Cerebellar interpositus nucleus exhibits time-dependent errors and predictive responses.

Learning is a functional state of the brain that should be understood as a continuous process, rather than being restricted to the very moment of its acquisition, storage, or retrieval. The cerebellum operates by comparing predicted states with actual states, learning from errors, and updating its internal representation to minimize errors. In this regard, we studied cerebellar interpositus nucleus (IPn) functional capabilities by recording its unitary activity in behaving rabbits during an associative learning task: the classical conditioning of eyelid responses. We recorded IPn neurons in rabbits during classical eyeblink conditioning using a delay paradigm. We found that IPn neurons reduce error signals across conditioning sessions, simultaneously increasing and transmitting spikes before the onset of the unconditioned stimulus. Thus, IPn neurons generate predictions that optimize in time and shape the conditioned eyeblink response. Our results are consistent with the idea that the cerebellum works under Bayesian rules updating the weights using the previous history.

In Vivo Fiber-Coupled Pre-Clinical Confocal Laser-scanning Endomicroscopy (pCLE) of Hippocampal Capillaries in Awake Mice.

The goal of this protocol is to describe fiber-optic-bundle-coupled pre-clinical confocal laser-scanning endomicroscopy (pCLE) in its specific application to elucidate capillary blood flow effects during seizures, driven by mural cells. In vitro and in vivo cortical imaging have shown that capillary constrictions driven by pericytes can result from functional local neural activity, as well as from drug application, in healthy animals. Here, a protocol is presented on how to use pCLE to determine the role of microvascular dynamics in neural degeneration in epilepsy, at any tissue depth (specifically in the hippocampus). We describe a head restraint technique that has been adapted to record pCLE in awake animals, to address potential side-effects of anesthetics on neural activity. Using these methods, electrophysiological and imaging recordings can be conducted over several hours in deep neural structures of the brain.

Functional properties of eyelid conditioned responses and involved brain centers.

For almost a century the classical conditioning of nictitating membrane/eyelid responses has been used as an excellent and feasible experimental model to study how the brain organizes the acquisition, storage, and retrieval of new motor abilities in alert behaving mammals, including humans. Lesional, pharmacological, and electrophysiological approaches, and more recently, genetically manipulated animals have shown the involvement of numerous brain areas in this apparently simple example of associative learning. In this regard, the cerebellum (both cortex and nuclei) has received particular attention as a putative site for the acquisition and storage of eyelid conditioned responses, a proposal not fully accepted by all researchers. Indeed, the acquisition of this type of learning implies the activation of many neural processes dealing with the sensorimotor integration and the kinematics of the acquired ability, as well as with the attentional and cognitive aspects also involved in this process. Here, we address specifically the functional roles of three brain structures (red nucleus, cerebellar interpositus nucleus, and motor cortex) mainly involved in the acquisition and performance of eyelid conditioned responses and three other brain structures (hippocampus, medial prefrontal cortex, and claustrum) related to non-motor aspects of the acquisition process. The main conclusion is that the acquisition of this motor ability results from the contribution of many cortical and subcortical brain structures each one involved in specific (motor and cognitive) aspects of the learning process.

The Spanish Intergenerational Study: Beliefs, Stereotypes, and Metacognition about Older People and Grandparents to Tackle Ageism.

Ageism can be seen as systematic stereotypes, prejudice, and discrimination of people because of their age. For a long time, society has accepted negative stereotypes as a norm. When referring to older adults, the United Nations Global Report on Ageism warns about a severe impact. The Intergenerational Study for a Healthy Aging, a questionnaire about believes, stereotypes, and knowledge about older people and grandparents, was administered to 326 Spanish biology and medical students. Here we report the results of stereotype analysis through adjective qualification of the youth and older people performed before the survey. Content analysis of two open questions about metacognition at the end of the survey is also presented. The results show that: (1) The questionnaire promoted metacognition; (2) Positive metacognition toward grandparents was higher than for the general old population; (3) Most participants were not conscious about ageism; (4) Gender was a key factor-male students were more ageist than females; (5) The feeling of guilt was higher in the questionnaire about older people; (6) The metacognition exercise elicited thoughts and, in few cases, the need to take action to tackle ageism. In conclusion, both activities promoted active thoughts about older people vs. grandparents and helped participants realize unconscious ageism-specifically toward the older population-serving as an awareness activity that may help tackle ageism.

El procesamiento temporal en el Trastorno por Déficit de Atención e Hiperactividad / Time Processing in Attention Deficit Hyperactivity Disorder

El procesamiento temporal es una actividad cerebral primordial para el adecuado funcionamiento de las personas en las actividades de la vida diaria y su afectación constituye uno de los signos de disfunción más importantes en el Trastorno por Déficit de Atención e Hiperactividad (TDAH). El objetivo de este trabajo es revisar los antecedentes y estudios científicos realizados sobre el procesamiento del tiempo en personas con TDAH, así como realizar una propuesta de valoración de esta función en poblaciones con este trastorno del neurodesarrollo. El procesamiento del tiempo ha sido poco estudiado clínicamente, aunque sí en el ámbito neurocientífico y experimental. La mayoría de los estudios se han basado en mecanismos relacionados con la percepción temporal y la reproducción de intervalos de tiempo a nivel motor, en los cuales se han descrito distorsiones en personas con TDAH. Se han propuesto diversas teorías basadas en una afectación primaria de la percepción del tiempo, aunque en otras ocasiones esta afectación se ha considerado secundaria a las alteraciones nucleares del trastorno. Entre las conclusiones del estudio destacamos que los procesos cognitivos relacionados con el procesamiento temporal son diversos y requieren del funcionamiento de distintos dominios cognitivos. Si bien se han desarrollado algunas pruebas para la evaluación de esta función, precisamos de nuevas herramientas para la adecuada valoración del procesamiento del tiempo en personas con TDAH

Time processing is a primary brain activity for the proper functioning of people in their daily activities. Its affectation is one of the most important signs of dysfunction in Attention Deficit Hyperactivity Disorder (ADHD). The aim was to review the background and scientific studies carried out on time processing in patients with ADHD, as well as top put forward a proposal for evaluating this function in populations with this neurodevelopmental disorder. Although time processing has not been studied clinically in detail, it has been approached experimentally in the neuroscientific field. Most studies of time processing have been based on functional phenomena related to time perception and timed motor reproductions; distortions of these two functions have been described in people with ADHD. Several theories based on a primary affectation of time processing have been proposed; however, on some occasions this affectation has been considered secondary to the nuclear alterations of the disorder. The cognitive processes related to temporal processing are rather diverse and require the functioning of different cognitive domains. Although some tests have been developed for the evaluation of this function, new tools are needed for the proper assessment of time processing in people with ADHD

Chronic adult-onset of growth hormone/IGF-I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats.

AIM: Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. METHODS: Adult rats were implanted with GC cells and checked 10 weeks later, when a GH/IGF-I-secreting tumour was already formed. RESULTS: Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. CONCLUSION: Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

Heterogeneidad sintomatológica. Perfiles de pacientes diagnosticados con demencia tipo Alzheimer en Antioquia (Colombia) / Symptomatology heterogeneity. Profiles of patients diagnosed with Alzheimer's type dementia in Antioquia (Colombia)

Resumen Objetivo: Describir y contrastar la variabilidad sintomatológica de los casos con demencia tipo Alzheimer esporádico (DTA+E) con los datos obtenidos de los casos con demencia tipo Alzheimer familiar precoz causado por la mutación E280A del Neurobanco del Grupo de Neurociencias de Antioquia (GNA). Materiales y Método: Este estudio fue de tipo exploratorio-descriptivo y correlacional, se tomaron 83 casos de donantes con DTA almacenados en el Neurobanco del GNA. Estos casos se dividen en dos grupos, i) un grupo definido genéticamente como portador de la mutación E280A en el gen de la Presenilina1; y ii) otro grupo no portador de la mutación diagnosticado con Demencia Tipo Alzheimer Esporádico (DTA+E); se contrastaron los marcadores y/o características neuropsiquiatricas, neuropsicológicas, neurológicas y neuropatológicas de ambos grupos. Resultados: El síntoma que mostró mayores diferencias entre ambos grupos fue la repetidera (DTAF E280A fue de 1.2% y el grupo de DTA+E fue 18.4%). Otros síntomas como la depresión o el tiempo de aparición de pérdida progresiva de memoria no mostraron grandes diferencias entre grupos (DTAF E2080A=55.9%; DTA+E =53.1%) y (DTAF E2080A=55.9%; DTA+E =53.1%). Los trastornos del lenguaje que se observaron con mayor frecuencia entre los donantes fueron la pérdida del lenguaje, mutismo, anomia y afasia. El signo de mayor frecuencia en ambos grupos fue descontrol de esfínteres. La atrofia se registró con mayor intensidad en los lóbulos temporales de los cerebros de los donantes con DTA +E (83.3%). Los pesos del cerebro y del contenido de la fosa posterior, tienen una relación moderada, directamente proporcional y altamente significativa desde el punto de vista estadístico. Conclusiones: Existen diferencias neuropatológicas entre DTA+E y E280A que pueden estar asociadas a la fisiopatología de la forma hereditaria de E280A.

Abstract Objective: To describe and contrast the symptomatic variability of cases with sporadic or non-sporadic Alzheimer's dementia (DTA + E) with the data obtained from the cases with early familial Alzheimer's dementia caused by the E280A of the Neurobank of the Neurosciences Group of Antioquia (GNA). Materials and Method: This study was of exploratory - descriptive and correlacional type, 83 donors' cases were taken with DTA stored in the Neurobank. These cases were divided in two groups, i) a group defined genetically like E280A; and ii) another not carrying group of the mutation (DTA+E); the scoreboards and / or characteristics neuropsychiatric, neuropsychological, neurological and neuropathological of both groups were confirmed Results: The symptom that showed higher differences between both groups was iteration (DTAF E280A with 1.2% and 18.4% for the DTA+E group). Other symptoms as depression or the time of appearance of progressive loss of memory did not show big differences among groups (DTAF E2080A=55.9%; DTA+E =53.1%) and (DTAF E2080A=55.9%; DTA+E =53.1%). The language disorders that were observed with major frequency among the donors were the loss of the language, mutism, anomia and aphasia. The sign with higher frequency in both groups was lost of sphincter control. The atrophy was with more intensity in the temporary lobes of the brains of the donors with DTA+E (83.3%). The weight of the brain and of the posterior fosse content, they have a moderate, directly proportional and highly significant relation from the statistical point of view. Conclusions: DTA +E has neuropathological differences with DTAF E280A that can be associated with the physiology hereditary from of DTAF E280A.

Abnormal Capillary Vasodynamics Contribute to Ictal Neurodegeneration in Epilepsy.

Seizure-driven brain damage in epilepsy accumulates over time, especially in the hippocampus, which can lead to sclerosis, cognitive decline, and death. Excitotoxicity is the prevalent model to explain ictal neurodegeneration. Current labeling technologies cannot distinguish between excitotoxicity and hypoxia, however, because they share common molecular mechanisms. This leaves open the possibility that undetected ischemic hypoxia, due to ictal blood flow restriction, could contribute to neurodegeneration previously ascribed to excitotoxicity. We tested this possibility with Confocal Laser Endomicroscopy (CLE) and novel stereological analyses in several models of epileptic mice. We found a higher number and magnitude of NG2+ mural-cell mediated capillary constrictions in the hippocampus of epileptic mice than in that of normal mice, in addition to spatial coupling between capillary constrictions and oxidative stressed neurons and neurodegeneration. These results reveal a role for hypoxia driven by capillary blood flow restriction in ictal neurodegeneration.

Neurodevelopmental Effects of Undernutrition and Placental Underperfusion in Fetal Growth Restriction Rabbit Models.

INTRODUCTION: Chronic reduction of oxygen and nutrient delivery to the fetus has been related to neurodevelopmental problems. Placental underperfusion induces a significant reduction in oxygen and nutrient delivery, whereas maternal undernutrition causes mainly nutrient deficiency. A comparison of the neurodevelopmental effects of both situations in pregnant rabbits was performed. MATERIALS AND METHODS: The placental underperfusion model was induced after uteroplacental vessel ligation at 25 days of pregnancy. The undernutrition model was induced after a reduction of 70% of the basal maternal intake at 22 days of pregnancy. Neurobehavioral tests were applied in the derived offspring at the neonatal period and over the long term. Structural brain differences were evaluated by brain networks obtained from diffusion magnetic resonance imaging. RESULTS: Birth weight was significantly lower in both cases. However, stillbirth was only increased in the placental underperfusion model. Cases from both models presented poorer neurobehavioral performance and network infrastructure, being more pronounced in the placental underperfusion model. DISCUSSION: Prenatal insults during the last third of gestation resulted in functional and structural disturbances. The degree of neurodevelopmental impairment and its association with structural brain reorganization seemed to be related to the type of the prenatal insult, showing stronger effects in the placental underperfusion model.

Synthetic tactile perception induced by transcranial alternating-current stimulation can substitute for natural sensory stimulus in behaving rabbits.

The use of brain-derived signals for controlling external devices has long attracted the attention from neuroscientists and engineers during last decades. Although much effort has been dedicated to establishing effective brain-to-computer communication, computer-to-brain communication feedback for "closing the loop" is now becoming a major research theme. While intracortical microstimulation of the sensory cortex has already been successfully used for this purpose, its future application in humans partly relies on the use of non-invasive brain stimulation technologies. In the present study, we explore the potential use of transcranial alternating-current stimulation (tACS) for synthetic tactile perception in alert behaving animals. More specifically, we determined the effects of tACS on sensory local field potentials (LFPs) and motor output and tested its capability for inducing tactile perception using classical eyeblink conditioning in the behaving animal. We demonstrated that tACS of the primary somatosensory cortex vibrissa area could indeed substitute natural stimuli during training in the associative learning paradigm.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

A Variable Oscillator Underlies the Measurement of Time Intervals in the Rostral Medial Prefrontal Cortex during Classical Eyeblink Conditioning in Rabbits.

We were interested in determining whether rostral medial prefrontal cortex (rmPFC) neurons participate in the measurement of conditioned stimulus-unconditioned stimulus (CS-US) time intervals during classical eyeblink conditioning. Rabbits were conditioned with a delay paradigm consisting of a tone as CS. The CS started 50, 250, 500, 1000, or 2000 ms before and coterminated with an air puff (100 ms) directed at the cornea as the US. Eyelid movements were recorded with the magnetic search coil technique and the EMG activity of the orbicularis oculi muscle. Firing activities of rmPFC neurons were recorded across conditioning sessions. Reflex and conditioned eyelid responses presented a dominant oscillatory frequency of ≈12 Hz. The firing rate of each recorded neuron presented a single peak of activity with a frequency dependent on the CS-US interval (i.e., ≈12 Hz for 250 ms, ≈6 Hz for 500 ms, and≈3 Hz for 1000 ms). Interestingly, rmPFC neurons presented their dominant firing peaks at three precise times evenly distributed with respect to CS start and also depending on the duration of the CS-US interval (only for intervals of 250, 500, and 1000 ms). No significant neural responses were recorded at very short (50 ms) or long (2000 ms) CS-US intervals. rmPFC neurons seem not to encode the oscillatory properties characterizing conditioned eyelid responses in rabbits, but are probably involved in the determination of CS-US intervals of an intermediate range (250-1000 ms). We propose that a variable oscillator underlies the generation of working memories in rabbits. SIGNIFICANCE STATEMENT: The way in which brains generate working memories (those used for the transient processing and storage of newly acquired information) is still an intriguing question. Here, we report that the firing activities of neurons located in the rostromedial prefrontal cortex recorded in alert behaving rabbits are controlled by a dynamic oscillator. This oscillator generated firing frequencies in a variable band of 3-12 Hz depending on the conditioned stimulus-unconditioned stimulus intervals (1 s, 500 ms, 250 ms) selected for classical eyeblink conditioning of behaving rabbits. Shorter (50 ms) and longer (2 s) intervals failed to activate the oscillator and prevented the acquisition of conditioned eyelid responses. This is an unexpected mechanism to generate sustained firing activities in neural circuits generating working memories.

Functional basis of associative learning and its relationships with long-term potentiation evoked in the involved neural circuits: Lessons from studies in behaving mammals.

While contemporary neuroscience is paying increasing attention to subcellular and molecular events and other intracellular phenomena underlying the acquisition, storage, and retrieval of newly acquired motor and cognitive abilities, parallel attention should be paid to the study of the electrophysiological phenomena taking place at selected cortical and subcortical neuronal and synaptic sites during the precise moment of learning acquisition, extinction, and recall. These in vivo approaches to the study of learning and memory processes will allow the proper integration of the important information collected from in vitro and delayed molecular studies. Here, we summarize studies in behaving mammals carried out in our laboratory during the past ten years on the relationships between experimentally evoked long-term potentiation (LTP) and activity-dependent changes in synaptic strength taking place in hippocampal, prefrontal and related cortical and subcortical circuits during the acquisition of classical eyeblink conditioning or operant learning tasks. These studies suggest that different hippocampal synapses are selectively modified in strength during the acquisition of classical, but not instrumental, learning tasks. In contrast, selected prefrontal and striatum synapses are more directly modified by operant conditioning. These studies also show that besides N-methyl-D-aspartate (NMDA) receptors, many other neurotransmitter, intracellular mediating, and transcription factors participate in these two types of associative learning. Although experimentally evoked LTP seems to prevent the acquisition of classical eyeblink conditioning when induced at selected hippocampal synapses, it proved to be ineffective in preventing the acquisition of operant conditioned tasks when induced at numerous hippocampal, prefrontal, and striatal sites. The differential roles of these cortical structures during these two types of associative learning are discussed, and a diagrammatic representation of their respective functions is presented.

The rostral medial prefrontal cortex regulates the expression of conditioned eyelid responses in behaving rabbits.

We studied the contribution of the rostral mPFC (rmPFC) to the acquisition and performance of classical eyeblink conditioning in rabbits using a delay paradigm. The rmPFC was determined by its afferent projections from the medial half of the mediodorsal thalamic nucleus. The rmPFC neurons were identified by their antidromic activation from the mediodorsal nucleus and/or by their firing characteristics. The rmPFC neurons increased their firing during the first conditioning sessions, but decreased it when conditioned responses (CRs) reached asymptotic values. Therefore, no significant relationships could be established between neuronal firing rates and the percentage of CRs or the electromyographic (EMG) activity of the orbicularis oculi muscle during conditioning. Electrical train stimulation of the rmPFC produced a significant inhibition of air-puff-evoked blinks and reduced the generation of CRs compared with controls. Inhibition of the rmPFC by the local injection of lidocaine produced an increase in the amplitude of evoked reflex and conditioned eyeblinks and in the percentage of CRs. The rmPFC seems to be a potent inhibitor of reflex and conditioned eyeblinks, controlling the release of newly acquired eyelid responses until advanced stages of the acquisition process--i.e., until the need for the acquired response is fully confirmed. Therefore, the rmPFC seems to act as a "flip-flop" mechanism in controlling behavior.

Effects of transcranial Direct Current Stimulation (tDCS) on cortical activity: a computational modeling study.

Although it is well-admitted that transcranial Direct Current Stimulation (tDCS) allows for interacting with brain endogenous rhythms, the exact mechanisms by which externally-applied fields modulate the activity of neurons remain elusive. In this study a novel computational model (a neural mass model including subpopulations of pyramidal cells and inhibitory interneurons mediating synaptic currents with either slow or fast kinetics) of the cerebral cortex was elaborated to investigate the local effects of tDCS on neuronal populations based on an in-vivo experimental study. Model parameters were adjusted to reproduce evoked potentials (EPs) recorded from the somatosensory cortex of the rabbit in response to air-puffs applied on the whiskers. EPs were simulated under control condition (no tDCS) as well as under anodal and cathodal tDCS fields. Results first revealed that a feed-forward inhibition mechanism must be included in the model for accurate simulation of actual EPs (peaks and latencies). Interestingly, results revealed that externally-applied fields are also likely to affect interneurons. Indeed, when interneurons get polarized then the characteristics of simulated EPs become closer to those of real EPs. In particular, under anodal tDCS condition, more realistic EPs could be obtained when pyramidal cells were depolarized and, simultaneously, slow (resp. fast) interneurons became de- (resp. hyper-) polarized. Geometrical characteristics of interneurons might provide some explanations for this effect.

Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits.

Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven after-effects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity-specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS.

Electrical stimulation of the rostral medial prefrontal cortex in rabbits inhibits the expression of conditioned eyelid responses but not their acquisition.

We have studied the role of rostral medial prefrontal cortex (mPFC) on reflexively evoked blinks and on classically conditioned eyelid responses in alert-behaving rabbits. The rostral mPFC was identified by its afferent projections from the medial half of the thalamic mediodorsal nuclear complex. Classical conditioning consisted of a delay paradigm using a 370-ms tone as the conditioned stimulus (CS) and a 100-ms air puff directed at the left cornea as the unconditioned stimulus (US). The CS coterminated with the US. Electrical train stimulation of the contralateral rostral mPFC produced a significant inhibition of air-puff-evoked blinks. The same train stimulation of the rostral mPFC presented during the CS-US interval for 10 successive conditioning sessions significantly reduced the generation of conditioned responses (CRs) as compared with values reached by control animals. Interestingly, the percentage of CRs almost reached control values when train stimulation of the rostral mPFC was removed from the fifth conditioning session on. The electrical stimulation of the rostral mPFC in well conditioned animals produced a significant decrease in the percentage of CRs. Moreover, the stimulation of the rostral mPFC was also able to modify the kinematics (latency, amplitude, and velocity) of evoked CRs. These results suggest that the rostral mPFC is a potent inhibitor of reflexively evoked and classically conditioned eyeblinks but that activation prevents only the expression of CRs, not their latent acquisition. Functional and behavioral implications of this inhibitory role of the rostral mPFC are discussed.

Microstimulation of the somatosensory cortex can substitute for vibrissa stimulation during Pavlovian conditioning.

The primary somatosensory cortex (S1) contains a map representation of the body surface. We hypothesized that S1 stimulation can successfully substitute for (or be substituted by) direct stimulation of skin receptors. We prepared rabbits for evoking eyelid conditioned responses (CRs) using a trace "shock-air puff" paradigm. In a first series of experiments, animals received a conditioned stimulus (CS, a train of electrical pulses) in the whisker pad or in the S1 areas for vibrissae or for the hind limb. In the three cases, the CS was followed 250 ms from its end by an air puff presented to the cornea as an unconditioned stimulus (US). Learning curves from the three groups presented similar values, although animals stimulated with a central CS acquired their CRs faster. In a second series of experiments, animals were divided into four groups and were presented either centrally or peripherally with the same CS for six conditioning sessions. Then, the CS was switched from central to peripheral, or vice versa, for 5 additional days. Conditioned animals were not able to discriminate between peripheral (vibrissae) stimuli and stimuli presented to the corresponding S1 (vibrissae) area, but they were able to discriminate between CSs presented to S1 (hind limb) and body (vibrissae) regions. The kinetic properties of evoked CRs were not modified by CS switching. It is proposed that S1 allows the construction of somatosensory percepts of the body surface but does not allow distinguishing the central or peripheral location of the evoking stimuli.

Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia.

Brain ischemia induces neuronal loss which is caused in part by excitotoxicity and free radical formation. Here, we report that mangiferin and morin, two antioxidant polyphenols, are neuroprotective in both in vitro and in vivo models of ischemia. Cell death caused by glutamate in neuronal cultures was decreased in the presence of submicromolar concentrations of mangiferin or morin which in turn attenuated receptor-mediated calcium influx, oxidative stress as well as apoptosis. In addition, both antioxidants diminished the generation of free radicals and neuronal loss in the hippocampal CA1 region due to transient forebrain ischemia in rats when administered after the insult. Importantly, neuroprotection by these antioxidants was functionally relevant since treated-ischemic rats performed significantly better in three hippocampal-dependent behavioral tests. Together, these results indicate that mangiferin and morin have potent neuroprotectant activity which may be of therapeutic value for the treatment of acute neuronal damage and disability.