Alzheimer’s disease (AD) is a multifactorial pathology characterized by β-amyloid (Aβ) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aβ and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aβ deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.

The activation of protease-activated receptor 1 (PAR1) in cultured rat hippocampal neurons triggers synaptic retrograde signaling through the endocannabinoid 2-arachidonoylglycerol, thereby activating the cannabinoid receptor 1 (CB1R). CB1R is a metabotropic receptor activated by marihuana and endocannabinoids that suppresses neurotransmitter release. Also, activation of the CB1R increases rapid eye movement sleep (REMS) and food intake. The lateral hypothalamus is a crucial structure to modulate both feeding and waking. To evaluate the effect of PAR1 stimulation in the lateral hypothalamus on food intake and on the sleep–waking cycle, we implanted rats with electrodes, for recording sleep, and cannulae, to administer S1820, a selective PAR1 agonist peptide, bilaterally into the lateral hypothalamus. To determine whether the effects induced by PAR1 stimulation were mediated by CB1R activation, we administered AM251, a CB1R inverse agonist, to block S1820 effects. Our results show that the stimulation of PAR1 into the lateral hypothalamus increases both food intake and REMS and such effects were prevented by AM251, indicating that PAR1 modulates both food intake and the sleep–waking cycle, in the lateral hypothalamus, through CB1R activation. This study shows novel behavioral changes induced by PAR1 activation and further supports the notion that endocannabinoids are food intake and REMS promoters.

We have previously reported that maternal separation (MS) for 3 h daily during the first two postnatal weeks increases wakefulness, whereas it reduces sleep in rats. Oleamide, an agonist of the cannabinoid receptor type 1, increases sleep in MS rats to such a level that we cannot differentiate their sleep patterns from those of their non-MS (NMS) siblings. However, 2-arachidonoylglycerol (2-AG), an endocannabinoid, infused into the lateral hypothalamus of NMS rats at the beginning of the dark phase of the cycle increases rapid eye movement sleep and the expression of c-Fos on the rapid eye movement sleep promoting melanin-concentrating hormone neurons. We recorded the sleep–wake cycle of adult rats subjected to MS for 3 h daily from postnatal days 2 to 16, as well as in their NMS siblings. Besides the electrodes for recording the sleep–wake cycle, a couple of cannulae aimed bilaterally to the lateral hypothalamus were implanted to infuse 2-AG. We found that administration of 2-AG into the lateral hypothalamus of MS rats at the beginning of the light phase of the cycle restores sleep, whereas sleep and wakefulness of NMS rats under 2-AG infusion do not show any significant change.