn1 protein expression level. Informed by the two studies above [23, 24], the present study explored the correlation of Stmn1 SNP rs182455 with cognitive function in a healthy Chinese population.

The present study investigated the association between Stmn1 gene polymorphism and cognitive function assessed by the SCWT and HVLT-R in a Chinese population for the first time. The results showed significant effects of the SNP rs182455 CC: (CT+TT) genotype on the SC score of the SCWT and TR score of the HVLT-R in the total sample, indicating that carriers of the rs182455 CC genotype have higher immediate free recall, cognitive flexibility, and ability to inhibit usual responses.

In the last decade, meta-analyses of genome-wide association studies (GWAS) have established that human general cognitive ability is highly heritable and polygenic [10, 34, 35, 36, 37, 38, 39, 40]. Prior studies focused on general cognitive ability, namely intelligence, and identified some loci, genes, and SNPs significantly associated with intelligence. Davies et al. [40] identified 148 independent loci associated with general cognitive function by GWAS and 709 genes associated with general cognitive function using gene-based analyses. Up to 4.3% of the variance in general cognitive function could be predicted by polygenic scores in independent samples [40]. However, Stmn1 was not one of the genes associated with general cognitive ability in previous studies.

Stmn1 was the first discovered member of the stathmin family of phylogenetically related MT-destabilizing phosphoproteins, which also includes superior cervical ganglia neural-specific 10 protein (SCG10; stathmin 2), SCG10-like protein (SCLIP; stathmin 3), and RB3 (stathmin 4). Among these, Stmn1 is the most abundantly expressed in the nervous system [41]. Stmn1, a 19 kDa cytosolic protein, is composed of 149 amino acids organized into four domains defined by limited proteolysis [42]. MTs are protein polymers composed of $\alpha$/$\beta$ tubulin heterodimers with essential roles in cellular structure and function, including cell motility, polarity and proliferation, intracellular transport, neurite branch growth, and synaptic plasticity [4, 43, 44, 45]. Unphosphorylated or hypophosphorylated Stmn1 interacts with tubulin heterodimers to prevent the formation of MTs [46]. Stmn1 has four phosphorylation domains: Ser 16, 25, 38 and 63 [47]. Stmn1 releases tubulin after phosphorylation, so that MT can be formed. Thus, Stmin1 is involved in MT dynamics by regulating both the formation of MT and disassembly [44] and influences neural functions. Based on these functions, researchers have investigated the impact of Stmn1 on neural function in both experimental animals and humans.

LTP is an important form of synaptic plasticity [48, 49] and is regarded as a neuronal correlate of fear, learning, and memory [50, 51]. In 2005, Shumyatsky et al. [21] reported that whole-cell recordings from amygdala slices isolated from Stmn1 knockout (KO) mice showed deficits in spike-timing-dependent LTP. Moreover, Stmn1 KO mice exhibited decreased amygdala-dependent fear conditioning memory and failed to recognize the danger in innately aversive environments [21]. In 2008, Martel et al. [52] reported that Stmn1 KO mice showed an increase in social interactions but a decrease in social recognition memory and affiliative maternal care, which were associated with Stmn1 expression in the basolateral amygdala. In 2014, Uchida et al. [53] demonstrated that Stmn1 transgenic mice expressing Stat4A, an unphosphorylatable Stmn1 mutant, showed reduced contextual fear memory, and that Stmn1-MT interactions were a possible mechanism underlying age-dependent memory loss. In 2019, Nguyen et al. [54] found that Stmn1 KO mice showed anxious hyperactivity, impaired object recognition, and decreased levels of neutral and social investigating behaviors at baseline. In a recent study, Shan et al. [55] demonstrated that Stmn1 in the brain memory loop, especially the hippocampus, regulated MT structure by phosphorylation at Ser 25 and Ser 38, and was thus involved in the mediation of fear memory abnormalities in post-traumatic stress disorder (PTSD). Therefore, animal experiments support a correlation between Stmn1 and cognitive functions like learning and memory, as well as related emotions like fear.

In contrast to the animal literature, studies on Stmn1 gene function in humans are rare. Brocke et al. [24] reported that two Stmn1SNPs (rs182455 and rs213641) had significant effects on fear and anxiety responses in humans, measured by startle and cortisol stress responses. Cao et al. [56] found that the Stmn1 rs182455 genotype significantly predicted the severity of reexperiencing symptoms in female patients with PTSD. There is only one report of a direct correlation between Stmn1 gene polymorphism and cognitive function in humans. Ehlis et al. [23] found altered cognitive-affective processing in carriers of the rs182455 SNP C allele, as probed using three experimental paradigms. Of note, the SNP rs182455 selected in the present study is consistent with the SNP studied in the three previous studies [23, 24, 56]. In terms of the correlation between Stmn1 variation and human cognitive function, our findings support the previous results [23]. However, the studies differ in several ways. First, different cognitive assessment tools were used in the study by Ehlis et al. [23] and the present study, and thus different aspects of cognitive functions were studied. The previous study mainly focused on emotion regulation, whereas the present study evaluated individual ability to inhibit habitual responses and react selectively to information, as well as verbal learning and memory. Second, the samples varied in terms of race and size: 59 healthy German participants were used by Ehlis et al. [23], whereas the present study involved 129 healthy Han Chinese participants. Therefore, our findings of a direct relationship between Stmn1 gene variants and cognitive function assessed by the SCWT and HVLT-R in a Chinese sample are a confirmation and extension of previous findings.

The present study found no significant differences in SW and SCW scores on the SCWT or DR, TP and FP scores on the HVLT-R between males and females. However, SC scores on the SCWT and TR scores on the HVLT-R were significantly higher for females than for males, indicating that females have higher immediate free recall, cognitive flexibility, and ability to inhibit usual responses than males. Numerous studies have reported significant sex differences in cognitive function in different groups [57, 58, 59, 60]. Some reviews also summarized and addressed such sex specificity for cognitive functions in detail [61, 62]. Therefore, the findings of the present study that two dimensions of cognitive assessment differed between males and females are consistent with the conclusions of previous related research.

The present study also demonstrated a significant female-specific difference in the SC dimension of the SCWT among the rs182455 genotype groups (females carrying the CC genotype had significantly higher SC scores than those with the TT and CT genotypes). Further analysis showed that the difference in SC dimensions between the two sexes might derive mainly from differences in SC scores between the two sexes with the rs182455 CC genotype. This suggests that the interaction between Stmn1 variants (especially the rs182455 CC genotype) and sex could influence an individual’s cognitive function. In previous studies, Brocke et al. [24] found that the Stmn1 rs182455 genotype interacted with sex to significantly impact fear and anxiety responses, Cao et al. [56] found that the rs182455 C allele was only significantly associated with reexperiencing PTSD symptoms in females, and Ehlis et al. [23] found that the effects of the rs182455 C allele appeared more significant on altered cognitive–affective processing in females. Thus, the female-specific results on the effect of the rs182455 CC genotype on cognitive function in the present study thus support and build upon previous findings.

We speculate why SC scores were higher in females than in males and why the rs182455 CC genotype was significantly associated with SC scores in females, but not in males. As Cahill pointed out, sex differences at the level of brain organization and function are neither small nor unreliable [63]. Given the large amount of evidence that males and females differ in terms of brain regions involved in emotional regulation and cognition, as well as in several neurotransmitter systems, the influence of sex as an additional factor—as well as a factor interacting with other variables—must be considered. Another potential reason for sex-specific findings is androgens secreted by the ovaries of women, which might be involved in MT dynamics that affect neurite branch growth and synaptic plasticity, ultimately affecting biological determination of cognitive function. Regarding the observed sex effects, in silico analysis has demonstrated the transcriptional influence of rs182455 with the T allele facilitating the binding of estrogen regulated transcription factors [23]. Therefore, the interaction between sex and Stmn1 SNP genotypes might be the underlying mechanism of individual differences in cognitive ability. However, this speculation needs to be confirmed by further biochemical experiments.

In summary, this study investigated associations between Stmn1 rs182455 polymorphisms and cognitive abilities measured by the SCWT and HVLT-R in a sample of healthy Han Chinese individuals, demonstrating the underlying biogenetic mechanisms regulating cognition. The results demonstrated a significant modulating influence of SNP rs182455 on the SC dimension of the SCWT and the TR dimension of the HVLT-R, indicating that individuals with the rs182455 CC genotype have higher immediate free recall and cognitive flexibility than those with the CT or TT genotypes. A significant difference in the SC dimension of the SCWT was also observed for the rs182455 genotype in females, indicating that this association is sex-specific. These results provide supporting evidence that Stmn1 gene variations and sex impact cognitive abilities in healthy Chinese individuals and may contribute to the etiopathogenesis of many neurodegenerative and psychiatric conditions since cognitive impairment is their core symptom. Moreover, the Stmn1 protein has been known to play an important role in neurite extension and growth, which typically occur during neural development, repair, and regeneration. Next, further studies, including experiments with gene knockout animals, should be conducted to determine the exact and specific role of the Stmn1 gene and protein in cognitive function. The results of the present study and further studies will provide empirical evidence for the abnormalities of neurodevelopment and synaptic plasticity in the pathogenesis of many neuropsychiatric disorders with cognitive impairment and provide indicators and an evidence-based basis for the prevention and treatment of such disorders in the future.

However, the results of the present study should be viewed with caution because of the limited sample size and age range, the limited number of studied SNPs, and the limitations of the neurocognitive assessment tools used, which might increase the potential bias. Moreover, the present study design was a cross-sectional observational study. This design can only describe the correlation between two variables, not directly prove causation, and it is difficult for this design to completely exclude the effects of confounding factors, which may mask or exaggerate the true association between two variables. In the future, studies of rs182455 SNP and other Stmn1 gene SNPs in larger Chinese or other ethnic samples, as well as a cohort study design, are needed to verify these findings. Research on the specific mechanisms underlying the influence of Stmn1 variants on individual cognitive function is also needed to develop a more comprehensive understanding of this effect.

All in all, the present findings suggest that rs182455 Stmn1 polymorphism might affect cognitive flexibility and immediate free recall in healthy Chinese individuals, especially females.

The raw data supporting the results and conclusions of this article are available upon request.

Conception–HM, ZC, MW; Design–HM, ZC, MW; Supervision–HM, MW; Fundings–HM, LL MW; Materials–HM, ZC, LL, ZS, JZ, HY, MW; Data Collection–HM, ZC, LL, ZS, JZ, HY, MW; Analysis and/or Interpretation–HM, MW; Literature Review–HM, ZC, MW; Writing–HM, ZC, LL, ZS, JZ, HY, MW; Critical Review–HM, MW. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Each volunteer was interviewed by a psychiatrist for enrollment. Each enrolled subject provided written informed consent. The Ethics Committee of Hainan Provincial Anning Hospital approved this study (No.202206). The study was conducted in accordance with the Declaration of Helsinki.

This study was supported by Hainan Province Clinical Medical Center, the Scientific Research Fund of National Natural Science Foundation of China (81771438), the Leading Talent Program of Hainan Medical University (RZ2300007451), and the Science and Technology Special Fund of Hainan Province (ZDYF2024SHFZ073).

The authors declare no conflict of interest.