Conditional inactivation of Npy1r gene in mice induces behavioural inflexibility and orbitofrontal cortex hyperactivity that are reversed by escitalopram

Abstract

Cognitive flexibility is the ability to rapidly adapt established patterns of behaviour in the face of changing circumstance and depends critically on the orbitofrontal cortex (OFC). Impaired flexibility also results from altered serotonin transmission in the OFC. The Y1 (Y1R) and Y5 (Y5R) receptors for neuropeptide Y (NPY) colocalize in several brain regions and have overlapping functions in regulating cognition and emotional behaviour. The targeted disruption of gene encoding Y1R (Npy1r gene) in Y5R containing neurons (Npy1r mice) increases anxiety-like behaviour and spatial reference memory. Here we used the same conditional system to analyse whether the coordinated expression of the Y1R and Y5R might be required for behavioural flexibility in reversal learning tasks, OFC serotoninergic tone and OFC neural activity, as detected by immunohistochemical quantification of the immediate-early gene, c-Fos. In addition, we investigated whether the acute treatment of Npy1r mice with the selective serotonin reuptake inhibitor escitalopram affected behavioural flexibility and OFC c-Fos expression. Npy1r male mice exhibit an impairment in performing the reversal task of the Morris water maze and the water T-maze but normal spatial learning, working memory and sociability, compared to their control siblings. Furthermore, Npy1r male mice display decreased 5-hydroxytriptamine (5-HT) positive fibres and increased baseline neural activity in OFC. Importantly, escitalopram normalizes OFC neural activity and restores behavioural flexibility of Npy1r male mice. These findings suggest that the inactivation of Y1R in Y5R containing neurons increases pyramidal neuron activity and dysregulates serotoninergic tone in OFC, whereby contributing to reversal learning impairment.

Transcriptomic Landscape of von Economo Neurons in Human Anterior Cingulate Cortex Revealed by Microdissected-Cell RNA Sequencing

“…By interacting with its receptors ( NPY1R , NPY2R , and PPYR1 ; Fig. 2 E ), NPY can influence food intake, anxiety, stress, pain perception, and circadian rhythm, consistent with the known functions of ACC, the brain area with rich VEN distribution (Kuo et al 2007; Loktev and Jackson 2013; Sohn et al 2013; Singh et al 2017; Longo et al 2018). In addition, NPY can regulate sleep by modulating noradrenergic signaling.…”

“…2 E ). Cluster-1, 2 and 3 included four VEN higher expression genes ( NPY , IGFBP2 , MEF2C , and VAT1L ), which were closely related with social-emotional-autonomic functions such as anxiety, stress, arousal and circadian rhythm (Kuo et al 2007; Haberland et al 2009; Fernandez and Torres-Aleman 2012; Zhao et al 2015; Singh et al 2017; Longo et al 2018). In Cluster-4, there were four VEN lower expression genes ( HPCA , HPCAL1 , NUBP2 , and RALGDS ) that interact with the hub genes RHOA and CDK5 .…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…In rodents, the alleviation of anxiety caused by overexpression of Y1R also corroborates the above findings ( 131 ). Similarly, knockout of Y1R leads to anxiety outcomes ( 132 ), and the intranasal administration of Y1R agonists is sufficient to prevent anxiety ( 133 ). Moreover, specific Y5R agonists were injected into the PVN, resulting in a reduction in anxiety-related behaviors in animals ( 134 ).…”

Sex differences in behavioral and metabolic effects of gene inactivation: The neuropeptide Y and Y receptors in the brain

“…Comparison between male and female conditional knockout rodent models. Chao et al, 2011;Ste Marie et al, 2005;Baldock et al, 2007;Bertocchi et al, 2011Bertocchi et al, , 2020Statello et al, 2016;Longo et al, 2014Longo et al, , 2015Longo et al, , 2018Loh et al, 2018;Acton et al, 2019;Baldock et al, 2006;Allison et al, 2006;Shi et al, 2010;Tasan et al, 2010;McCall et al, 2013. ARC, hypothalamus arcuate nucleus; DMH, dorsomedial hypothalamus; HFD, high fat diet; nd, not determined; PP, pancreatic polypeptide; VGAT, vesicular GABA transporter; WAT, white adipose tissue. For references: blue characters, study performed only on males; black characters, study performed in both males and females.…”

“…To analyze the specific contribution of Y1Rs co-expressed with Y5Rs on NPY mediated physiological functions (Naveilhan et al, 1998;Oberto et al, 2007;Wolak et al, 2003), we used the same recombination system to generate conditional Npy1r knockout mice (Npy1 rY5R− /− ) exhibiting inactivation of Y1Rs selectively in Y5R containing neurons of adult animals (Longo et al, 2018(Longo et al, , 2015. Interestingly, Npy1 r Y5R-/mice did not display a sex-biased metabolic phenotype since no significant differences were observed in body weight growth, food intake before and after fasting and HPA axis activity in mutant mice compared to their control littermates, independently of sex (Longo et al, 2014) (Table 6).…”