Emotion Processing, Major Depression, and Functional Genetic Variation of Neuropeptide Y

Abstract

Context Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proved particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). Objective To determine whether low-expression NPY genotypes are associated with negative emotional processing at three levels of analysis. Design Cross-sectional, case-control. Setting Academic medical center. Participants Forty-four individuals with MDD and 137 healthy controls; 152 (84%) were classified by NPY genotype as low, intermediate, or high, according to previously established haplotype-based expression data. Main Outcome Measures Healthy subjects participated in functional magnetic resonance imaging while viewing negative (versus neutral) words (n=58), and rated positive and negative affect during a pain-stress challenge (n=78). Genotype distribution was compared between 113 control and 39 MDD subjects. Results Among healthy individuals, negatively valenced words activated medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (p=0.029). Whole-brain regression of responses to negative words showed that rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (p<0.05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (p=0.002). Low-expression NPY genotypes were over-represented in MDD after controlling for age and sex (p=0.004). Population stratification did not account for the results. Conclusions These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…Epac is thought to be a key mediator in the effects of PACAP (Ster et al, 2009), a peptide that has been recently implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and fear memory formation (Ressler et al, 2011). Thus, NPY may modulate a variety of behaviors, including conditioned fear (Gutman et al, 2008) and human stress reactivity (Mickey et al, 2011;Witt et al, 2011) via Epac pathways and serve as a critical element in the pathophysiology of depression, PTSD, and other neuropsychiatric disorders. Indeed, several studies implicate changes in NPY levels in depression (Domschke et al, 2010;Nikisch and Mathe, 2008), anxiety disorders (Amstadter et al, 2010;Wu et al, 2011), and PTSD (Rasmusson et al, 2010;Sah et al, 2009).…”

The role of adipocytokines on depressive symptoms of patients with chronic kidney disease

“…Leptin, adiponectin, neuropeptide Y, ghrelin and resistin were reported to be involved in pathophysiology of depressive disorders among subjects with normal kidney function. 11,13,15,16,17 To our knowledge the role of adipocytokines in etiology of depressive disorders of CKD patients have not been explored yet.…”

“…Low neuropeptide Y levels have been reported in major depressive disorder. 13,14 Adiponectin which is an adipocytokine with anti-inflammatory and antiatherogenic effects was also found to be reduced by 30% in premenopausal women with major depressive disorder. 15 Resistin, a low grade inflammation marker, was studied and found to be correlated with atypical depressive symptoms.…”

Neuropeptides and the Microbiota-Gut-Brain Axis

“…NPY as well as Y1, Y2 and Y5 receptors are widely expressed in cerebral areas critical to the regulation of stress resilience [81][82][83][84]. The expression of NPY in the human brain is related to polymorphisms in the NPY gene, and a low NPY expression genotype is associated with negative emotional processing, diminished stress resilience, a risk for major depression, and a reduced antidepressant treatment response [120][121][122]. If individuals with a low NPY expression genotype are exposed to negative stimuli, there is an exaggerated activation of the amygdala, medial prefrontal cortex and anterior cingulate cortex [120][121][122].…”

“…The expression of NPY in the human brain is related to polymorphisms in the NPY gene, and a low NPY expression genotype is associated with negative emotional processing, diminished stress resilience, a risk for major depression, and a reduced antidepressant treatment response [120][121][122]. If individuals with a low NPY expression genotype are exposed to negative stimuli, there is an exaggerated activation of the amygdala, medial prefrontal cortex and anterior cingulate cortex [120][121][122]. The concentration of NPY in the cerebrospinal fluid and plasma is reduced in patients with post-traumatic stress disorder, while trauma-exposed individuals who do not develop or have recovered from post-traumatic stress disorder have enhanced plasma levels of NPY [123][124][125].…”