5HTTLPR Polymorphism and Enlargement of the Pulvinar: Unlocking the Backdoor to the Limbic System Keith A. Young, Leigh A. Holcomb, Willy L. Bonkale, Paul B. Hicks, Umar Yazdani, and Dwight C. German Background: The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. Methods: Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n  11), bipolar disorder (n  11), schizophrenia (n  12), and control (n  15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. Results: Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. Conclusions: The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression. Key Words: Depression, human, postmortem, pulvinar, serotonin, thalamus T he serotonin transporter (SERT) plays an important role in regulating serotonin (5HT) levels in the brain by transport- ing 5HT from the extracellular space into the neuron. A 44 – base pair polymorphism in the transcriptional control region upstream of the coding sequence of the SLC6A4 SERT gene (5HT transporter-linked polymorphic region; 5HTTLPR) results in short (SERT-s) and long (SERT-l) alleles. Although this genetic variant does not directly affect amino-acid sequence, it can alter SERT expression (Bradley et al 2005; Lesch et al 1996). Inheri- tance of the SERT-s allele has been associated with a heightened response of the limbic system to emotional stimuli (Hariri et al 2005; Pezawas et al 2005), elevated levels of subclinical depres- sive symptoms (Gonda et al 2005), and an increased incidence of major depression and suicidal behavior (Hoefgen et al 2005; Lin and Tsai 2004). In addition, 5HTTLPR genetic variants have been associated with a variety of emotion-related behaviors and conditions, including shyness, aggression, anxiety, bipolar disor- der, posttraumatic stress disorder, autism, and attention-deficit/ hyperactivity disorder (Arbelle et al 2005; Cho et al 2005; Curran et al 2005; Gerra et al 2005; Lee et al 2005; Yirmiya et al 2001; You et al 2005). Genetic variation of 5HTTLPR is emerging as an important factor contributing to structural changes in the brain. In a recent study, Pezawas and colleagues (2005) found that normal, non- psychiatric SERT-s carriers have a 25% reduction in the volume of the anterior cingulate cortex and a 15% reduction in the volume of the amygdala. In addition to reduced volumes, the study identified functional alterations in limbic circuits in SERT-s carriers. These data are compelling because the anterior cingu- late cortex and amygdala are intimately involved in the process- ing of emotional responses, and identification of anatomical changes in these limbic circuits raises the possibility that SERT-s carriers possess a unique brain structural phenotype predispos- ing them to depression and related disorders. The thalamus participates in the neural processing of emotion and mood by mediating information flow within the limbic system and cerebral cortex (Alexander et al 1986). For example, during an endogenous depressive episode, or when symptoms of depression are induced experimentally by a reduction in serotonin synthesis, there are metabolic alterations in the thalamus (Drevets 2003; Neumeister et al 2004). In addition to processing ongoing activity of the limbic system, the pulvinar nucleus of the thalamus receives visual and auditory sensory signals and relays informa- tion related to the emotional content of the environment into the limbic system (Ohman 2005). This nucleus directly is connected to both the anterior cingulate cortex and the amygdala (Jones and Burton 1976; Romanski et al 1997). Because the thalamus contains one of the highest levels of SERT in the human brain (Frankle et al 2004) and because SERT is intimately involved in thalamic development and function (Esaki et al 2005; Monckton and McCormick 2002; Persico et al 2001), we investigated the possibility that 5HTTLPR genotype influences thalamic anatomy by measuring neuron number and volume of the pulvinar in postmortem tissue from normal and psychiatric patients of the Stanley Foundation Neuropathology Consortium. The data indi- cate that the SERT-ss genotype is associated with an enlargement of the pulvinar, an anatomic variation that may enhance input of emotionally relevant stimuli into the limbic system and provide a mechanism for predisposition to psychiatric conditions associ- ated with alterations in emotion and mood. Methods and Materials Forty-nine specimens from the Stanley Foundation Neuropa- thology Consortium (Torrey et al 2000), with a complete series of From the Neuropsychiatry Research Program, Central Texas Veterans Health Care System (KAY, LAH, WLB, PBH) and the Texas A&M Health Science Center, Department of Psychiatry and Behavioral Science (KAY, LAH, WLB, PBH), Temple, Texas; and the Department of Psychiatry, University of Texas Southwestern Medical School (UY, DCG), Dallas, Texas. Address reprint requests to Keith A. Young, Ph.D., Central Texas Veterans Health Care System, Neuropsychiatry Research Program (151N), 1901 S. 1st Street, Temple, TX 76504; E-mail: kayoung@medicine.tamhsc.edu. Received February 21, 2006; revised August 2, 2006; accepted August 28, 2006. BIOL PSYCHIATRY 2007;61:813– 818 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.08.047 © 2007 Society of Biological Psychiatry