Biology subjects

Fernandez de Sevilla, M. E.

Publications and source records attributed to Fernandez de Sevilla, M. E..

5 recordsLinked to original sources

bioRxiv2023

A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults by deleting it using tamoxifen-regulated Cre deletion in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detetected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion, including aquaporin 4, complement 1q subunit a, early growth response protein 1, and C-C motif chemokine ligand 2, were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

neuroscience↗

bioRxiv2021

INTEROCEPTIVE INFORMATION OF PHYSICAL VIGOR: OREXIN NEURONS GAUGE CIRCULATING IGF-I FOR MOTIVATIONAL MOTOR OUTPUT

The brain relies on interoceptive feedback signals to regulate bodily functions. Mice with low serum IGF-1 levels (LID mice) exhibit reduced spontaneous running, a behavior that normalizes after sustained systemic IGF-1 treatment. This observation led us to hypothesize that circulating IGF-1--a key regulator of skeletal muscle and bone mass that crosses the blood-brain barrier during physical activity--may convey body vigor information to the brain. Since hypothalamic orexin neurons, that are involved in regulating physical activity, express IGF-1 receptors (IGF-1R) and are modulated by this growth factor, we hypothesized that these neurons might gauge circulating IGF-1 levels to modulate physical activity. Indeed, inactivation of IGF-1R in mouse orexin neurons (Firoc mice) was associated to less time spent in free running. These mice maintain physical fitness but display altered mood and are less sensitive to the rewarding actions of exercise. Further, in response to exercise, Firoc mice showed limited c-fos activation of hypothalamic orexin neurons and monoaminergic neurons of the ventro-tegmental area (VTA) in the brainstem. This area is involved in the rewarding component of exercise that seems to be modulated by IGF-1, as mice receiving systemic IGF-1 showed increased c-fos expression in VTA neurons, while mice with reduced IGF-1R expression in VTA neurons showed no improved mood after exercise. Collectively, these results suggest that circulating IGF-1 is gauged by orexin neurons to modulate physical activity, and that VTA neurons convey the rewarding properties of exercise through direct actions of IGF-1 on them. Hence, serum IGF-1 may constitute an interoceptive signal acting onto orexin/VTA neurons to modulate physical activity according to physical vigor (muscle and bone mass).

neuroscience↗

bioRxiv2021

INSULIN-LIKE GROWTH FACTOR I SENSITIZATION REJUVENATES SLEEP PATTERNS IN OLD MICE

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG stimulation and activation of orexin neurons by systemic IGF-I is abrogated in old mice. Moreover, stimulation of orthodromically activated LH neurons by either systemic or local IGF-I in young mice is absent in old mice. As orexin neurons of old mice show markedly increased IGF-I receptor (IGF-IR) levels, suggesting loss of sensitivity to IGF-I, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

neuroscience↗

bioRxiv2021

Insulin-Like Growth Factor I Couples Metabolism With Circadian Activity Through Hypothalamic Orexin Neurons

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.

neuroscience↗

bioRxiv2020

INSULIN-LIKE GROWTH FACTOR I MODULATES VULNERABILITY TO STRESS THROUGH OREXIN NEURONS

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.

neuroscience↗