Angel Nuñez

Circulating Insulin-Like Growth Factor I Mediates Effects of Exercise on the Brain

Physical exercise increases brain activity through mechanisms not yet known. We now report that in rats, running induces uptake of blood insulin-like growth factor I (IGF-I) by specific groups of neurons throughout the brain. Neurons accumulating IGF-I show increased spontaneous firing and a protracted increase in sensitivity to afferent stimulation. Furthermore, systemic injection of IGF-I mimicked the effects of exercise in the brain. Thus, brain uptake of IGF-I after either intracarotid injection or after exercise elicited the same pattern of neuronal accumulation of IGF-I, an identical widespread increase in neuronal c-Fos, and a similar stimulation of hippocampal brain-derived neurotrophic factor. When uptake of IGF-I by brain cells was blocked, the exercise-induced increase on c-Fos expression was also blocked. We conclude that serum IGF-I mediates activational effects of exercise in the brain. Thus, stimulation of the uptake of blood-borne IGF-I by nerve cells may lead to novel neuroprotective strategies.

Astrocytes Mediate In Vivo Cholinergic-Induced Synaptic Plasticity

In vivo and in vitro studies reveal that astrocytes, classically considered supportive cells for neurons, regulate synaptic plasticity in the mouse hippocampus and are directly involved in information storage.

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.

Cholinergic-mediated IP3-receptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons

Cholinergic–glutamatergic interactions influence forms of synaptic plasticity that are thought to mediate memory and learning. We tested in vitro the induction of long-lasting synaptic enhancement at Schaffer collaterals by acetylcholine (ACh) at the apical dendrite of CA1 pyramidal neurons and in vivo by stimulation of cholinergic afferents. In vitro ACh induced a Ca2+ wave and synaptic enhancement mediated by insertion of AMPA receptors in spines. Activation of muscarinic ACh receptors (mAChRs) and Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores were required for this synaptic enhancement that was insensitive to blockade of NMDA receptors and also triggered by IP3 uncaging. Activation of cholinergic afferents in vivo induced an analogous atropine-sensitive synaptic enhancement. We describe a novel form of synaptic enhancement (LTPIP3) that is induced in vitro and in vivo by activation of mAChRs. We conclude that Ca2+ released from postsynaptic endoplasmic reticulum stores is the critical event in the induction of this unique form of long-lasting synaptic enhancement.

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.

Unit activity of rat basal forebrain neurons: relationship to cortical activity.

Unit activity in the magnocellular basal forebrain nucleus was examined to characterize discharge patterns during synchronized and desynchronized electroencephalogram. Two types of basal forebrain neurons were identified by their firing pattern under urethane anaesthesia: bursting and tonic neurons. Bursting neurons (62.9%) were characterized by a spontaneous firing that consisted of periodic bursts of two to six spikes that occurred at 0.3 to 2 Hz and were phase-locked with the electroencephalogram slow waves. Tonic neurons (37.1%) displayed spontaneous single spike firing at 12.1 + or - 1.6Hz. The firing of most of them was not related to the slow waves. Both neuronal types changed their firing patterns during the electroencephalogram desynchronization elicited by either electrical stimulation of the pedunculopontine tegmentum or pinching the rats tail. Bursting neurons changed from the bursting mode to a tonic mode of discharge pattern, increasing their firing rate, while tonic cells were inhibited during electroencephalogram desynchronization. Multiunit recordings revealed that bursting cells discharged synchronously during periods of electroencephalogram slow waves, but that synchronization disappeared during electroencephalogram desynchronization. No correlation was found between the spike discharges of different tonic cells nor between bursting and tonic cells. However, bursting neurons, but not tonic neurons, were correlated with the spike firings of neocortical neurons during electroencephalogram slow waves. The rhythmic activity of neither neocortical nor bursting basal forebrain cells was found under pentobarbital anaesthesia. The characteristics of the discharge pattern shown by bursting basal forebrain neurons suggest that this type of cell could be cholinergic. Thus, bursting basal forebrain neurons may release acetylcholine in the cortex rhythmically, enhancing the rhythmic activity of cortical neurons during slow-wave sleep. It is concluded that basal forebrain neurons may contribute to the generation of the electroencephalogram slow waves.

Nucleus incertus contribution to hippocampal theta rhythm generation

The hippocampal theta rhythm is generated by the pacemaker activity of the medial septum‐diagonal band of Broca (MS/DBB) neurons. These nuclei are influenced by brainstem structures that modulate the theta rhythm. The aim of the present work is to determine whether the nucleus incertus (NI), which has important anatomical connections with the MS/DBB, contributes to the hippocampal theta rhythm generation in rats. Hippocampal field activity was recorded in urethane‐anaesthetized rats. Electrical stimulation of the NI not only evoked theta rhythm in the hippocampus, but also decreased the amplitude of delta waves. Unit recordings in the NI revealed either a non‐rhythm discharge pattern in most neurons (76%), or a rhythm activity at 13–25 Hz in the remaining neurons. The firing rate of these neurons increased during the presence of theta rhythm evoked by either sensory or reticularis pontis oralis nucleus (RPO) stimulation. Electrolytic lesions of NI, or the microinjection of the γ‐aminobutyric acid (GABA)A agonist muscimol, abolished the theta rhythm evoked by RPO stimulation. Consequently, the NI may be a relay station between brainstem structures and the MS/DBB in the control of the hippocampal theta rhythm generation.

Relationships of nucleus reticularis pontis oralis neuronal discharge with sensory and carbachol evoked hippocampal theta rhythm

SummaryThe activity of 72 neurons recorded in the reticularis pontis oralis nucleus (RPO) was examined in anesthetized and curarized rats during hippocampal theta (θ) rhythm elicited by either sensory stimulation or carbachol microinjections. During hippocampal θ rhythm evoked by sensory stimulation, 63.9% of RPO neurons increased their discharge rate while the firing rate decreased in 20.8%. In all cases, the RPO neurons maintained a non-rhythmic discharge pattern. In 44% of the neurons the discharges tended to occur on the positive wave of the θ rhythm. Similar firing patterns were seen in 18 RPO neurons recorded during θ rhythm elicited by both, sensory stimulation and a carbachol microinjection; this effect was blocked by atropine. These results indicate that the RPO region contributes to the generation of hippocampal θ rhythm with a tonic and nonrhythmic outflow through a cholinergic system which may be muscarinic.

Sedentary life impairs self-reparative processes in the brain: the role of serum insulin-like growth factor-I.

Regular exercise has long being recognized as an important contributor to appropriate health status and is currently recommended to reduce the incidence of many diseases. More recent is the notion that sedentary life may also be a risk factor for neurodegenerative diseases even though for the last decade the beneficial effects of exercise on brain function have been widely documented. In the brain, exercise exerts both acute and long-term changes that can be interpreted as beneficial, such as increased levels of various neurotrophic factors or enhanced cognition. However, the signals involved in exercise-induced changes in the brain are not yet well known. It is generally thought that they arise from the periphery as a direct consequence of increased metabolic activity and aim to elicit adaptive changes in brain function. However, body-to-brain signaling induced by exercise also underlies a different aspect. Exercise induces changes in the brain that are essential for proper brain function. In this view, sedentarism, a relatively new cultural trait, negates the beneficial effects of exercise and paves the way to pathological derangement. A critical step in this process is exercise-induced uptake by the brain of insulin-like growth factor-I (IGF-I), a circulating hormone with potent neurotrophic activity. We summarize the evidence supporting the hypothesis that serum IGF-I is a neuroprotective hormone within a neuroprotective network modulated by physical activity.

Local anaesthesia induces immediate receptive field changes in nucleus gracilis and cortex.

The reorganization of receptive fields of nucleus gracilis neurones after local anaesthesia, and its relationship to the reorganization of cortical maps were studied in the rat. Cutaneous stimulation was performed using electronically gated air jets. Single unit recordings were obtained in gracilis nucleus and somatosensory cortex. Temporary anaesthesia was induced with lidocaine (2%, 5–15 µl s.c.), which blocked the responses in <2 min and provoked the simultaneous appearance of new overlapping receptive fields in gracilis and cortical neurones in 2–30 min. The present results suggest that the early reorganization of somatosensory cortical maps after temporary anaesthesia may be partly due to the emergence of new receptive fields in nucleus gracilis neurones.