How feedback from cortex helps mammals make fine distinctions about odors

Everyday tasks we may regard as 'simple' -- for example, knowing the difference between the smell of an orange and a pickle -- are actually marvels of evolutionary development, the work of eons. A neuroscience team reports results of experiments that suggest how the mammalian brain distinguishes odors -- not just dissimilar ones but, perhaps more importantly, odors that are nearly identical, such as the scents of oranges and tangerines. 

Precise discrimination of olfactory signals from the environment is nothing less than a survival skill, more so for mice, our mammalian cousins, than for us. Mice have relatively poor vision, and it is only thanks to their other senses, notably their incredible ability to identify and discriminate odors, that they can successfully hunt for food or choose a mate. Understanding how they do this, in turn, sheds light on the workings of our much more complex, but structurally related, brains.

Led by CSHL Assistant Professor Florin Albeanu, the team explored a function in the mouse brain that scientists still don't know much about. After a mouse samples a smell by sniffing, and signals from that activity are gathered and subjected to preliminary processing in the animal's olfactory bulb, the bulb sends "output" signals to the brain's higher processing center, the cerebral cortex. Albeanu's team focused on "feedback" -- the signal that the olfactory cortex, in turn, sends back to the olfactory bulb. While there are theories aplenty about the nature and purpose of this feedback signal, very little is known about it.

Even in the mouse brain, the feedback loop is a good deal more complex than just described. The olfactory bulb sends output to and receives feedback from multiple parts of the brain. Albeanu's team focused on one such feedback loop: signals sent from two principal cell types in the bulb, called mitral cells and tufted cells. These signals travel over long-distance axons to various parts of the brain, but most prominently to the piriform cortex. That's the brain's primary center for higher olfactory processing.

Some theorists have speculated that the piriform cortex works as a pattern-recognition device that compares incoming sensory inputs with representations of previously experienced odors, stored up in memory. Not only is the piriform cortex thought to do this job; it is also involved in the integration of this information with contextual information (ranging from other data about the environment to whether the animal is hungry, amorous, afraid, etc.). Further, it is theorized that based on this data, the piriform cortex sends signals back to the olfactory bulb -- feedback -- that is essentially predictive, helping the animal to make decisions based on all available information.

Albeanu's team, which included co-first authors Drs. Gonzalo Otazu and Hongggo Chae, as well as technician Martin Davis, made a series of discoveries in two related sets of experiments that support some of these theories. In one set, as they exposed awake mice to a panel of about 30 odorants, one by one, they traced the axons projecting back to the olfactory bulb from the piriform cortex -- the "wires," in effect, that carry the feedback signal -- and measured the responses of tiny button-like structures called synaptic boutons, the sites where these cortical feedback axons form connections, or synapses, in the bulb with local receiving neurons. These so-called interneurons are inhibitory.

"The idea was to image the responses of the boutons in the olfactory bulb to a set of odorants," explains Albeanu. "It's very hard to physically access the piriform cortex for optical imaging, so we used these boutons as a proxy to indicate the nature of the signal that the cortex is feeding back to the bulb."

The results were "striking," says Albeanu. First, it was clear that any given bouton responded only to a small fraction of the 30 odorants -- perhaps two or three, on average. This is what neuroscientists call a "sparse" response, and it indicates specificity. This immediately cast doubt on an existing theory suggesting that the feedback to the bulb is non-specific and acts like the volume, or "gain," control on an audio system. Rather, the response was specific and highly selective. Not only did a given bouton respond to very few odors; if it responded to one by amplifying the feedback signal (above the background level, since there is always activity in the circuit), it tended to perform that same function, amplification, on all of the odors it responded to. Conversely, those boutons that tamped down the signal coming back from the cortex tended to do that for all of the odors they responded to.

A second set of experiments enabled Albeanu's team to offer a new hypothesis of the purpose of this particular cortical feedback. By injecting mice with a drug that inactivates the piriform cortex, they were able to examine the activity of the output cells in the olfactory bulb that normally integrate the cortical feedback via inhibitory interneurons. Again a striking result: as compared with their activity profiles when receiving feedback, mitral cells in the olfactory bulb tended to have overlapping responses when the feedback was cut off. In other words, their activity profiles started to look quite similar. This suggests that without feedback from the cortex, mitral cells are no longer to supply the animal with information that can sharply distinguish odors, particularly odors that are chemically similar.

Taken together, the results lead Albeanu to propose that feedback from the cortex is highly specific, and likely used to create a useful representation of the animal's environment, "in a very specific and selective fashion that, in turn, is used to extract the identity of a given odor and to separate it from other odors," Albeanu says. The research continues now in experiments featuring animals that are actively engaged in odor discrimination in their environment, in order to obtain behavioral evidence to correlate with the results of the experiments published today.

This story is taken from Science Daily

Cracking the function of the fly olfactory system to understand how neural circuits work

Scientists have undertaken to map the neural circuitry involved in the conversion of olfactory inputs into navigational behaviors in the fruit fly larva. The work is a new example on how systems biology allows scientists to approach complex questions such as brain functions. 

This research, which has been published this week in the journal Current Biology, paves the way for a systematic investigation of the neural computations that underlie sensory navigation in a miniature brain.
The work is a new example on how systems biology allows scientists to approach complex questions such as brain functions.
If a banana is rotting in the fruit basket of your kitchen, chances are that a fruit fly will find it long before you do. How is the nervous system of a tiny fly capable of ascending the odour trail created by a banana? This question has been addressed in a new study conducted by the Sensory Systems and Behaviour laboratory led by Matthieu Louis at the EMBL-CRG Systems Biology Unit of the CRG. The fruit fly Drosophila melanogaster is an excellent model system to explore how complex behaviours, such as chemotaxis, are controlled by the activity of neural circuits. Although the word neuroscience may evoke the human brain to most of us, research in smaller genetic model organisms often represents the most direct entry point into the molecular and cellular basis neural functions.
The research carried out by the Louis lab is a new example on how the combination of interdisciplinary tools permits to probe basic principles underlying complex biological processes. In this case, CRG scientists dive deep into the fruit fly neural circuits, which could be the entrance to more complex systems as the human brain.
To identify the neural circuits involved in chemotaxis, the team decided to concentrate on the fruit fly larva, which comprises 10,000 neurons -- 10 times less than adult flies and 10 million times less than humans. In temerarious efforts, the team screened over 1,100 fly strains where the function of a small subset of neurons of the brain could be genetically turned off. "At the beginning of this project, we had the feeling to be looking for a needle in a haystack. We knew about the 21 olfactory neurons in the head of the larva and the motor neurons in the equivalent of spinal cord in the larva. In contrast, we had virtually no clue about the identity of the neurons in between, the synapses responsible for the processing of the olfactory information and its conversion into navigational decisions," says Matthieu Louis.
From this screen, the attention of the team was drawn onto a handful of neurons located in a region traditionally associated with reflexive taste behaviour. When the function of the identified neurons was silenced, larvae became unable to make accurate decision to navigate odour gradients. Using optogenetics, a method that exploits light to control and monitor neurons, Ibrahim Tastekin, one of the co-first authors of the work, was able to activate individual neurons. To his astonishment, he found that brief excitations were sufficient to trigger a change in orientation. "This was like magic: optogenetics gave us a means to remote control an elementary form of decision making. The fly genetic toolkit creates unprecedented possibilities to probe the function of individual neurons in a semi high-throughput manner. Here we proved the necessity and sufficiency of a couple of neurons to control a fundamental aspect of chemotaxis: the conversion of sensory information into behaviour." The team went further by demonstrating that the neurons identified in this zone are involved in the processing of odour, light and temperature. "We are very excited to define how these neurons operate in concert with the rest of the circuitry in charge of chemotaxis," says Matthieu Louis.
Beyond identifying which brain regions control individual feature of a behaviour of interest, the aim of the Louis lab is to understand how neurons form neural circuits, how circuits work together to achieve computations and how complex behaviours emerge from brain computations. In a paper recently published in Learning & Memory, the Louis lab focused on learned olfactory behaviour. Louis and colleagues had previously described the navigational algorithm that allows the larva to chemotax. Based on this model of the movement of larvae in response to chemical stimuli, the team has now described the impact of appetitive memory and learning on the navigational algorithm. This work explains how larvae become more efficient at locating the source of an odour that has been previously associated with a food reward.
Little is known about the neural circuits connecting the sensory neurons to the motor system. By adopting a systems neuroscience approach the Louis lab hopes to understand how a relatively small nervous system of 10,000 neurons represents and integrates changes in sensory signals to direct navigational decisions, and how learning affects the function of neural circuits. "By unravelling the computations achieved by single neurons in a numerically simple brain, we aim to advance our knowledge about similar functions in much bigger brains like ours. Our approach is complementary to studies in higher model organisms, including the Human Brain Project," concludes Matthieu Louis.

This story is taken from Science Daily

The fly's time: Biological clockwork of human beings and flies is comparable

The Drosophila, the so-called fruit fly, attends all day long to its activities. It flutters, has naps, lays its eggs or emerges from the pupa, the stage of metamorphosis preceding maturity. Researchers are now using the fruit fly as a model organism for the study of circadian rhythms in the animal kingdom. 

In animals, rhythms of sleep, reproduction and nutrition are part of activities controlled by a clock nearing twenty-four hours -or "circadian"- and this in Drosophila as well as human beings. The diverse activities of the insect are controlled by a central pacemaker, composed of about 150 neurons clustered in various regions of the brain. Each of these neurons possesses a set of genes whose expression reaches a specific peak in twenty-four hours: the "clock genes." The main clock, which is settled by the alternation of the day and night, synchronizes the peripheral oscillators that control the fluctuation of various processes of the organism during the day.
Nuclear receptors at the heart of the clock
"The rhythmic expression of the clock genes, which leads to the production of proteins, is the result of a loop of autoregulation: when the proteins reach a specific threshold, they indirectly repress their own gene expression," explains Emi Nagoshi, researcher in biology at the Department of Genetics and Evolution of the Faculty of Science from the UNIGE. In order to compare the clock gears of the Drosophila with ours, the scientist first looked for the missing pieces of the puzzle in the insect.
"In mammals, certain molecules belonging to the family of nuclear receptors play essential roles in the regulation of the circadian clock. We discovered that the Drosophila possesses a nuclear receptor homologous to the one present in humans, which also performs a crucial function in the regulation," says Edouard Jaumouillé, first author of the publication of these results in Current Biology.
The hands of the clock point towards other directions
Although both homologous receptors do not act in an identical way, the fact that they modulate the expression of clock genes in Drosophila as well as in mammals demonstrates that very distant organisms, displaying different circadian activities, can present the same type of biological clock gears.
Humans and flies produce specific molecules that cross the membranes of cells and control the nuclear receptors during the course of their daily activities.
"Our results contribute to strengthen the emergent hypothesis according to which the physiological states and the circadian clocks exercise a mutual control over one another, and that nuclear receptors play key roles in this process," explains Pedro Machado Almeida, other co-author of the study.
This is the next step that needs to be verified to better apprehend the twenty-four hour tempo which gives rhythm to the life of organisms.