Overexpression of neuropeptide Y decreases responsiveness to neuropeptide Y

Abstract

Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age of high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.

Neuropeptide Y and Peptide YY in Association with Depressive Symptoms and Eating Behaviours in Adolescents across the Weight Spectrum: From Anorexia Nervosa to Obesity

“…The decreased NPY levels in malnourished patients with AN suggests no NPY response to starvation, which could be relevant for maintaining a negative energy balance and upholding the disease symptoms. Moreover, it has been proven that the elevation of NPY reduces anxiety, fear learning, and locomotor activity [79]. Therefore, the authors of the present study suggest that the increased anxiety and physical activity observed in patients with AN might be partially associated with a decreased level of NPY.…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…Conversely, activation of the Y2R is anxiogenic by inhibiting GABAergic input ( 136 ), and treatment with specific Y2R antagonists can reduce anxiety behavior in rodents ( 137 ). Surprisingly, overexpression of NPY in cells that regularly express NPY in mice did not lead to the expected reduction in anxiety-like behavior ( 138 ).…”

Chronic overexpression of neuropeptide Y in the skin is sufficient to induce inflammation and epidermal and dermal pathology

“…1. Npy tet/tet skin is brotic with hyperkeratosis To interrogate whether skin pathologies are present in Npy tet/tet mice, we performed histopathological evaluations on the dorsal skin of 22-week-old (i.e., pre-graying stage; [9]) and 35-week-old (i.e., postgraying stage; [9]) Npy +/+ and Npy tet/tet mice (Figure 1). 22-week-old Npy tet/tet skin appears to exhibit epidermal thickening with hyperkeratosis, compared to their Npy +/+ littermates, as evidenced by hematoxylin and eosin (H&E) stained sections (Figure 1A).…”

“…Neuropeptide Y (NPY) is a highly conserved, 36 amino acid neuropeptide that is widely distributed throughout the nervous system and peripheral tissues [1][2][3][4]. In the central nervous system, it is mainly synthesized by sympathetic nerves or in the hypothalamus, where it plays important roles in regulation of feeding behavior and storage of energy [5][6], along with stress and anxiety responses [7][8][9]. Due to its wide distribution peripherally, NPY also has known roles in many biological processes, including the regulation of cell proliferation and migration [10][11][12][13][14], as well as immune responses [15][16][17].…”

“…We recently identi ed that the B6;129S4-Npy tm2Rpa /J mouse, which contains a knock-in mutation that induces entopic overexpression of NPY [9,28], is a novel model with which to study NPY-mediated melanocyte pathology [29]. In our previous study, we found that mice homozygous for the knock-in mutation (Npy tet/tet ) display premature and progressive hair graying starting at approximately 3-4 months of age in comparison to their wildtype (Npy +/+ ) and heterozygous (Npy tet/+ ) siblings, which do not.…”