Molecular Mechanisms Underlying Mood Disorders
The anterior cingulate cortex (ACC) is a part of the brain particularly implicated in bipolar disorder (BD). Eastwood and Harrison (pages 1010–1016) measured the expression of the gene coding for the vesicular glutamate transporter 1 (VGluT1), a protein that influences the release of glutamate, in the ACC and found it to be increased in subjects with BD, but not in schizophrenia. The result is consistent with findings from magnetic resonance spectroscopy studies of patients with mood disorders that report elevated levels of glutamate. The authors also report differences in expression of two other genes, netrin-G1 and netrin-G2, which suggest that the glutamate abnormalities in BD may be due, in part, to underlying plasticity differences in the affected circuitry.
In order to understand the neurobiology of suicidal behavior, it will be critical to decode the steps in cellular metabolism that influence brain growth and function. Previous research suggests that one of these neuronal enzymes, phosphoinositide 3-kinase (PI 3-K) is altered in the brains of suicide subjects. Dwivedi et al. (pages 1017–1025) studied Akt, a protein that PI 3-K acts on, and upstream Akt regulators, PDK1 and PTEN, in postmortem brains of suicide subjects. They found reductions in the activation and phosphorylation of a selective Akt1 isoform in prefrontal cortex and hippocampus of brain tissue from people who committed suicide. In addition, they found that activation and phosphorylation of PDK1 were decreased and expression of PTEN was increased in these brain areas, suggesting that reduction in Akt1 activation is regulated by PDK1 and PTEN.
Effects of Early Life Stress
Prenatal stress has lasting effects on multiple brain systems in offspring that persist into adulthood. Bergman et al. (pages 1026–1032) evaluated prenatal cortisol levels in pregnant women and cognitive abilities in their offspring, and assessed mother-infant attachment. Their findings in humans provide evidence that increased exposure to cortisol prenatally is associated with impaired cognitive development in a manner that is related to the quality of the mother-infant relationship. Findings from this study highlight the potential of early interventions to alter biological risk in a developing child.
Arabadzisz et al. (pages 1106–1109) investigated whether primates that experienced early life stress exhibited long-term changes in brain expression levels for the targets for steroid stress hormones in the brain, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). At adolescence, brain tissue from primates that were previously stressed had MR and GR levels that were significantly reduced in hippocampus, but not in other brain regions. The link between altered hippocampal MR and GR and behavioral changes in these primates remains to be established.
Genetic Associations of Depression and Sleep
Perlis et al. (pages 1110–1113) sought to replicate previously described associations between polymorphisms in eight candidate genes (PDE1A, PDE1C, PDE6A, PDE11A, ABCB1, GRIK4, SLC6A4, and OPRM1) and antidepressant treatment response. The authors evaluated major depressive disorder (MDD) patients receiving duloxetine treatment. Prior associations were not replicated in this study, suggesting that the associations may be specific to serotonin reuptake inhibitors.
Variation in the serotonin transporter gene (5-HTTLPR) has been associated with a higher risk of developing winter depression. Kalbitzer et al. (pages 1033–1039) used in vivo molecular imaging in healthy individuals to measure serotonin transporter binding in the brain and related the outcome to season of the year. The serotonin system changed over seasons only in carriers of the S-allele. These results suggest that reactivity of the serotonin system to environmental stressors is heritable.
Clock genes are associated with dysfunctional timing of sleep and mood and obesity disorders, which are factors commonly associated with sleep duration. To study the association of clock genes with sleep duration, Allebrandt et al. (pages 1040–1047) investigated 19 candidate genes in healthy individuals. They found that CLOCK was associated with sleep duration in two independent European populations.
Examining Mechanisms of Antidepressant Efficacy
Chronic, but not acute, treatment with antidepressants increases hippocampal neurogenesis. Because chronic treatment with antidepressants also up-regulates p11, Egeland et al. (pages 1048–1056) hypothesized that p11 may regulate effects of antidepressants on aspects of neurogenesis. In response to fluoxetine, mice lacking p11 showed reduced cell proliferation, neurogenesis, cell survival and cell apoptosis in hippocampus when compared to wildtype mice. The behavioral effects of fluoxetine in a neurogenesis-dependent behavioral test were also abolished in mice lacking p11, indicating that p11 does play a role in antidepressant effects.
Iñiguez et al. (pages 1057–1066) exposed rats to fluoxetine during their adolescent developmental period to examine the consequences on behavioral reactivity. As adults, these rats were less sensitive to stressful situations, and more sensitive to the rewarding aspects of sucrose and anxiety-eliciting environments. These rats also exhibited impairments in sexual behavior. These findings highlight the need to improve our understanding of the alterations that psychotropic exposure may induce on the developing nervous system and the potential enduring effects resulting from such treatments.
Medical Implications of Depression
The increased association of MDD and cardiovascular disease (CVD) is well recognized; yet, few studies have examined the impact of MDD without CVD on heart rate variability, a predictor of cardiac arrhythmia. In their meta-analysis, Kemp et al. (pages 1067–1074) report that MDD without CVD is associated with reductions in heart rate variability, and that antidepressants do not reverse this deficit. These data further support the need for adequate long-term medical follow-up among patients who present with MDD.
Clinicians have long noted the association between obesity and mental illnesses such as MDD and posttraumatic stress disorder, although the cause of this association is unclear. In a mouse model of chronic social stress, Chuang et al. (pages 1075–1082) now report that chronic signaling through b3-adrenergic receptors during social stress is an adaptive response that improves mood symptoms by altering leptin signaling and central melanocortin function, but at the expense of weight gain and metabolic abnormalities.
Depression and chronic pain often co-occur, but the underlying mechanisms are largely unknown. Berna et al. (pages 1083–1090) used brain imaging along with a mood induction manipulation to make healthy volunteers feel sad while receiving painful stimuli. They found that altered brain processing of emotional stimuli in depressed patients contributes to their perceiving pain more unpleasantly.
Van Veen et al. (pages 1091–1096) found a markedly delayed daily rhythm in adults with attention-deficit/hyperactivity disorder (ADHD), compared to healthy control subjects. An ADHD subgroup without rhythm delay included more inattentive subjects, which may suggest that diurnal rhythms may differ among ADHD subtypes.
Gray Matter Volume in Bipolar Disorder
Bora et al. (pages 1097–1105) conducted a meta-analysis of voxel-based morphometry studies of gray matter volumes related to BD. The most robust gray matter reductions associated with BD in their meta-analysis occurred in anterior limbic regions, which may be related to the executive control and emotional processing abnormalities seen in this patient population. Clinical factors, such as illness duration and lithium treatment, also have an impact on case-control comparisons of gray matter volume.
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