Memory and learning allow animals to appropriate certain properties of nature with which they can navigate in it successfully. Memory is acquired slowly and consists of two major phases, a fragile ...early phase (short‐term memory, <4 h) and a more robust and long‐lasting late one (long‐term memory, >4 h). Erythropoietin (EPO) prolongs memory from 24 to 72 h when animals are trained for 5 min in a place recognition task but not when training lasted 3 min (short‐term memory). It is not known whether it promotes the formation of remote memory (≥21 days). We address whether the systemic administration of EPO can convert a short‐term memory into a long‐term remote memory, and the neural plasticity mechanisms involved. We evaluated the effect of training duration (3 or 5 min) on the expression of endogenous EPO and its receptor to shed light on the role of EPO in coordinating mechanisms of neural plasticity using a single‐trial spatial learning test. We administered EPO 10 min post‐training and evaluated memory after 24 h, 96 h, 15 days, or 21 days. We also determined the effect of EPO administered 10 min after training on the expression of arc and bdnf during retrieval at 24 h and 21 days. Data show that learning induces EPO/EPOr expression increase linked to memory extent, exogenous EPO prolongs memory up to 21 days; and prefrontal cortex bdnf expression at 24 h and in the hippocampus at 21 days, whereas arc expression increases at 21 days in the hippocampus and prefrontal cortex.
(A) Exploring the experimental arena for 3 min induces an increase in the expression of endogenous EPO and its receptor in the hippocampus and the prefrontal cortex. The increase is higher if training is prolonged to 5 min. (B) Animals identify object displacement and explore more the moved object, but only up to 4 h after training. (C) Exogenously applied EPO 10 min after training prolongs memory up to, at least 21 days, and correlates with an increased expression of plasticity‐related genes.
Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria‐fornix (FF). The mechanisms for this improvement involve early ...gene expression and synthesis of BDNF, MAP‐2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c‐Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF‐lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c‐Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF‐lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF‐lesioned, but not stimulated group, like the c‐Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.
Bone marrow stromal cells (BMSC) have attracted interest through their possible use for cell therapy in neurological diseases. Recent reports demonstrated that these cells are able to migrate and ...have potential for neuronal differentiation after transplantation into brain parenchyma. The objective of this work was determine whether rat BMSC express NGF and GDNF, in order to study its potential application for treatment of neurodegenerative diseases. BMSC were harvested from male rats and cultured in DMEM supplemented with 20% fetal bovine serum. At passage 6 the total RNA was isolated using TriZol reactive. RT-PCRs to evaluate the expression of NGF and GDNF using specific primers were carried out. Our results indicate that rat BMSC have potential to produce NGF and GDNF. We have not found any report in favor of GDNF or NGF production from rat BMSC.
Novelty processing can transform short-term into long-term memory. We propose that this memory-reinforcing effect of novelty could be explained by mechanisms outlined in the "synaptic tagging ...hypothesis." Initial short-term memory is sustained by a transient plasticity change at activated synapses and sets synaptic tags. These tags are later able to capture and process the plasticity-related proteins (PRPs), which are required to transform a short-term synaptic change into a long-term one. Novelty is involved in inducing the synthesis of PRPs Moncada D, et al. (2011) Proc Natl Acad Sci USA 108:12937–12936, which are then captured by the tagged synapses, consolidating memory. In contrast to novelty, stress can impair learning, memory, and synaptic plasticity. Here, we address questions as to whether novelty-induced PRPs are able to prevent the loss of memory caused by stress and if the latter would not interact with the tag-setting process. We used water-maze (WM) training as a spatial learning paradigm to test our hypothesis. Stress was induced by a strong foot shock (FS; 5 x 1 mA, 2 s) applied 5 min after WM training. Our data show that FS reduced long-term but not short-term memory in the WM paradigm. This negative effect on memory consolidation was time- and training-dependent. Interestingly, novelty exposure prevented the stress-induced memory loss of the spatial task and increased BDNF and Arc expression. This rescuing effect was blocked by anisomycin, suggesting that WM-tagged synapses were not reset by FS and were thus able to capture the novelty-induced PRPs, re-establishing FS-impaired long-term memory.
Background. Erythropoietin (EPO) upregulates the mitogen activated protein kinase (MAPK) cascade, a central signaling pathway in cellular plastic mechanisms, and is critical for normal brain ...development. Objective. We hypothesized that EPO could modulate the plasticity mechanisms supporting spatial memory recovery in fimbria-fornix-transected animals. Methods. Fimbria-fornix was transected in 3 groups of rats. Seven days later, EPO was injected daily for 4 consecutive days within 10 minutes after training on a water maze task. Results. Our results show that EPO injections 10 minutes after training produced a substantial spatial memory recovery in fimbria-fornix-lesioned animals. In contrast, an EPO injection shortly after fimbria-fornix lesion surgery does not promote spatial-memory recovery. Neither does daily EPO injection 5 hours after the water maze performance. EPO, on the other hand, induced the expression of plasticity-related genes like arc and bdnf, but this effect was independent of training or lesion. Conclusions. This finding supports our working hypothesis that EPO can modulate transient neuroplastic mechanisms triggered by training in lesioned animals. Consequently, we propose that EPO administration can be a useful trophic factor to promote neural restoration when given in combination with training.
Huntington's disease (HD) is an inherited, neurodegenerative disorder that results from the degeneration of striatal neurons, mainly GABAergic neurons. The study of neurochemical activity has ...provided reliable markers to explain motor disorders. To treat neurodegenerative diseases, stem cell transplants with bone marrow (BM) have been performed for several decades. In this work we determine the effect of mononuclear bone marrow cell (mBMC) transplantation on the rotational behavior and neurochemical activity in a model of Huntington's disease in rats. Four experimental groups were organized: Group I: Control animals (
= 5); Group II: Lesion with quinolinic acid (QA) in the striatum (
= 5); Group III: Lesion with QA and transplant with mBMC (
= 5); Group IV: Lesion with QA and transplant with culture medium (Dulbecco's modified Eagle's medium (DMEM) injection) (
= 5). The rotational activity induced by D-amphetamine was evaluated and the concentration of the neurotransmitter amino acids (glutamate and GABA) was studied. The striatal cell transplantation decreases the rotations induced by D-amphetamine (
< 0.04, Wilcoxon matched pairs test) and improves the changes produced in the levels of neurotransmitters studied. This work suggests that the loss of GABAergic neurons in the brain of rats lesioned with AQ produces behavioral and neurochemical alterations that can be reversed with the use of bone marrow mononuclear cell transplants.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
: The knowledge that the cholinergic neurons from pedunculopontine nucleus (PPN) are vulnerable to the degeneration in early stages of the Parkinson disease progression has opened new perspectives to ...the development of experimental model focused in pontine lesions that could increase the risk of nigral degeneration. In this context it is known that PPN lesioned rats exhibit early changes in the gene expression of proteins responsible for dopaminergic homeostasis. At the same time, it is known that nicotinic cholinergic receptors (nAChRs) mediate the excitatory influence of pontine-nigral projection. However, the effect of PPN injury on the expression of transcription factors that modulate dopaminergic neurotransmission in the adult brain as well as the α7 nAChRs gene expression has not been studied. The main objective of the present work was the study of the effects of the unilateral neurotoxic lesion of PPN in nuclear receptor-related factor 1 (Nurr1), paired-like homeodomain transcription factor 3 (Pitx3), and α7 nAChRs mRNA expression in nigral tissue.
: The molecular biology studies were performed by means of RT-PCR. The following experimental groups were organized: Non-treated rats, N-methyl-D-aspartate (NMDA)-lesioned rats, and Sham operated rats. Experimental subjects were sacrificed 24 h, 48 h and seven days after PPN lesion.
: Nurr1 mRNA expression, showed a significant increase both 24 h (
< 0.001) and 48 h (
< 0.01) after PPN injury. Pitx3 mRNA expression evidenced a significant increase 24 h (
< 0.001) followed by a significant decrease 48 h and seven days after PPN lesion (
< 0.01). Finally, the α7 nAChRs nigral mRNA expression remained significantly diminished 24 h, 48 h (
< 0.001), and 7 days (
< 0.01) after PPN neurotoxic injury.
: Taking together these modifications could represent early warning signals and could be the preamble to nigral neurodegeneration events.
Introducción. El núcleo pedunculopontino (NPP) desempeña un papel esencial en el control motor. La literatura sugiere que el NPP participa en el inicio y progresión de la enfermedad de Parkinson, y ...que su degeneración temprana precede a la muerte de las neuronas dopaminérgicas. Objetivos: determinar el efecto de la lesión neurotóxica del NPP sobre la función motora, la homeostasis oxidante nigroestriatal y la expresión génica de proteínas responsables de la homeostasis dopaminérgica. Métodos. La ejecución motora se evaluó mediante las pruebas de la barra transversal, del cilindro y de la huella. Se estudiaron la actividad enzimática catalasa (CAT), colinesterasa (AChE AE) y las concentraciones de malondialdehído (MDA) y glutatión (GSH). Los estudios moleculares contemplaron la expresión del ARNm de la tirosina hidroxilasa (TH), transportador vesicular de dopamina (VMAT), factor neurotrófico derivado del cerebro (BDNF) y transportador de dopamina (DAT). Resultados. Los estudios conductuales revelaron leves trastornos de la coordinación y cambios sutiles de la deambulación de las ratas con lesión pontina. Los estudios bioquímicos mostraron un incremento de la actividad CAT y de las concentraciones de MDA y GSH. Los estudios moleculares demostraron un incremento transitorio de la expresión nigral de BDNF y TH junto a una disminución de la expresión génica de VMAT y DAT.
Neurotoxic lesion of the pedunculopontine nucleus (PPN) is known to cause subtle motor dysfunctions. However, motor coordination during advance on a discontinuous and elevated surface has not been ...studied. It is also not known whether there are changes in the mRNA expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in nigral tissue. Methods: The effects of the unilateral neurotoxic lesion of the PPN in motor coordination evaluated through grid test and Nrf2 mRNA expression in nigral tissue were evaluated. Two experimental designs (ED) were organized: ED#1 behavioral study (7 and 30 days after PPN lesion) and ED#2 molecular biology study (24 h, 48 h and 7 days) after PPN lesion. Results: ED#1—The number of faults made with left limbs, were significant higher in the lesioned groups (p < 0.01) both 7 and 30 days post-lesion. The number of failures made by the right limbs, was also significantly higher (p < 0.05) vs. control groups. ED#2—Nrf2 mRNA expression showed an increase 24 h after PPN injury (p < 0.01), followed by a peak of expression 48 h post injury (p < 0.001). Conclusions: Disorders of motor coordination associated with PPN injury are bilateral. The increased Nrf2 mRNA expression could represent an adaptive response to oxidative stress in the nigral tissue following pontine injury.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that ...a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function.
In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats.
Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (
< 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (
< 0.01). DAT mRNA expression showed a significant decrease (
< 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury.
Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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