¿Es el alzhéimer una enfermedad de la memoria?

Por Ignacio Morgado Bernal

El alzhéimer es un trastorno neurodegenerativo que puede acabar afectando a todo el cerebro, aunque, por razones todavía no conocidas, suele empezar afectando a las neuronas de partes del mismo, como el hipocampo, implicadas en la memoria y por eso ha ganado la reputación que le caracteriza.

Cada vez olvido más dónde he puesto las llaves. Abro el frigorífico y no recuerdo que es lo que voy a buscar en él. ¿Qué me pasa? Las anteriores son frases y preguntas que oigo a veces en boca de algunos amigos de cierta edad, sabedores ellos de mi particular dedicación a la ciencia del cerebro y la memoria. Lo que en realidad preguntan, sin atreverse a hacerlo directamente, es si pueden estar empezando a tener alzhéimer, una enfermedad que la mayoría de las personas consideran como propia del la memoria. Para tranquilizarles me suelo reír cariñosamente de ellos diciéndoles que no me consulten cuando pierdan las llaves, sino cuando las tengan en la mano y no sepan para qué sirven.

Es cierto que mientras que la neurociencia no tenga más claro el origen de la enfermedad de Alzheimer y cómo evitarla no podemos negar que todos estamos expuestos a ella, es decir, cualquiera de nosotros puede acabar teniéndola. Pero el alzhéimer no es una enfermedad de la memoria. El alzhéimer es una enfermedad neurodegenerativa que puede acabar afectando a todas las neuronas del cerebro, aunque, por razones todavía no conocidas, suele empezar afectando a las neuronas de partes del mismo, como el hipocampo, implicadas en la memoria y por eso ha ganado la reputación que le caracteriza.

Desafortunadamente, la enfermedad no se queda ahí, en la memoria, pues puede acabar afectando progresivamente al movimiento, las emociones o el razonamiento de las personas que la padecen. El paciente puede acabar no conociendo a las demás personas y ni siquiera a sí mismo, lo que quizá suponga eventualmente una ventaja para evitar o reducir su sufrimiento. Los familiares del enfermo son casi siempre quienes peor lo pasan, por lo que a ellos, a esos familiares y su estado, hay que prestarles también una especial atención. Todo eso es la triste verdad, pero, por lo que comento a continuación, tampoco debemos preocuparnos más de la cuenta cuando al hacernos mayores empezamos a perder la capacidad de recordar.

Todas las personas al llegar a cierta edad vamos a sufrir un deterioro de la memoria, una pérdida de capacidad para almacenar información, y eso es algo tan natural como perder fuerza muscular o capacidades sensoriales cuando envejecemos. La mayoría de las pérdidas de memoria de quienes tienen la fortuna de alcanzar una cierta edad son además superables mediante una buena y variada cantidad de recursos, como agendas, notas, despertadores y alarmas, avisos de familiares o amigos, etc, además de los esfuerzos mentales especiales que incluso los mayores pueden hacer cuando están muy interesados en que alguna cosa importante para ellos no se les olvide. Las personas mayores olvidan mucho, pero no todo. Algunas cosas que son muy importantes para ellos no suelen olvidarlas, como darles de comer a su gato, por poner un ejemplo trivial pero indicador de que la capacidad de memorizar no se pierde completamente. En general, las rutinas, es decir, lo habitual, se olvida menos que lo que es más accidental o coyuntural.

Ocurre además que muchas cosas que olvidamos con frecuencia más que un olvido propiamente dicho son sólo una incapacidad para acceder a la información pretendida, y prueba de ello es que lo que olvidamos en un momento dado podemos recordarlo más tarde, cuando cambiamos de lugar o de estado mental. Le ocurre mucho a los mayores, y ese recuerdo posterior es buena prueba de que no han entrado en un proceso de deterioro cerebral importante. El alzhéimer es una enfermedad basada en alteraciones de la química cerebral que pueden tener su origen en los genes,  en exposiciones a ciertos agentes ambientales o en combinaciones de ambos, por lo que podemos estar bastante seguros de que, tarde o temprano, la neurociencia va a descubrir los secretos que permitan prevenir o incluso curar tan amenazante enfermedad. Es por ello que puede resultar absurdo pasarnos media vida preocupados por cosas que nunca van a suceder.

Para saber más: Morgado, I. (2014) Aprender, recordar y olvidar: Claves cerebrales de la memoria y la educación. Barcelona: Ariel

Tomado de: http://www.investigacionyciencia.es/blogs/psicologia-y-neurociencia/37/posts/es-el-alzhimer-una-enfermedad-de-la-memoria-13796

How Obesity May Impair Memory

Researchers uncover a molecular link between obesity and memory deficits in mice—as well as a potential treatment.

By Jordana Cepelewicz on February 11, 2016

It’s no secret that obesity, which plagues more than 600 million people worldwide—more than one in three adults in the U.S. alone—leads to serious health problems: cardiovascular disease, diabetes and even several types of cancer. But obesity has also been established as a risk factor for cognitive decline, particularly in middle-aged and older people.

What’s not as well understood is this link’s underlying molecular mechanism—and that’s exactly what a group of researchers at the University of Alabama at Birmingham sought to decipher in a four-part experiment on mice published last month in The Journal of Neuroscience.
First, the researchers studied behavior in healthy and obese mice during memory tasks involving object recognition and location. Much like previous research from other groups, the Alabama team found that compared with their healthy counterparts, the overweight mice performed poorly on a spatial memory task, which relies on the brain’s hippocampus.

Next, the researchers took a look at epigenetic differences in the hippocampi of healthy and obese mice—in other words, at whether environmental factors, in this case obesity, may have influenced the expression of genes in the hippocampus in either group of mice. Using a molecular purification technique to isolate for and analyze methylated DNA sequences (which are associated with gene suppression), the team confirmed that four genes associated with memory formation were not expressed as strongly in the obese mice—suggesting that their obesity had somehow influenced how cells “read” these genes. “One of the particularly exciting things is that this finding links two hot areas of neuroscience: epigenetic mechanisms and cognitive effects of obesity,” says David Sweatt, a neurobiologist at Alabama and study co-author.

One gene in particular, Sirtuin 1 (Sirt1), showed further epigenetic changes that were not observed in the other three genes. “This meant that Sirt1 could lie at the nexus of metabolic dysfunction and memory formation,” says lead author Frankie Heyward, a graduate student in Sweatt’s laboratory. “We were the first to explicitly implicate reduced Sirt1 and increased Sirt1 DNA methylation in the etiology of obesity-induced memory impairment.”

To test this theory, the researchers experimentally reduced the expression of Sirt1 in otherwise healthy mice and found that, just like obese mice, they performed poorly in the hippocampus-dependent memory task. Finally, to investigate possible treatment, they turned to resveratrol, a molecule that activates Sirt1. The team successfully demonstrated that obese mice whose diet was supplemented with resveratrol had enhanced memory, indistinguishable from that of the healthy mice. Heyward still has questions, though. “We didn’t look at our target genes in an unbiased manner,” he says. “We had particular a priori hypotheses and assumptions that focused on certain genes.” In the future he hopes to use recent innovations in RNA sequencing and other technologies to expand his study of gene dysregulation to the entire genome.

Terry Davidson, a neuroscientist at American University who was not involved with the study, says there is a need for further research into what the obesity-related causes of these epigenetic changes may be. “Is it a change in the blood–brain barrier that allows toxins to cross the barrier and get into the hippocampus?” he asks. “It could be a sequence of events that occur as part of a breakdown of our response to inflammation or something like that.” He notes that further analysis of these results could yield a better understanding of specific correlations between Sirt1 expression and body weight as well as how time and exposure may play detrimental roles.

And of course, the researchers wonder how accurately these behavioral models reflect what is happening in humans. Sirt1 is already being considered as a potential therapy for improving metabolic dysfunction and enhancing life span as well as for improving cognitive outcomes in older populations. Heyward believes that his findings provide motivation to design clinical trials geared toward determining whether targeting Sirt1 can also help salvage the memories of people who are obese. “And one other interesting question,” he adds, “is whether these alterations in gene expression and DNA methylation can be reversed or whether they’re permanent. That, at present, is unknown.”

Tomado de: http://www.scientificamerican.com/article/how-obesity-may-impair-memory/

La realidad virtual, una nueva herramienta para la evaluación de la memoria

La memoria humana es un complejo sistema cognitivo cuya estrecha relación con las funciones ejecutivas hace que, en muchas ocasiones, un déficit mnémico lleve aparejadas dificultades para operar con contenidos correctamente almacenados. Los tests de memoria tradicionales, que se centran más en el almacenamiento de la información que en su procesamiento, pueden ser poco sensibles tanto al funcionamiento cotidiano de los sujetos como a los cambios originados por los programas de rehabilitación.

Una revisión ha estudiado la evaluación neuropsicológica de la memoria basada en entornos de realidad virtual y ha analizado los tests existentes para la evaluación del aprendizaje, memoria prospectiva, episódica y espacial, así como los intentos más recientes de realizar una evaluación integral de todos los componentes de la memoria.

Según los investigadores, hay abundante evidencia acerca de la necesidad de mejorar la evaluación de la memoria mediante tests que ofrezcan una mayor validez ecológica, con información que pueda presentarse en varias modalidades sensoriales y que se produzca de modo simultáneo, tal como sucede en la vida real, con la presencia gradual y controlada de distractores. En este sentido, la realidad virtual puede aportar el puente necesario entre los tests neuropsicológicos convencionales y la observación comportamental en contexto real.

La investigación futura debería centrarse en la construcción de procedimientos de evaluación estándares con características psicométricas adecuadas, aunque estas tecnologías necesitan adaptarse a las necesidades clínicas específicas y resolver problemas técnicos.

[Rev Neurol 2016]
Díaz-Orueta U, Climent G, Cardas-Ibáñez J, Alonso L, Olmo-Osa J, Tirapu-Ustárroz J

Tomado de: http://www.neurologia.com/sec/RSS/noticias.php?idNoticia=5521

Street View of the Cognitive Map

Cian O’Donnell1 and Terrence J. Sejnowski2,3,*

1Department of Computer Science, Faculty of Engineering, University of Bristol, Bristol BS8 1UB, UK 
2Howard Hughes Medical Institute at the Salk Institute for Biological Studies, La Jolla, CA 92037, USA 
3Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92161, USA *Correspondence: sejnowski@salk.edu 
http://dx.doi.org/10.1016/j.cell.2015.12.051

To understand the origins of spatial navigational signals, Acharya et al. record the activity of hippocampal neurons in rats running in open two-dimensional environments in both the real world and in virtual reality. They find that a subset of hippocampal neurons have directional tuning that persists in virtual reality, where vestibular cues are absent.

The hippocampus is a brain structure crucial for both memory and spatial navigation. For the past our decades, the dominant theory for the role of the hippocampus in spatial navigation has been that certain hippocampal neurons, called ‘‘place cells,’’ are active selectively when animals or people occupy certain locations in space and act as the building blocks for a cognitive map (O’Keefe and Dostrovsky, 1971; O’Keefe and Nadel, 1978). Although this theory has been hugely successful—John O’Keefe was awarded the 2014 Nobel Prize in Physiology or Medicine for this work, along with May-Britt and Edvard Moser—three challenges to this model have lurked in the shadows, all of which feature in a new study from Acharya et al. (2016) in this issue of Cell.

First, the cognitive map theory rests upon the idea that place cells encode spatial location and little else. However, various data have mounted to suggestthat place cell firing is influenced by a host of other high-level variables, such as the shape of the environment, running speed, time elapsed during a run, and even the current goal of the task (reviewed by Hartley et al., 2014). In addition, and more controversially, place cells have been reported to be tuned to low-level properties such as the direction the animal is facing (McNaughton et al., 1983). Interestingly, this directional tuning was even reported in the original place cell study by O’Keefe and Dostrovsky (1971), but the field later came to the conclusion that this effect was simply an artifact of the analysis methods (Muller et al., 1994). The purported lack of directional information in the hippocampus proper was puzzling because such signals are believed necessary for the hippocampus to accurately track the animal’s location.

A second difficulty for the cognitive map theory is that it is almost exclusively based on data recorded from rodents. In contrast, hippocampal recordings from other mammals such as bats, monkeys, and humans have either found strong directional tuning in addition to spatial selectivity (in the case of bats) (Rubin et al., 2014) or a paucity of cells showing place field responses at all (in the case of monkeys and humans) (Rolls, 1999). Instead, hippocampal neurons in primates typically appear to act more like ‘‘spatial view’’ cells: active when the animal or person is looking at a particular place or object but irrespective of their own location in their environment (Rolls, 1999), which implies an egocentric reference frame rather than an allocentric one.

A third paradox has been that rodent place cells can show strong directional selectivity when a rat is let run in familiar one-dimensional linear tracks or mazes. Confusingly, however, the same place cells that show directional selectivity in such circumstances don’t seem to care about the animal’s direction when the rat is let forage in an open two-dimensional environment (Muller et al., 1994). Acharya et al. (2016) set out to resolve these questions by analyzing activity of hippocampal neurons recorded from rats as they explored two-dimensional space in two complementary scenarios (Figure 1A): first on a real world platform and second in a virtual reality setup in which the rat is actually head-fixed but can navigate a virtual world projected on a screen in front of the rat by running on a rotatable Styrofoam ball. The wall cues in the virtual reality were made to match the wall cues in the real world. The key dissociation between the real-world and virtual environments is that in the real world both visual and vestibular cues are informative as the rat runs around, whereas in virtual reality, vestibular cues should be minimized since the rat is head-fixed while visual cues are preserved.

Figure 1. Hippocampal Neurons in a Real-World Environment and in Virtual Reality

(A) Schematic diagram of experimental recording set up. A rat is allowed to explore either a circular

platform in the real world (left) or on a rotatable ball in virtual reality while head-fixed (right).

(B) Firing properties from one example neuron recorded while the rat explores in the real world (left) and

another example neuron recorded in the virtual reality setup (right). The black circles represent the spatial

environment the rat could explore, and colored dots represent the locations that the rat occupied when the

neuron fired. The open circles represent the directional tuning curve of the same cells in polar co-ordinates. Figure adapted from Acharya et al. (2016), Figures 1 and 2. 

(C) Schematic diagram of the approximate relative proportions of hippocampal CA1 neurons showing spatial tuning (green), directional tuning (magenta), conjunctive tuning (green and magenta), or no tuning (white) in the real world (left) and virtual reality (right) experiments.

These experiments lead to two central findings. First, a subset of roughly 25% of hippocampal neurons show directional tuning in two-dimensional open field realworld environments (Figure 1B, left). The authors suggest that the reason they find directional tuning where many others have not is because they use a rich visual environment and more sensitive analysis methods. Second, this  directional tuning is preserved in virtual reality (Figure 1B, right), implying that vestibular signals are not necessary to generate directionality.

Indeed, further experiments in which the experimenters manipulated the virtual reality visual cues demonstrate a causal role for vision in the process. These findings on the directional tuning properties of hippocampal neurons are especially striking because of the complete differences with the spatial tuning properties of the same population of neurons. A previous study by the same authors had found that, unlike the directionality tuning, place cell firing is substantially degraded in virtual reality two-dimensional environments (Aghajan et al., 2015). Also, the subset of neurons that show spatial tuning ( 75% in real-world, 12% in virtual reality) seem to be statistically independent of the subset of neurons that show head-direction tuning ( 25% in both cases) (seeFigure 1C). Finally, certain place cells that had two firing fields even show different directional tuning in each field. Hence, directional tuning appears to be mechanistically distinct from spatial tuning in hippocampus.

A possible explanation for the discrepancy between the results in the virtual reality and in the real world is the presence of odor cues to which rats are particularly sensitive that are absent in the virtual reality. Odors are strong cues that could override visual cues in determining the place tuning of a hippocampal neurons.

This could be tested by introducing virtual odors within the virtual  environment to see how they affect the response to visual stimuli.

What are the implications for the field? A first challenge will be to figure out the mechanistic origin of this head-direction signal. As discussed above, it appears to be dissociated from the spatial signals that drive place cells. Also, since the canonical head direction nuclei show strong vestibular dependence (Stackman and Taube, 1997), a different directional information pathway may be involved.

Second, it is unknown whether or how this hippocampal CA1 head-direction information is used by downstream neural circuits. This will be especially important to understand given CA1’s role as the primary output station of the hippocampus.

Third, these findings prompt a revision of the cognitive map theory. What is the computational role of these conjunctive place-direction signals for spatial navigation? This study has uncovered a new level of complexity in the firing patterns of neurons in the rat hippocampus that ultimately will give us a deeper understanding of its function. There may be another Nobel Prize up the road for whoever makes this discovery.

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Tomado de: http://papers.cnl.salk.edu/PDFs/Street%20View%20of%20the%20Cognitive%20Map%202016-4474.pdf