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1.
Mol Psychiatry ; 27(2): 956-966, 2022 02.
Article in English | MEDLINE | ID: mdl-34728797

ABSTRACT

Doublecortin (DCX) has long been implicated in, and employed as a marker for, neurogenesis, yet little is known about its function in non-neurogenic brain regions, including the amygdala. This study sought first to explore, in rodents, whether fear learning and extinction modulate amygdala DCX expression and, second, to assess the utility of peripheral DCX correlates as predictive biomarkers of trauma response in rodents and humans. Pavlovian conditioning was found to alter DCX protein levels in mice 24 h later, resulting in higher DCX expression associated with enhanced learning in paradigms examining both the acquisition and extinction of fear (p < 0.001). This, in turn, is associated with differences in freezing on subsequent fear expression tests, and the same relationship between DCX and fear extinction was replicated in rats (p < 0.001), with higher amygdala DCX levels associated with more rapid extinction of fear. RNAseq of amygdala and blood from mice identified 388 amygdala genes that correlated with DCX (q < 0.001) and which gene ontology analyses revealed were significantly over-represented for neurodevelopmental processes. In blood, DCX-correlated genes included the Wnt signaling molecule Cdk14 which was found to predict freezing during both fear acquisition (p < 0.05) and brief extinction protocols (p < 0.001). High Cdk14 measured in blood immediately after testing was also associated with less freezing during fear expression testing (p < 0.01). Finally, in humans, Cdk14 expression in blood taken shortly after trauma was found to predict resilience in males for up to a year post-trauma (p < 0.0001). These data implicate amygdala DCX in fear learning and suggest that Cdk14 may serve as a predictive biomarker of trauma response.


Subject(s)
Extinction, Psychological , Fear , Amygdala/metabolism , Animals , Conditioning, Classical/physiology , Extinction, Psychological/physiology , Fear/physiology , Individuality , Male , Mice , Rats
2.
Mol Psychiatry ; 22(5): 774-783, 2017 05.
Article in English | MEDLINE | ID: mdl-27595594

ABSTRACT

Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10-8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.


Subject(s)
Emotions/physiology , Happiness , MicroRNAs/genetics , Pleasure/physiology , Adult , Black or African American/genetics , Alleles , Chromosomes, Human, Pair 1 , Female , Gene Frequency , Genetic Variation , Genome-Wide Association Study/methods , Humans , Introns , Male , MicroRNAs/biosynthesis , Middle Aged , Polymorphism, Single Nucleotide
3.
Transl Psychiatry ; 6: e820, 2016 05 24.
Article in English | MEDLINE | ID: mdl-27219346

ABSTRACT

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.


Subject(s)
Brain/physiopathology , Cell Adhesion Molecules, Neuronal/genetics , Stress Disorders, Post-Traumatic/genetics , Adult , Black or African American/genetics , Amygdala/diagnostic imaging , Amygdala/physiopathology , Brain/diagnostic imaging , Facial Expression , Facial Recognition , Fear , Female , Functional Neuroimaging , Genetic Predisposition to Disease , Genome-Wide Association Study , Histocompatibility Antigens Class I/genetics , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Polymorphism, Single Nucleotide , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/physiopathology , Reflex, Startle/physiology , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/psychology , Temporal Lobe/diagnostic imaging , Temporal Lobe/physiopathology , Thalamus/diagnostic imaging , Thalamus/physiopathology , White People/genetics , Young Adult
4.
Am J Med Genet B Neuropsychiatr Genet ; 168B(4): 307-15, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25921615

ABSTRACT

Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n= 803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD.


Subject(s)
Angiotensins/metabolism , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide/genetics , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/genetics , Adult , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Demography , Female , Humans , Male , Racial Groups
5.
Acta Psychiatr Scand ; 118(5): 347-56, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18727689

ABSTRACT

OBJECTIVE: Long-term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta-analysis of available research. METHOD: We reviewed randomized controlled trials for BPD involving >or=6 months of treatment with AD +/- mood stabilizer (MS) vs. placebo +/- MS, using meta-analyses to compare reported risks of new depression vs. mania. RESULTS: In seven trials (350 BPD patients) involving 12 contrasts, long-term treatments that included ADs yielded 27% lower risk of new depression vs. MS-only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55-0.97; number-needed-to-treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23-2.41; number-needed-to-harm (NNH) = 7]. Compared with giving an MS-alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56-1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81-2.33; NNH = 16). CONCLUSION: Long-term adjunctive AD treatment was not superior to MS-alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.


Subject(s)
Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Adult , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Antimanic Agents/administration & dosage , Antimanic Agents/adverse effects , Dose-Response Relationship, Drug , Drug Therapy, Combination , Humans , Long-Term Care , Randomized Controlled Trials as Topic , Recurrence , Risk Assessment
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