incerta2cortex · Neocortical long-range inhibition for learning and memory

Neocortical long-range inhibition for learning and memory

The ability to learn from experience and remember one’s past is one of the most fundamental and fascinating functions of the brain that is also a central element of individual and collective human identity. A mechanistic understanding of memory has implications reaching from treatment of memory disorders to artificial intelligence and efficient hard- and software design. While by now we have a tolerable understanding of how local circuits implement the plastic changes that underlie learning and memory, brain areas do not function in isolation. Therefore, the critical next step in learning and memory research is to dissect how long-range interactions between different brain areas contribute to, and interact with, local plasticity to enable functional circuit plasticity. A range of excitatory brain-wide afferent systems targeting layer 1 of sensory neocortex have been identified in recent years as key regulators of memory. However, the brain also contains a sparser and much less understood complement of long-range inhibitory projections. During my Marie Curie postdoctoral fellowship, I sought to determine whether such inhibitory systems might uniquely influence memory encoding in neocortical circuits, since this had never before been investigated. The goal of the project was to determine whether long-range inhibitory projections deriving from a subthalamic nucleus, the zona incerta, contribute to memory encoding in sensory neocortex, using the auditory cortex as a model system, by addressing the following objectives: i) Characterize connectivity from zona incerta to auditory cortex ii) Resolve what information zona incerta conveys to auditory cortex during learning iii) Determine the contribution of zona incerta afferents in auditory cortex to behavioral learning and cortical computation Using a combination of in vivo 2-photon synaptic calcium imaging, circuit mapping, cortex-dependent threat learning and chemogenetics, I established inhibitory projections from zona incerta as a major source of memory-related information in neocortex with connectivity and plasticity unlike all previously studied excitatory pathways. The highlight of this work entailed performing synaptic 2-photon calcium imaging with a head-fixed conditioning paradigm I developed to longitudinally dissect memory, which revealed two distinct plasticity regimes during learning

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