José Luis Trejo

The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis

Knowledge about the effects of physical exercise on brain is accumulating although the mechanisms through which exercise exerts these actions remain largely unknown. A possible involvement of adult hippocampal neurogenesis (AHN) in the effects of exercise is debated while the physiological and pathological significance of AHN is under intense scrutiny. Recently, both neurogenesis-dependent and independent mechanisms have been shown to mediate the effects of physical exercise on spatial learning and anxiety-like behaviors. Taking advantage that the stimulating effects of exercise on AHN depend among others, on serum insulin-like growth factor I (IGF-I), we now examined whether the behavioral effects of running exercise are related to variations in hippocampal neurogenesis, by either increasing or decreasing it according to serum IGF-I levels. Mutant mice with low levels of serum IGF-I (LID mice) had reduced AHN together with impaired spatial learning. These deficits were not improved by running. However, administration of exogenous IGF-I ameliorated the cognitive deficit and restored AHN in LID mice. We also examined the effect of exercise in LID mice in the novelty-suppressed feeding test, a measure of anxiety-like behavior in laboratory animals. Normal mice, but not LID mice, showed reduced anxiety after exercise in this test. However, after exercise, LID mice did show improvement in the forced swim test, a measure of behavioral despair. Thus, many, but not all of the beneficial effects of exercise on brain function depend on circulating levels of IGF-I and are associated to increased hippocampal neurogenesis, including improved cognition and reduced anxiety.

Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I.

The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid β (Aβ) by modulating transport/production of Aβ carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of Aβ carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Aβ and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimers disease.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.

Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimers disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.

An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat

Interdependence between estradiol and insulin‐like growth factor‐I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin‐like growth factor‐I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin‐like growth factor‐I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5‐bromo‐2‐deoxyuridine and were killed 24 h after the last injection. The total number of 5‐bromo‐2‐deoxyuridine‐positive neurons was significantly increased in animals treated with insulin‐like growth factor‐I, compared with rats treated with vehicles, while rats treated with both insulin‐like growth factor‐I and estradiol showed a higher number of 5‐bromo‐2‐deoxyuridine‐positive neurons than rats treated with insulin‐like growth factor‐I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin‐like growth factor‐I on the number of 5‐bromo‐2‐deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus, and that estradiol and insulin‐like growth factor‐I have a cooperative interaction to promote neurogenesis. The interaction between insulin‐like growth factor‐I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.

Brain repair and neuroprotection by serum insulin-like growth factor I.

The existence of protective mechanisms in the adult brain is gradually being recognized as an important aspect of brain function. For many years, self-repair processes in the post-embryonic brain were considered of minor consequence or nonexistent. This notion dominated the study of neurotrophism. Thus, although the possibility that neurotrophic factors participate in brain function in adult life was prudently maintained, the majority of the studies on the role of trophic factors in the brain were focused on developmental aspects. With the recent recognition that the adult brain keeps a capacity for cell renewal, although limited, a new interest in the regenerative properties of brain tissue has emerged. New findings on the role of insulin-like growth factor I (IGF-I), a potent neurotrophic peptide present at high levels in serum, may illustrate this current trend. Circulating IGF-I is an important determinant of proper brain function in the adult. Its pleiotropic effects range from classical trophic actions on neurons such as housekeeping or anti-apoptotic/pro-survival effects to modulation of brain-barrier permeability, neuronal excitability, or new neuron formation. More recent findings indicate that IGF-I participates in physiologically relevant neuroprotective mechanisms such as those triggered by physical exercise. The increasing number of neurotrophic features displayed by serum IGF-I reinforces the view of a physiological neuroprotective network formed by IGF-I, and possibly other still uncharacterized signals. Future studies with IGF-I, and hopefully other neurotrophic factors, will surely reveal and teach us how to potentiate the self-reparative properties of the adult brain.

Reviews: Mechanisms Mediating Brain Plasticity: IGF1 and Adult Hippocampal Neurogenesis:

This review addresses the role of serum insulin-like growth factor 1 (IGF1) as one mechanism of adult neural plasticity, specifically, its regulation of hippocampal neurogenesis among other plasticity-related processes. It is suggested that IGF has been reused advantageously both for the control of energy expenditure as a function of the organisms activity and to protect, repair, and plastically modulate the brain. Moreover, because as the main source of IGF1 in the adult organism is outside the brain and its presence in this organ is a function of the activity, IGF1 becomes an ideal factor to induce plastic/neuroprotective functions as a function of the organisms activity. The link for this point of view comes from the original function of IGF1 during ontogeny/phylogeny, the promotion of cell survival and control of neural cell numbers, whereas one of the IGF1 functions in the adult brain is the control of hippocampal neurogenesis. The investigation of the IGF1 role as mediator of exercise effects suggests that many but not all the effects of physical activity are mediated by IGF1. These investigations have contributed to delimit the role of IGF1 as mediator of exercise actions, but at the same time are unveiling new roles for serum IGF1 inside the brain.

Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: New cues into the human disease?

The possibility that perturbed insulin/insulin-like growth factor I (IGF-I) signalling is involved in development of late-onset forms of Alzheimers disease (AD) is gaining increasing attention. We recently reported that circulating IGF-I participates in brain amyloid beta (Abeta) clearance by modulating choroid plexus function. We now present evidence that blockade of the IGF-I receptor in the choroid plexus originates changes in brain that are reminiscent of those found in AD. In rodents, IGF-I receptor impairment led to brain amyloidosis, cognitive disturbance, and hyperphosphorylated tau deposits together with other changes found in Alzheimers disease such as gliosis and synaptic protein loss. While these disturbances were mostly corrected by restoring receptor function, blockade of the IGF-I receptor exacerbated AD-like pathology in old mutant mice already affected of brain amyloidosis and cognitive derangement. These findings may provide new cues into the causes of late-onset Alzheimers disease in humans giving credence to the notion that an abnormal age-associated decline in IGF-I input to the choroid plexus may contribute to development of AD in genetically prone subjects.

Role of insulin-like growth factor I signaling in neurodegenerative diseases.

Disturbed trophic support to neurons has long been considered a potential mechanism in neurodegeneration. Recent evidence indicates that intracellular trophic signaling may be compromised in several neurodegenerative diseases. Changes in the levels of insulin-like growth factor I (IGF-I), a trophic hormone with multiple neuroprotective actions, have recently been observed in several human neurodegenerative illnesses. Therefore analysis of IGF-I pathways could help provide greater insight into trophic disturbances to neurons. However, neurodegenerative diseases with similar clinical manifestations show either high or low levels of circulating IGF-I. This apparently puzzling observation can be explained if we consider that IGF-I input to target neurons is disrupted by either lower IGF-I availability or by reduced cell sensitivity to IGF-I. The latter disturbance may be associated with high IGF-I levels. We hypothesize that in the majority of neurodegenerative diseases compromised IGF-I support to neurons emerges as part of the pathological cascade during the degenerative process and contributes to neuronal demise. In addition, loss of IGF-I input to specific neuronal populations might be the cause of a small group of neurodegenerative diseases.

Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour

While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety--as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of exercise, as well as to extend the role of serum IGF1 in the brain in basal conditions. Moreover, these data reveal the complexity of the interaction between neurogenesis, behaviour, and IGF1 under different levels of physical activity.