Posts tagged brain

Debora A Rothmond, Cynthia S Weickert and Maree J Webster

BMC Neuroscience 2012, 13:18 doi:10.1186/1471-2202-13-18 Published: 15 February 2012           

Background

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).

Results

Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p<0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p<0.001) and D2L (p=0.003) isoforms, monoamine oxidase A (p<0.001) and catechol-O-methyltransferase (p=0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32kDa, p=0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p=0.002) and dopamine D1 receptor protein expression increased throughout development (p<0.001) with adults having the highest D1 protein levels (p[less than or equal to]0.01). Monoamine oxidase B mRNA and protein (p<0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r=-0.31, p=0.018) in an expression profile opposite to that of the dopamine D1 receptor.

Conclusions

We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function. 

Source: BMC Neuroscience

February 24, 2012 by Stuart Mason Dambrot

Mechanisms of fluorescent voltage sensing. (A) Electrochromic voltage-sensitive dyes (VDSs) sense voltage when the chromophore interacts directly with the electric field. Changes in the energy levels of the chromophore result in small spectral shifts in the emission of the dye. (B) Fluorescence resonance energy transfer-pair voltage sensors use lipophilic anions (red). Depolarization causes translocation of the anion, which can now quench the fluorescence of an immobilized fluorophore (green). (C) Molecular wire photo-induced electron transfer (PeT) VSDs depend upon the voltage-sensitive electron transfer from an electron-rich donor (orange) through a membrane-spanning molecular wire (black) to a fluorescent reporter (green). Image Copyright © PNAS, doi: 10.1073/pnas.1120694109

(Medical Xpress) — Optically monitoring the brain’s neuronal activity can be accomplished in several ways, including electrochromic dyes, hydrophobic anions, calcium imaging, or voltage-sensitive ion channels. Fluorescence imaging is an attractive method due to its ability to map the electrical activity and communication of multiple spatially resolved neurons. While this complements traditional electrophysiological measurements, historically fluorescent voltage imaging has been limited by the difficulty of developing sensors that give both large and fast responses to voltage changes. Recently, however, scientists in the Department of Pharmacology and other areas in the University of California at San Diego’s Howard Hughes Medical Institute have designed, synthesized, and implemented fluorescent sensors in the form of photo-induced electron transfer (PeT)-based molecular wire probes for voltage imaging in neurons. Moreover, they have used these so-called VoltageFluor sensors to perform single-trial detection of synaptic and action potentials in cultured hippocampal neurons and intact leech ganglia.

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February 23rd, 2012

Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.

They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.

The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons – a finding that could unlock a new class of drug targets to treat memory disorders.

The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging,” said the study’s senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.

Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.

In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.

Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. “Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients,” Tonegawa said.

Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury — was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.

The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.

“By studying mice genetically modified to block neuronal communication from old neurons — or by wiping out their adult-born young neurons — we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it,” co-author Toshiaki Nakashiba said. “Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”

Source: Neuroscience News

ScienceDaily (Feb. 23, 2012) — After we sense a threat, our brain center responsible for responding goes into gear, setting off a chain of biochemical reactions leading to the release of cortisol from the adrenal glands.

Dr. Gil Levkowitz and his team in the Molecular Cell Biology Department have now revealed a new kind of ON-OFF switch in the brain for regulating the production of a main biochemical signal from the brain that stimulates cortisol release in the body. This finding, which was recently published in Neuron, may be relevant to research into a number of stress-related neurological disorders.

This signal is corticotropin releasing hormone (CRH). CRH is manufactured and stored in special neurons in the hypothalamus. Within this small brain region the danger is sensed, the information processed and the orders to go into stress-response mode are sent out. As soon as the CRH-containing neurons have depleted their supply of the hormone, they are already receiving the directive to produce more.

The research — on zebrafish — was performed in Levkowitz’s lab and spearheaded by Dr. Liat Amir-Zilberstein together with Drs. Janna Blechman, Adriana Reuveny and Natalia Borodovsky and Maayan Tahor. The team found that a protein called Otp is involved in several stages of CRH production. As well as directly activating the genes encoding CRH, it also regulates the production of two different receptors on the neurons’ surface for receiving and relaying CRH production signals — in effect, ON and OFF switches.

The team found that both receptors are encoded in a single gene. To get two receptors for the price of one, Otp regulates a gene-editing process known as alternative splicing, in which some of the elements in the sequence encoded in a gene can be “cut and pasted” to make slightly different “sentences.” In this case, it generates two variants of a receptor called PAC1: The short version produces the ON receptor; the long version, containing an extra sequence, encodes the OFF receptor. The researchers found that as the threat passed and the supply of CRH was replenished, the ratio between the two types of PAC1 receptor on the neurons’ surface gradually changed from more ON to mostly OFF. In collaboration with Drs Laure Bally-Cuif and William Norton of the Institute of Neurobiology Alfred Fessard at the Centre National de la Recherche Scientifique (CNRS) in France, the researchers showed that blocking the production of the long receptor variant causes an anxiety-like behavior in zebrafish.

Together with Drs. Alon Chen and Yehezkel Sztainberg of the Neurobiology Department, Levkowitz’s team found the same alternatively-spliced switch in mice. This conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain.

Faulty switching mechanisms may play a role in a number of stress-related disorders. The action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder, as well as in schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder and autism.

Source: Science Daily

February 21, 2012

There are a number of drugs and experimental conditions that can block cognitive function and impair learning and memory. However, scientists have recently shown that some drugs can actually improve cognitive function, which may have implications for our understanding of cognitive disorders such as Alzheimer’s disease. The new research is reported 21 February in the open-access journal PLoS Biology.

The study, led by Drs. Jose A. Esteban, Shira Knafo and Cesar Venero, is the result of collaboration between researchers from The Centro de Biología Molecular Severo Ochoa and UNED (Spain), the Brain Mind Institute (EPFL, Switzerland) and the Department of Neuroscience and Pharmacology (Faculty of Health Sciences, Denmark).

The human brain contains trillions of neuronal connections, called synapses, whose pattern of activity controls all our cognitive functions. These synaptic connections are dynamic and constantly changing in their strength and properties. This process, known as synaptic plasticity, has been proposed as the cellular basis for learning and memory. Indeed, alterations in synaptic plasticity mechanisms are thought to be responsible for multiple cognitive deficits, such as autism, Alzheimer’s disease and several forms of mental retardation.

The study by Knafo et al. provides new information on the molecular mechanisms of synaptic plasticity, and how this process may be manipulated to improve cognitive performance. They find that synapses can be made more plastic by using a small protein fragment (peptide) derived from a neuronal protein involved in cell-to-cell communication. This peptide (called FGL) initiates a cascade of events inside the neuron that results in the facilitation of synaptic plasticity. Specifically, the authors found that FGL triggers the insertion of new neurotransmitter receptors into synapses in a region of the brain called the hippocampus, which is known to be involved in multiple forms of learning and memory. Importantly, when this peptide was administered to rats, their ability to learn and retain spatial information was enhanced.

Dr. Esteban remarks: “We have known for three decades that synaptic connections are not fixed from birth, but they respond to neuronal activity modifying their strength. Thus, outside stimuli will lead to the potentiation of some synapses and the weakening of others. It is precisely this code of ups and downs what allows the brain to store information and form memories during learning”.

Within this framework, these new findings demonstrate that synaptic plasticity mechanisms mechanisms can be manipulated pharmacologically in adult animals, with the aim of enhancing cognitive ability. Dr. Knafo adds: “These are basic studies on the molecular and cellular processes that control our cognitive function. Nevertheless, they shed light into potential therapeutic avenues for mental disorders where these mechanisms go awry”.

Source: medicalxpress.com