Periodic Reporting for period 5 - PrefrontalMap (Organization and learning-associated dynamics of prefrontal synaptic connectivity)
Okres sprawozdawczy: 2025-02-01 do 2025-07-31
The prefrontal cortex is one of the most densely interconnected regions of the mammalian brain, as it needs to perform countless actions related to cognitive function, memory storage, regulation of emotional states and adaptations to a rapidly changing environment. While we know quite a bit about the wiring and function of simpler cortical regions, such as those in charge of processing vision, touch or audition, we know relatively little about how associative regions such as the prefrontal cortex are organized, how their neurons connect with one another, and how this connectivity pattern changes with experience and following traumatic events. Understanding the structure and function of the prefrontal cortex is a crucially important goal, since numerous psychiatric disorders are linked with various forms of dysfunction in this circuit. In PrefrontalMap, we developed innovative optogenetic methodology and used it to dissect the connectivity map and the behavioral roles of prefrontal cortex and its related circuits. We elucidated how neurons in this brain region and its interconnected circuits drive social behavior and emotional learning, and how their properties change with experience.
During the first stage of the project, we developed a set of techniques and approaches that allow robust and highly reliable single-neuron optogenetic stimulation in parallel with electrophysiological recordings to reveal the input structure of single neurons in the prefrontal cortex of mice. Optogenetics is a powerful neuroscience method, but it has been limited in several domains: one is the ability to accurately inhibit the release of neurotransmitter from synaptic terminals, and the other is to perform precise single-neuron manipulations while reading out neural activity. We developed new light-activated tools that allow precise silencing of neurotransmitter release with minimal light intensity. We also created viral vectors that allow the expression of both an actuator (channelrhodopsin) and a neural activity reporter. Each one of these tools made new experiments possible, and we shared these tools widely through open-access repositories.
In the realm of synaptic connectivity mapping, we focused our efforts on the cells projecting from the prefrontal cortex to the amygdala, a brain region that is crucial for emotional processing, learning and memory. We were able to describe with great detail how these neurons interact with one another and with non-amygdala-projecting neurons, paving the way for an investigation of how these connections change over time and with behavioral experience. In the second part of the project, we developed an optical system that allows neural activity recording and simultaneous photostimulation of single neurons, or neuronal ensembles, in awake and behaving mice. With this system, we are currently studying how neural activity and synaptic connectivity evolve through the process of memory consolidation.
To understand how the prefrontal circuit processes behaviorally-relevant information, we studied the encoding of social stimuli in this circuit, revealing that prefrontal neurons are tuned to social odors, and that this tuning is degraded in a genetic mouse model of autism spectrum disorder. This led us to investigate how social behavior is regulated during early life, since this is a critical period for both the maturation of the prefrontal cortex and for the development of healthy attachment behavior. We found that oxytocin, a neurotransmitter release in the prefrontal cortex during social encounters, is critical for the behavior of mouse pups toward their mother, and that disrupting the activity of oxytocin neurons leads to selective impairment in vocal communication at these very young ages. Our ongoing work is aimed at discovering the mechanism through which vocal behavior is encoded and regulated in the prefrontal cortex.
In the realm of synaptic connectivity mapping, we focused our efforts on the cells projecting from the prefrontal cortex to the amygdala, a brain region that is crucial for emotional processing, learning and memory. We were able to describe with great detail how these neurons interact with one another and with non-amygdala-projecting neurons, paving the way for an investigation of how these connections change over time and with behavioral experience. In the second part of the project, we developed an optical system that allows neural activity recording and simultaneous photostimulation of single neurons, or neuronal ensembles, in awake and behaving mice. With this system, we are currently studying how neural activity and synaptic connectivity evolve through the process of memory consolidation.
To understand how the prefrontal circuit processes behaviorally-relevant information, we studied the encoding of social stimuli in this circuit, revealing that prefrontal neurons are tuned to social odors, and that this tuning is degraded in a genetic mouse model of autism spectrum disorder. This led us to investigate how social behavior is regulated during early life, since this is a critical period for both the maturation of the prefrontal cortex and for the development of healthy attachment behavior. We found that oxytocin, a neurotransmitter release in the prefrontal cortex during social encounters, is critical for the behavior of mouse pups toward their mother, and that disrupting the activity of oxytocin neurons leads to selective impairment in vocal communication at these very young ages. Our ongoing work is aimed at discovering the mechanism through which vocal behavior is encoded and regulated in the prefrontal cortex.
The work conducted during PrefrontalMap has allowed us to probe the organization of connections among prefrontal neurons projecting to key centers in the brain involved in learning from rewards and punishment, and how these connections reorganize with learning. We are currently investigating how local-circuit inhibitory neurons influence the dynamics of this circuit, and how their activation or suppression alters the process of learning. Using the custom-built holographic microscope that was established in the lab as part of this project, we now routinely perform single-neuron optogenetic stimulation in the living brain, asking how stimulation of single neurons - or precisely targeted neuronal ensembles - recruits neural activity in the local network, and how this recruitment changes through the process of memory consolidation.