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lunes, 4 de noviembre de 2013

Circuitos nerviosos al desnudo

En su último número especial la revista"Science" trata la conectividad del cerebro. Es decir, la estructura y funciones del complejo cableado que permite todas las funciones de dicho órgano. He seleccionado dos estudios básicos en torno a la depresión. Se desconocen sus mecanismos  fisiológicos pero los nuevos enfoques y técnicas han permitido avances significativos.

Short-Circuiting Depression

A decade ago, Helen Mayberg first tried to treat a person with depression through deep brain stimulation (DBS) of the brain region called area 25. She and other groups, some targeting different brain regions, have subsequently used DBS to treat depression in more than 200 people. Between 40% and 60% of these patients demonstrated significant improvements, she says. The prospect that this experimental procedure can bring recovery for people who had given up hope has "reinvigorated the field" of depression treatment, says Husseini Manji, former director of the National Institute of Mental Health's Mood and Anxiety Disorders Program and head of therapeutic neuroscience at Janssen Pharmaceuticals. And it has given researchers a powerful way to pursue an old but largely untested hypothesis: that much depression results not from an imbalance in the soup of neurochemicals that bathes the brain, but from disrupted neural "circuits."


Reversal of Depressed Behaviors in Mice by p11 Gene Therapy in the Nucleus Accumbens

  1. Michael G. Kaplitt1,*
+Author Affiliations
  1. 1Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
  2. 2Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA.
  3. 3Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021, USA.
  4. 4Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm 17177, Sweden.
  5. 5Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  6. 6Neurologix Inc., Fort Lee, NJ 07024, USA.
  1. *To whom correspondence should be addressed. E-mail: mik2002@med.cornell.edu


The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT1B)] and serotonin 4 (5-HT4) receptor–binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)–mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.

Connection, Connection, Connection…

There are approximately 86 billion neurons in the human brain. Over the past decades, we have made enormous progress in understanding their molecular, genetic, and structural makeup as well as their function. However, the real power of the central nervous system lies in the smooth coordination of large numbers of neurons. Neurons are thus organized on many different scales, from small microcircuits and assemblies all the way to regional brain networks. To interact effectively on all these levels, neurons, nuclei, cortical columns, and larger areas need to be connected. The study of neuronal connectivity has expanded rapidly in past years. Large research groups have recently joined forces and formed consortia to tackle the difficult problems of how to experimentally investigate connections in the brain and how to analyze and make sense of the enormous amount of data that arises in the process.
This year's neuroscience special issue is devoted to general and also several more specific aspects of research on connectivity in the brain. We invited researchers to review the most recent progress in their fields and to provide us with an outlook on what the future may hold in store.
To make sense of larger structures, we first have to understand the composition of their basic building blocks. Markov et al. (p. 578) describe how interareal connectivity at the single-cell level, revealed by quantitative anatomical tract tracing, is relevant to our understanding of large-scale cortical networks and their hierarchical organization.
A different but also rapidly growing research direction deals with the use of connectivity measures to link brain structure and cognition. From the perspective of network theory, Park and Friston (p. 579) review our current understanding of structure-function relationships in large-scale brain networks and their underlying mechanisms.
One of the biggest breakthroughs in understanding the heavily connected brain has been the development of noninvasive brain-scanning methods, especially functional magnetic resonance imaging (fMRI). Turk-Browne (p. 580) provides an overview of recent exciting developments in large-scale fMRI data analysis, with a focus on unbiased approaches for examining whole-brain functional connectivity during cognitive tasks. Increased computational power now allows investigation of the whole-brain correlation matrix, the temporal correlation of every voxel with every other voxel throughout the brain, and the application of multivariate pattern analysis to these correlational data.
A sophisticated system that depends on the astonishingly precise interaction of a large number of cortical areas is the human ability to produce and understand language and music. Zatorre (p. 585) discusses how brain plasticity in the music and speech domains can be affected by predisposing factors that relate to brain structure and function.