Mariana Alonso - Academia.edu (original) (raw)

Papers by Mariana Alonso

Cellular and Molecular Neurobiology, 2002

Given that brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and... more Given that brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, here we examined signaling mechanisms in vivo in the hippocampus mediating BDNF modulation of long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the CA1 region of the dorsal hippocampus decreased extracellular-signal regulated kinase 2 (ERK2) and CREB activation and impaired LTM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects and also reduced CREB phosphorylation. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 and CREB activation and facilitated LTM. Activated-p38, activated-PKC isoforms, and activated-AKT were unaltered after BDNF or anti-BDNF infusion. In addition, no changes were found on αPKA and βPKA catalytic subunits in nuclear samples. Thus, our results suggest that BDNF exerts its role in LTM formation in vivo in CA1 region of the hippocampus, at least in part, via CREB activation. Moreover, BDNF-induced CREB activation appears to be mediated mainly through the activation of ERK1/2 signaling pathway.

Journal of Neuroscience, 2006

In the olfactory bulb (OB), new neurons are added throughout life, forming an integral part of th... more In the olfactory bulb (OB), new neurons are added throughout life, forming an integral part of the functioning circuit. Yet only some of them survive more than a month. To determine whether this turnover depends on olfactory learning, we examined the survival of adult newborn cells labeled with the cell division marker BrdU, administered before learning in an olfactory discrimination task. We report that discrimination learning increases the number of newborn neurons in the adult OB by prolonging their survival. Simple exposure to the pair of olfactory cues did not alter neurogenesis, indicating that the mere activation of sensory inputs during the learning task was insufficient to alter neurogenesis. The increase in cell survival after learning was not uniformly distributed throughout angular sectors of coronal sections of the OB. Monitoring odor activation maps using patterns of Zif268 immediate early gene expression revealed that survival was greater in regions more activated by the non-reinforced odorant. We conclude that sensory activation in a learning context not only controls the total number of newborn neurons in the adult OB, but also refines their precise location. Shaping the distribution of newborn neurons by influencing their survival could optimize the olfactory information processing required for odor discrimination.

Journal of Neuroscience, 2008

Neurogenesis persists within a few restricted areas of the adult mammalian brain, giving rise to ... more Neurogenesis persists within a few restricted areas of the adult mammalian brain, giving rise to neurons that functionally integrate into preexisting circuits. One of these areas, the subventricular zone (SVZ), was believed, until recently, to be the unique source providing the adult olfactory bulb (OB) with newborn neurons. Because of the fact that neuroblasts derived in the SVZ migrate through the rostral migratory stream (RMS) en route to the OB, the existence of candidate neural stem cells within the RMS was long overlooked. Here, we confirm and considerably extend recent evidence for the existence of adult neural stem cells within the RMS, and go on to investigate their proliferative regulation. Specifically targeting RMS-astrocytes with lentiviral vectors encoding GFP, we demonstrate that glial cells in the RMS differentiate into both OB granule and periglomerular interneurons. In addition, ultrastructural analysis unambiguously reveals the astrocytic nature of stem cells in the adult RMS, and patch-clamp recordings demonstrate the functional integration of RMS-derived interneurons into OB circuitry. Proliferative regulation was investigated via two contrasting manipulations: exposure to an odor-enriched environment that enhances candidate stem cell proliferation in both the RMS and SVZ, and chemical lesion of the main olfactory epithelium that increases cell proliferation in the RMS only. New neurons in the adult OB can therefore arise from different neurogenic areas that can be separately regulated.

Hippocampus, 2002

Information storage in the brain is a temporally graded process involving different memory types ... more Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. Because brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, we examined the role of BDNF in STM and LTM formation of a hippocampal-dependent one-trial fear-motivated learning task in rats. Using a competitive RT-PCR quantitation method, we found that inhibitory avoidance training is associated with a rapid and transient increase in BDNF mRNA expression in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody into the CA, region of the dorsal hippocampus decreased extracellular signal-regulated kinase 2 (ERK2) activation and impaired STM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 activation and facilitated STM. The infusion of anti-BDNF antibody impaired LTM when given 15 min before or 1 and 4 hr after training, but not at 0 or 6 hr posttraining, indicating that two hippocampal BDNF-sensitive time windows are critical for LTM formation. At the same time points, PD098059 produced no LTM deficits. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of an inhibitory avoidance learning. Additionally, they suggest that this requirement involves ERK1/2-dependent and -independent mechanisms.

Hippocampus, 2004

The interleukin-1 (IL-1) cytokine family (IL-1alpha, IL-beta, and the IL-1 receptor antagonist) i... more The interleukin-1 (IL-1) cytokine family (IL-1alpha, IL-beta, and the IL-1 receptor antagonist) is involved in immune and inflammatory responses both in the brain and in the periphery. Recently, it has also been shown to influence behavior and memory consolidation. However, within the experimental systems studied, it has remained unclear whether the role of IL-1beta is associated solely with a pathophysiological process or whether it is a neuromodulator in normal adult brain. To evaluate the involvement of the nonpathological endogenous IL-1 system in learning, we studied the expression of IL-1alpha, IL-1beta, and IL-1ra during memory consolidation. We observed a learning-specific hippocampal IL-1alpha mRNA induction, but not that of IL-1beta or IL-1ra mRNAs, after inhibitory avoidance training. Moreover, when IL-1 receptor activity was inhibited using an adenoviral vector that expresses the IL-1 receptor antagonist (IL-1ra) in the hippocampus, both short-term and long-term memory retention scores were facilitated. In contrast, endogenous hippocampal IL-1 played no role in the habituation to a novel environment. These results demonstrate that endogenous hippocampal IL-1 specifically modulates a fear-motivated learning task, and suggest that IL-1alpha activity in the CNS is part of the hippocampal memory processing.

Neuroscience, 2000

The ability to recall past events is a major determinant of survival strategies in all species an... more The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. In contrast to memory formation, the information about the molecular mechanisms of memory retrieval is surprisingly scarce and fragmentary. Here we show that pretest inhibition of the specific upstream activator of mitogen-activated protein kinase kinase, or of protein kinase A in the hippocampus, blocked retrieval of long-term memory for an inhibitory avoidance task, a hippocampal-dependent learning task. An activator of protein kinase A enhanced retrieval. Mitogen-activated protein kinase activation increased in the hippocampus during retrieval, while protein kinase A activity remained unchanged. Pretest intrahippocampal blockade of metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, but not N-methyl-D-aspartate receptors or calcium/calmodulin dependent-protein kinase II, impaired retrieval. Thus, recall of inhibitory avoidance activates mitogen-activated protein kinase, which is necessary, along with metabotropic glutamate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, and protein kinase A, for long-term memory expression. Our results indicate that memory formation and retrieval may share some molecular mechanisms in the hippocampus.

NeuroReport, 2003

Using the specific inhibitor of p38MAPK, SB203580, we show a direct involvement of this protein k... more Using the specific inhibitor of p38MAPK, SB203580, we show a direct involvement of this protein kinase in short- and long-term memory. When given into the CA1 region of the rat dorsal hippocampus immediately, but not 30 or 120 min after training in a one-trial inhibitory avoidance task, SB203580 blocked short- and long-term memory formation. The SB203580 inactive analog, SB202474, had no effect whatsoever. Learning of the avoidance task was accompanied by an immediate and transient increase in hippocampal p38MAPK phosphorylation. No change in p38MAPK phosphorylation was detected in control animals that only received the electric foot-shock associated with the learning paradigm. Therefore, formation of short and long-term memory for inhibitory avoidance requires p38MAPK activation in the rat hippocampus.

NeuroReport, 1998

THE selectivity of the muscarinic toxin MT3 from green mamba snake venom was corroborated by inhi... more THE selectivity of the muscarinic toxin MT3 from green mamba snake venom was corroborated by inhibition of the binding of [ 3 H]NMS, a classical muscarinic radioligand, to native and cloned muscarinic receptors, showing 214-fold higher affinity for m4 than for m1 subtype, without significant binding to the others. The highest concentrations of MT3 sites (putative m4 receptors) in the rat brain were found in striatum and olfactory tubercle, intermediate concentration in dentate gyrus and CA1, and lower but still conspicuous levels in CA3 and frontal cortex. MT3 caused retrograde amnesia of an inhibitory avoidance task, when injected into the dorsal hippocampus of rats after training, suggesting a positive role of these MT3 sensitive sites, which are probably m4 muscarinic receptors, in memory consolidation of this task. NeuroReport 9: 1407-1411

Neurobiology of Learning and Memory, 2002

Nature Reviews Neuroscience, 2006

New neurons are continually being generated in the adult brain. Two regions -the olfactory bulb a... more New neurons are continually being generated in the adult brain. Two regions -the olfactory bulb and the dentate gyrus of the hippocampus -receive and integrate newborn neurons throughout adult life. In these regions, the addition of new neurons represents another means, further to molecular, synaptic or morphological alterations in individual cells, by which the brain can make changes to its own functional circuitry. Indeed, this cell-level renovation is not static or merely restorative -instead, adult neurogenesis constitutes an adaptive response to challenges imposed by an animal's environment and/or its internal state. This raises some important questions about the role of neurogenesis in mature neuronal circuits. Owing to space constraints, we concentrate on the neurogenic systems of vertebrates, and primarily those of mammals.

Nature Neuroscience, 2012

Learning & Memory, 2002

One of the most rigorously investigated problems in modern neuroscience is to decipher the mechan... more One of the most rigorously investigated problems in modern neuroscience is to decipher the mechanisms by which experience-induced changes in the central nervous system are translated into behavioral acquisition, consolidation, retention, and subsequent recall of information. Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Recent experimental evidence indicates that BDNF modulates synaptic transmission and plasticity by acting across different spatial and temporal domains. BDNF signaling evokes both short-and long-term periods of enhanced synaptic physiology in both pre-and postsynaptic compartments of central synapses. Specifically, BDNF/TrkB signaling converges on the MAP kinase pathway to enhance excitatory synaptic transmission in vivo, as well as hippocampal-dependent learning in behaving animals. Emerging concepts of the intracellular signaling cascades involved in synaptic plasticity induced through environmental interactions resulting in behavioral learning further support the contention that BDNF/TrkB signaling plays a fundamental role in mediating enduring changes in central synaptic structure and function. Here we review recent literature showing the involvement of BDNF/TrkB signaling in hippocampal-dependent learning paradigms, as well as in the types of cellular plasticity proposed to underlie learning and memory.

Learning & Memory, 2005

Information storage in the brain is a temporally graded process involving different memory phases... more Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.

Journal of Neurochemistry, 2004

Intracellular activation and trafficking of extracellular signalregulated protein kinases (ERK) p... more Intracellular activation and trafficking of extracellular signalregulated protein kinases (ERK) play a significant role in cell cycle progression, contributing to developmental brain activities. Additionally, mitochondria participate in cell signalling through energy-linked functions, redox metabolism and activation of pro-or anti-apoptotic proteins. The purpose of the present study was to analyze the presence of ERK1/2 in mitochondria during rat brain development. Immunoblotting, immune electron microscopy and activity assays demonstrated that ERK1/2 are present in fully active brain mitochondria at the outer membrane/intermembrane space fraction. Besides, it was observed that ERK1/2 translocation to brain mitochondria follows a developmental pattern which is maximal between E19-P2 stages and afterwards declines at P3, just before maximal translocation to nucleus, and up to adulthood. Most of mitochondrial ERK1/2 were active; upstream phospho-MAPK/ERK kinases (MEK1/2) were also detected in the brain organelles. Mitochondrial phospho-ERK1/2 increased at 1 lM hydrogen peroxide (H 2 O 2 ) concentration, but it decreased at higher 50-100 lM H 2 O 2 , almost disappearing after the organelles were maximally stimulated to produce H 2 O 2 with antimycin. Our results suggest that developmental mitochondrial activation of ERK1/2 cascade contributes to its nuclear translocation effects, providing information about mitochondrial energetic and redox status to the proliferating/differentiating nuclear pathways. Keywords: development, extracellular signal-regulated kinases 1/2, hydrogen peroxide, MAPK/ ERK kinases 1/2, mitochondria, rat brain.

European Journal of Neuroscience, 2001

It has been recently demonstrated that ubiquitin±proteasome-mediated proteolysis is required for ... more It has been recently demonstrated that ubiquitin±proteasome-mediated proteolysis is required for long-term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long-term memory in the rat. Bilateral infusion of lactacystin, a speci®c proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one-trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin±proteasome cascade, in hippocampus 4 h after training. Together, these ®ndings indicate that the ubiquitin±proteasome cascade is crucial for the establishment of LTM in the behaving animal.

Cellular and Molecular Neurobiology, 2006

1. According to its duration there are, at least, two major forms of memory in mammals: short ter... more 1. According to its duration there are, at least, two major forms of memory in mammals: short term memory (STM) which develops in a few seconds and lasts several hours and long-term memory (LTM) lasting days, weeks and even a lifetime. In contrast to LTM, very little is known about the neural, cellular and molecular requirements for mammalian STM formation.

Journal of Visualized Experiments, 2011

Local interneurons are continuously regenerated in the olfactory bulb of adult rodents. In this p... more Local interneurons are continuously regenerated in the olfactory bulb of adult rodents. In this process, called adult neurogenesis, neural stem cells in the walls of the lateral ventricle give rise to neuroblasts that migrate for several millimeters along the rostral migratory stream (RMS) to reach and incorporate into the olfactory bulb. To study the different steps and the impact of adult-born neuron integration into preexisting olfactory circuits, it is necessary to selectively label and manipulate the activity of this specific population of neurons. The recent development of optogenetic technologies offers the opportunity to use light to precisely activate this specific cohort of neurons without affecting surrounding neurons. Here, we present a series of procedures to virally express Channelrhodopsin2(ChR2)-YFP in a temporally restricted cohort of neuroblasts in the RMS before they reach the olfactory bulb and become adult-born neurons. In addition, we show how to implant and calibrate a miniature LED for chronic in vivo stimulation of ChR2-expressing neurons.