Jeanne Paz - US grants

DESCRIPTION (provided by applicant): Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy in the elderly and in children. Neural plasticity after stroke that tends to compensate lost functions involves reorganization of the surviving neural circuits. However, some aspects of the reorganization might be maladaptive and lead to epileptogenesis over time. Thalamocortical circuits mediate neural network oscillations associated with epilepsy. While there is a large body of evidence supporting thalamic involvement in the generalized idiopathic epilepsies, very little is known about the role of thalamus in post-injury epileptogenesis. Cortical infarcts lead to retrograde cell death of a subset of excitatory - but not inhibitory - thalamic cells. My preliminary data indicate that after several weeks following focal cortical infarcts, isolated thalamic slices (that do not contain the cortex) spontaneously generate epileptiform network oscillations. This is paralleled by increases in intra-thalamic excitatory connectivity and decreases in intra-thalamic inhibition. Surprisingly, despite a major loss of excitatory afferents from the cortex, synaptic excitation is enhanced in thalamocortical cells located in the gliotic area functionally related to the region of focal cortial stroke. Altogether, these results suggest that cortical infarcts lead to robust circuit rewiring within the thalamus. Some aspects of this reorganization could support functional recovery. For example, reduced inhibition of relay nuclei could increase the output of TC cells and enhance thalamocortical excitation, which may facilitate recovery of thalamic and cortical sensory circuits However, the presence of epileptiform network oscillations in the injured thalamus suggests that some aspects of the thalamic reorganization could be maladaptive, participating in injury-induced epilepsy. The two main goals of this research proposal are as follows: (1) To determine the mechanisms underlying the aberrant network excitability and synaptic excitation in the thalamus; (2) To determine whether this enhanced activity in the injured thalamus might amplify corticothalamic network excitability and contribute to epileptogenesis. These questions are crucial to our understanding of the mechanisms of post-stroke thalamocortical reorganization leading to epilepsy. I have designed several experiments to answer these goals. Several of them rely on techniques - optrodes using optogenetic approaches in vivo , glutamate imaging, laser photostimulation/ glutamate uncaging, EEG recordings in freely moving animals - that I will learn from my mentor and consultants who have agreed to train me during the mentored phase of the proposal. My long- term goal is to continue studying the mechanisms generating abnormal neural network oscillations associated with neurological disorders such as epilepsy or Parkinson's disease in an independent academic setting. PUBLIC HEALTH RELEVANCE: Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy. Recovery of function after stroke involves not only surviving neural circuits but also the establishment of new neural circuits. This proposal aims to understand how neural circuits reorganize after stroke and what aspects of this reorganization can lead to epilepsy. This may lead into new insights on therapeutic approaches that promote functional recovery while limiting its health-impairing outcomes and preventing epilepsy.

The prefrontal cortex of the brain controls how people remember sizes of things, such as a number of items or the pitch of a sound, within a short time frame of about a few seconds. This ability, called parametric working memory (PWM), helps people to interpret their world, make decisions, and act or behave. Dysfunction in PWM may be involved in many brain diseases, including Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, and bipolar disorders. These diseases affect more than 200 million people worldwide. Through this research project, researchers will learn more about how the prefrontal cortex controls PWM in healthy and diseased brains. With this new information, they may be able to create new treatments for many people suffering from brain diseases.

PWM relies on the persistent activity of neurons in the prefrontal cortex. This persistent activity is graded such that the firing rate of neurons correlates with the quantity of things to be remembered, which can emerge from network interactions with the local microcircuitry. Yet, to robustly display graded persistent activity, these networks must incorporate neurons with bistability, such that stable quiescence and activity coexist in their range of input. Neurons in the prefrontal cortex can display bistability that depends on non-selective cationic (CAN) currents activated by calcium. However, cellular bistability in the prefrontal cortex occurs under very specific experimental conditions of stimulation and neuromodulation. The researchers' overall goal is to determine whether CAN-mediated conditional bistability in the prefrontal cortex is a genuine physiological property of neurons and whether it supports graded persistent activities within local recurrent networks. They will develop a multidisciplinary research program of computational and experimental analysis to study properties ranging from molecular interactions to the behavior of neural networks. With theoretical modeling at the molecular, cellular, and network levels, extensive numerical simulations, intracellular recordings, and optogenetics, the researchers will identify and control neural substrates that mediate PWM. In this way, they will learn the causal mechanisms and dynamic principles of PWM in the prefrontal cortex, including the multi-stability that characterizes its graded persistent activity. These efforts will help researchers to better understand higher cognitive and behavioral functions and pathologies related to PWM, and also advance theories of fundamental properties in neuroscience. A companion project is being funded by the French National Research Agency (ANR).