TY - JOUR
T1 - Local cannabinoid receptor type-1 regulates glial cell activity and insulin-like growth factor-1 receptor signaling in the mediobasal hypothalamus
AU - Palmisano, Michela
AU - Ramunno, Carla Florencia
AU - Farhat, Eli
AU - Dvir-Ginzberg, Mona
AU - Lutz, Beat
AU - de Almodovar, Carmen Ruiz
AU - Bilkei-Gorzo, Andras
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/8
Y1 - 2024/8
N2 - As organisms age, the activity of the endocannabinoid system in the brain declines, coinciding with increased neuroinflammation and disrupted hypothalamic functions. Notably, cannabinoid receptors type-1 (CB1) are highly expressed in the ventromedial hypothalamic nucleus (VMH) within the mediobasal hypothalamus, a central area of neuroendocrine regulation. This study investigates whether the CB1 receptor influences age-related changes in a brain region-dependent manner. Therefore, we performed stereotaxic injections of rAAV1/2 expressing Cre recombinase in 2-month-old CB1flox/flox male animals to delete the CB1 gene and in CB1-deficient (CB1-STOP) mice to induce its re-expression. The intensity of pro-inflammatory glial activity, gonadotropin-releasing hormone (GnRH) and insulin-like growth factor-1 receptor (IGF-1R) expression was assessed in the hypothalamus of mice at 18–19 months of age. Site-specific CB1 receptor deletion induced pro-inflammatory glial activity and increased hypothalamic Igf1r mRNA expression. Unexpectedly, GnRH levels remained unaltered. Importantly, rescuing the receptor in null mutant animals had the opposite effect: it reduced pro-inflammatory glial activation and decreased Igf1r mRNA expression without affecting GnRH production. Overall, the study highlights the important role of the CB1 receptor in the VMH in reducing age-related inflammation and modulating IGF-1R signaling.
AB - As organisms age, the activity of the endocannabinoid system in the brain declines, coinciding with increased neuroinflammation and disrupted hypothalamic functions. Notably, cannabinoid receptors type-1 (CB1) are highly expressed in the ventromedial hypothalamic nucleus (VMH) within the mediobasal hypothalamus, a central area of neuroendocrine regulation. This study investigates whether the CB1 receptor influences age-related changes in a brain region-dependent manner. Therefore, we performed stereotaxic injections of rAAV1/2 expressing Cre recombinase in 2-month-old CB1flox/flox male animals to delete the CB1 gene and in CB1-deficient (CB1-STOP) mice to induce its re-expression. The intensity of pro-inflammatory glial activity, gonadotropin-releasing hormone (GnRH) and insulin-like growth factor-1 receptor (IGF-1R) expression was assessed in the hypothalamus of mice at 18–19 months of age. Site-specific CB1 receptor deletion induced pro-inflammatory glial activity and increased hypothalamic Igf1r mRNA expression. Unexpectedly, GnRH levels remained unaltered. Importantly, rescuing the receptor in null mutant animals had the opposite effect: it reduced pro-inflammatory glial activation and decreased Igf1r mRNA expression without affecting GnRH production. Overall, the study highlights the important role of the CB1 receptor in the VMH in reducing age-related inflammation and modulating IGF-1R signaling.
KW - Ageing
KW - Cannabinoid type-1 receptor
KW - Hypothalamus
KW - Insulin-like growth factor-1 signaling
KW - Neuroinflammatory glial activity
UR - http://www.scopus.com/inward/record.url?scp=85195022022&partnerID=8YFLogxK
U2 - 10.1016/j.mad.2024.111954
DO - 10.1016/j.mad.2024.111954
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C2 - 38821184
AN - SCOPUS:85195022022
SN - 0047-6374
VL - 220
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
M1 - 111954
ER -