The "uncertainty zone" in Neuron affects the brain's ability to form new memories

The neocortex is the largest and most complex part of the brain and has long been considered the ultimate storage place
for long-term memories.
But how do past events and experiences leave their mark there? Researchers from the University of Freiburg Faculty of Medicine, led by Professor Johannes Letzkus and the Max Planck Institute for Brains, have discovered that a rarely studied area of the brain, the "uncertainty zone" or "uncertainty zone", communicates with the neocortex in an unconventional way to quickly control memory formation
.
Their work is the first functional analysis
of how long-term inhibition affects information processing in the cerebral cortex.
The signals identified in this study may be crucial not only for memory, but also for a number of other brain functions, such as attention
.
The results of the study have just been published in
the journal Neuron.

"Top-down signaling" is at the heart of the study

Memory is one of the most basic functions of the brain, which allows people to learn from experiences and remember the past
.
In addition, the mechanistic understanding of memory can influence everything from the treatment of memory and anxiety disorders to the development of
artificial intelligence and efficient hardware and software design.
To form memories, the brain must link "bottom-up" sensory signals from the environment with internally generated "top-down" signals that convey past experiences and current goals
.
These top-down signals are the central focus
of current research.

In recent years, researchers have begun to identify many of these top-down projection systems, all of which share some common characteristics: They signal through synaptic excitation, a standard way of sending information between cortical regions, and they also exhibit a common mechanism
of memory encoding.
Learning-related stimuli elicit stronger responses in these systems, suggesting that this positive enhancement is part of the mystery of
memory traces.

Impact on network functionality

Remote suppression pathways are much sparser and far less numerous than these systems, but there is growing evidence that they can still have surprisingly powerful effects on network function and behavior," says
Professor Johannes Letzkus, professor at the University of Freiburg and former head of the Max Planck Brain Institute.
"We set out to determine whether this input exists in the neocortex and, if so, how they uniquely promote memory
.
"

Dr.
Anna Schroeder, the first author of the study and a postdoctoral researcher in Letzkus' lab, decided to focus on a major inhibitory subthalamic nucleus, the uncertainty zone, to address this problem
.
Although the function of this brain region is as mysterious as its name suggests, her preliminary findings suggest that the indeterminate band sends inhibitory projections that selectively dominate neocortical regions
known to be important for learning.
In her efforts to study the plasticity of the system at all stages of learning, she implemented an innovative approach that allowed her to track the responses
of individual uncertainty bands synapses in the neocortex before, during, and after the learning paradigm.

Redistribution of activities in the learning process

"The results were amazing," Schroeder recalls
.
"While about half of the synapses produced a stronger positive response during the learning process, the other half did the opposite
.
In fact, what we observe is a complete redistribution
of inhibitions within the system due to learning.
"This suggests that indeterminate band synapses encode prior experience
in a unique bidirectional way.
" This is especially evident
when scientists compare the magnitude of plasticity to the strength of acquired memory.
They found a positive correlation, suggesting that uncertainty band projections encode learned correlations
for sensory stimuli.

In separate experiments, Schroeder found that silencing these projections during the learning phase impairs memory traces later onward, suggesting that the bidirectional plasticity that occurs in these projections is necessary for
learning.
She also found that these inhibitory projections preferentially formed functional connections with other inhibitory neurons in the neocortex, effectively forming a remote desuppression circuit
.
"This connectivity means that activation of uncertain bands should lead to net excitability of neocortical circuits," Schroeder said
.
"However, combining this with the redistribution of inhibition we saw in learning suggests that this pathway may have richer computational results
for neocortical processing.
"

Changes in stimulus representation

Scientists are particularly interested in uncertain band synaptic groups that exhibit negative enhancement, as this type of plasticity has never been observed in top-down excitatory pathways previously studied
.
They believe that computational methods may provide valuable insights
into how these unique responses develop.
Further analysis with Prof.
Dr.
Henning Sprekeler and his team at the Technical University of Berlin revealed that, remarkably, these negative responses are the main drivers of changes in stimulus representations during learning
.

In addition, the uncertainty zone is one of the few standard target regions for deep brain stimulation in Parkinson's patients, which opens up an interesting possibility
for future translational work.
"Ultimately, this study is also expected to inspire other researchers to continue exploring the role of remote inhibition in regulating neocortical function, including uncertain bands and other as-yet-unidentified sources
," Letzkus said.

Anna Schroeder, M.
Belé n Pardi, Joram Keijser, Tamas Dalmay, Ayelé n I.
Groisman, Erin M.
Schuman, Henning Sprekeler, Johannes J.
Letzkus.
Inhibitory top-down projections from zona incerta mediate neocortical memory.
Neuron, 2023