Genetics of Affective and Anxiety Disorders
Department of Pharmacology, Columbia University, New York, New York, United States Annual Review of Psychology
(Impact Factor: 21.81).
02/2006; 57(1):117-37. DOI: 10.1146/annurev.psych.57.102904.190118
The study of the genetics of complex behaviors has evolved dramatically from the days of the nature versus nurture debates that dominated much of the past century. Here we discuss advances in our understanding of the genetics of affective and anxiety disorders. In particular, we highlight our growing understanding of specific gene-environment interactions that occur during critical periods in development, setting the stage for later behavioral phenotypes. We review the recent literature in the field, focusing on recent advances in our understanding of the role of the serotonin system in establishing normal anxiety levels during development. We emphasize the importance of understanding the effect of genetic variation at the level of functional circuits and provide examples from the literature of how such an approach has been exploited to study novel genetic endpoints, including genetically based variation in response to medication, a potentially valuable phenotype that has not received much attention to date.
Available from: Tina B Lonsdorf
- "These well described neural underpinnings of fear learning provide a starting point to dissect the molecular pathways underlying individual differences in fear acquisition, an approach that is currently at the forefront of research (Graham, Callaghan, and Richardson 2014). In this respect, laboratory models of fear conditioning which can be directly translated across species, are optimally suited because of substantial heritability of both experimental fear conditioning (Hettema et al. 2003; Lonsdorf and Kalisch 2011; Merrill et al. 1999) and clinical anxiety disorders (Gordon and Hen 2004; Leonardo and Hen 2006). In addition, fear conditioning represents a simple behavioral paradigm that elicits robust behavioral responses with sufficient inter-individual variability and adequate re-test reliability (Zeidan et al. 2012) that can be easily measured and quantified (Lonsdorf and Baas 2015; Lonsdorf and Kalisch 2011). "
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ABSTRACT: Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic
basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified
NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional
and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous
carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were
characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated
startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was
significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological
differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral,
subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious
apprehension but provide only limited evidence for a role in (contextual) fear conditioning.
Available from: Yu-Qiang Ding
- "The central serotonin (5-HT) system is known to be involved in emotion, learning and memory (Barnes and Sharp, 1999; Duman and Voleti, 2012), and 5-HT deficiency in the brain is believed to be a major causative factor in anxiety and depression (Brigitta, 2002; Leonardo and Hen, 2006). Selective 5-HT reuptake inhibitors (SSRIs), which can promote monoamine system functions, attenuate anxiety-like behaviors (Graeff et al., 1996) and also produce certain beneficial effects in patients with depression (Artigas et al., 1996; Blier and Ward, 2003). "
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ABSTRACT: Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders.
Available from: PubMed Central
- "Importantly, these manipulations result in models of both anxiety and depression. While anxiety and depression are generally conceived of as distinct psychiatric disorders, they have a high comorbidity with co-occurrence rates up to 60% in patients (Gorman, 1996; Leonardo and Hen, 2006). Ultimately, given that depression is a highly heterogenous disease, no one animal model will accurately replicate the various combinations of phenotypes that are seen in depression. "
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ABSTRACT: Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance.
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