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SummaryLifestyle induces long lasting effects on brain and cognition, with some interventions like stress including transgenerational inheritance mediated by epigenetic mechanisms. Physical exercise is one lifestyle intervention driving robust improvements of cognition, including intergenerational transmission to the litter. However, little is known about whether exercise effects are transgenerationally transmitted. Here we analyzed adult hippocampal neurogenesis (AHN) and behavioral phenotype of sedentary adult male mice of F2 generation of exercised grandfathers (F0). Both F1 and F2 were sedentary, while F0 performed moderate exercise. We found F2 mice from exercised F0 acquired and recalled both spatial and non-spatial information better than F2 from sedentary F0. Contextual fear conditioning was not affected, together with no differences in AHN markers. Hippocampal smallRNAseq analysis revealed 35 significant differentially expressed (sDE) microRNAs (miRNAs) associated to relevant brain function families. Moreover, 11 of the 35 miRNAs target gene sets were found also enriched in F0 and F1, as well as target genes of 6 of them were differentially expressed also in F0 or F1. One of these 6 is miRNA-144, that together with miRNA-298 were found inversely correlated to cognitive index in F2. These results demonstrate that transgenerational transmission of the effects of exercise on specific cognitive tasks persists after two generations, even though some cellular changes induced in F1 vanish in F2. Thus, they suggest moderate exercise training has longer-lasting effects than previously thought, probably mediated by a small group of miRNAs acting across generations, and this is worth taking into account in public health programs.

Uncoupling of metabolism and circadian activity is associated with an increased risk of various pathologies, including neurodegeneration. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Moreover, both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain undefined. We analyzed whether IGF-I targets orexin neurons in the lateral hypothalamus, as these neurons are involved in circadian rhythms and energy allocation, and are modulated by IGF-I. Mice with disrupted IGF-IR activity in orexin neurons show phase shifts in circadian feeding behavior, loss of circadian orexin expression, and gradually develop sex-dependent metabolic alterations. In addition, modulation by IGF-I of hepatic KLF transcription factors involved in peripheral glucose metabolism is mediated by orexin neurons. Thus, IGF-I entrains energy metabolism and circadian rhythms through hypothalamic orexin neurons.

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on brain Aβ load, a major landmark of AD pathology. Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain Aβ clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral Aβ clearance. We found that Aβ uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral Aβ clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with Aβ precursor protein (APP), and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly less activation of brain IGF-IR phosphorylation and APP/IGF-IR association was found in overweight mice as compared to lean controls. Collectively, these results indicate that diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ clearance probably because its brain entrance is reduced.

Knowledge of mechanisms involved in vulnerability/resilience to stress disorders is crucial for prevention and treatment schemes. We previously documented that insulin-like growth factor I (IGF-I) is associated to vulnerability to stress both in mice and humans. Since hypothalamic orexin neurons express IGF-I receptors and are involved in responses to stress, we analyzed their role in the modulatory actions of IGF-I on stress. Anxiolytic actions of IGF-I after exposure to a predator were absent in mice lacking IGF-I receptors in orexin neurons (Firoc mice). Based on these observations we speculated that Firoc mice may be prone to develop fear-related disturbances, including post-traumatic stress disorder (PTSD)-like symptoms when confronted to fear learning, a process that is postulated to be altered in PTSD. Firoc mice submitted to fear conditioning showed increased freezing responses, suggesting aberrant fear learning. Exaggerated freezing was accompanied by increased levels of orexin, together with enhanced c-fos staining of these neurons –an indicator of increased cell activity, and of noradrenergic neurons of the locus coeruleus nucleus, a region downstream of orexinergic activation. After fear conditioning, Firoc mice developed PTSD-like behavioral traits such as prolonged context-dependent fear and post-stress anhedonia. Since abnormal fear learning was ameliorated by chemogenetic (DREADD) inhibition of orexin neurons, reduced IGF-I input to orexin neurons in Firoc mice seems to enhance their excitability to fear-related inputs. Collectively, these results suggest that IGF-I input to orexin neurons is an important determinant of vulnerability to stress disorders, which provides additional targets for therapy of these high social impact conditions.