A neural mechanism has been discovered that combines the internal information about our moods and the information received by the senses

Dr. Ivo Spiegel's laboratory in the Department of Neurobiology at the Weizmann Institute deals with "adult learning" - that is, how different types of nerve cells in the cerebral cortex regulate the "plasticity" of brain circuits. Although researchers have previously assumed that the integration of information from outside and inside occurs in the cerebral cortex, there have been no significant findings regarding these mechanisms until now.

Serenity or nervousness, concentration or distraction: our moods affect the way we learn and make memories. The internal information about moods is transmitted through separate neural pathways from those in which external information received by the senses is transmitted, but the combination of the two types of pathways determines how our brain will process the information. Weizmann Institute of Science scientists have discovered a cellular mechanism that combines these two streams of information in the uppermost layer of the outer part of the brain - layer 1 of the cerebral cortex. This mechanism apparently plays a central role in controlling the "plasticity" of the brain - the flexibility it needs for us to learn new things.

Dr. Ivo Spiegel's laboratory in the Department of Neurobiology deals with "adult learning" - that is, how different types of nerve cells in the cerebral cortex regulate the "plasticity" of brain circuits. Although researchers have previously assumed that the integration of outside and inside information occurs in the cerebral cortex, there have been no significant findings regarding these mechanisms until now. "One way to approach the question," says Dr. Spiegel, "is to identify the different players, and then understand how they all work together; A bit like trying to 'reverse engineer' the mechanism of a particularly complex watch."

In a new study recently published in the scientific journal Neuron, Dr. Spiegel, along with his research group and other colleagues, focused on specific neurons in layer 1. The neurons in the cerebral cortex are divided into two general types - excitatory and inhibitory. While most of the neurons in the cerebral cortex are excitatory, the research team focused specifically on the inhibitory neurons thinking that they are the ones essential to the process of information integration. To examine how the inhibitory nerve cells work, they first had to find genes that are expressed only in these cells.

While most of the neurons in the cerebral cortex are excitatory, the research team focused specifically on the inhibitory neurons, thinking that they are the ones that are essential for the process of information integration."

From the right: Daniela Appleblat, Dalia Koshinsky and Dr. Ivo Spiegel. Use of inside information

Dr. Spiegel, together with research students Daniela Appleblatt and Dalia Koshinsky and with the research group of Dr. Johannes Letzkos at the Max Planck Institute for Brain Research in Frankfurt, Germany, identified such a gene, called Ndnf, and showed that Ndnf expression in layer 1 inhibitory neurons is unique among All inhibitory neurons. Later, the researchers created genetically modified mice, so that it is possible to control their neurons that express Ndnf, and monitor their activity. Using these mice, the research team tested whether Ndnf cells in layer 1 of the auditory cortex play a role in a standard learning experiment, in which the mice associate a certain sound with an electric shock, producing a fear response that is activated when the sound is played.

Neurons work through connections to other neurons - and neurons containing Ndnf are no different in this. Therefore, the researchers traced their closest connections, and found that these lead to excitatory neurons located deeper in the cerebral cortex through branching processes, called dendrites. Analysis of the connections led to the discovery of another type of inhibitory neurons, Martinotti cells, acting on Ndnf cells. Further investigation showed that the two cell types cannot operate at the same time - when one is "on" the other is "off", and vice versa. This circuit has not been seen before. Spiegel: "The relationship between the inhibitory cells is particularly interesting, since Martinotti cells are considered to influence the dendrites of the excitatory nerve cells in the learning process."

The team then examined to what extent each of the two types of cells - Martinotti cells and Ndnf cells - is involved in learning; That is, do these cells change their response to the sound following the learning experiment? Surprisingly, the responses of the Martinotti cells did not change, but the learned fear response was expressed in the Ndnf cells, whose response to the sound became much stronger. In fact, the researchers found that the more the mouse learned to fear the sound, the stronger response was observed in the Ndnf cells. This finding indicates the possibility that neurons with Ndnf play a role in encoding the strength of the learned experience.

The research findings indicate that Ndnf cells and Martinotti cells divide the work between them: Ndnf cells have a preference in mediating the response to internal stimuli, and Martinotti cells respond more to external stimuli. The fact that the two types of cells are apparently connected to a third type of inhibitory cells probably indicates the existence of complex feedback mechanisms acting on inhibitory cells in the learning process. Inhibitory cells are considered to be more flexible than excitatory ones, and therefore may contribute much more to the brain's ability to change. In other words, proper functioning of inhibitory cells may be the key to our ability to learn new things.

Dr. Spiegel says: "Although the research is at the beginning, there has been a great deal of interest in the transgenic mice we created, as they are a new tool for studying learning, memory and the 'plasticity' of the cerebral cortex. We are now planning some experiments that will take the research in new directions. For example, signals about internal moods are transmitted through acetylcholine - a neurotransmitter that often decreases in the elderly. We believe that this substance may play a role in maintaining the flexibility of nerve cells in the cerebral cortex, and we intend to examine the possible connection between these mechanisms and Alzheimer's."