ENHANCED HISTAMINERGIC NEUROTRANSMISSION COUNTERACTS OBESITY-INDUCED COGNITIVE IMPAIRMENTS

Chronic exposure to a high-fat diet (HFD) is associated with impairments in cognitive performance. Histaminergic neurons originate in the tuberomammillary nucleus (TMN) and project widely throughout the brain, where neuronal histamine regulates both food intake and cognitive function. Here, we investigated whether acute and chronic stimulation of histaminergic neurotransmission could modulate obesity-associated memory deficits. Hdc-Cre mice (8 weeks old) received bilateral infusions of viral vectors encoding excitatory DREADDs into the TMN. Following surgery, mice were fed an HFD (60% fat) for 10 weeks. Food intake and body weight were monitored daily, and cognitive performance was assessed using the social discrimination (SD) paradigm. After five weeks of HFD exposure, mice showed a significant increase in body weight accompanied by memory deficits. From the sixth week onward, animals were treated for three weeks with either vehicle or clozapine-N-oxide (CNO; 1 mg/kg, i.p.). While vehicle-treated mice continued to gain weight and remained amnesic, chronic CNO treatment induced weight loss and restored social memory. We next examined the effects of acute histaminergic stimulation. To this end, separate cohorts of animals received a single injection of vehicle, CNO, or the H3 receptor antagonist pitolisant (10 mg/kg, i.p.) 30 minutes before the SD training session. As expected, vehicle-treated mice exhibited memory deficits, whereas both CNO and pitolisant treatments rescued social memory without affecting body weight. These findings confirm a critical role for neuronal histamine in the regulation of feeding and cognition and highlight histaminergic signaling as a potential target for treating obesity-related cognitive dysfunction.