Neocortical long-range inhibition for learning and memory

Project Information

incerta2cortex

Grant agreement ID: 840701

DOI

10.3030/840701

Project closed

EC signature date 9 April 2019

Start date 1 September 2020

End date 31 August 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 174 806,40

EU contribution

€ 174 806,40

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 1 - incerta2cortex (Neocortical long-range inhibition for learning and memory)

Reporting period: 2020-09-01 to 2022-08-31

Summary of the context and overall objectives of the project

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

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Using anterograde and retrograde circuit tracing, I found that incertocortical afferents preferentially target auditory cortex over other areas of sensory neocortex, and in particular densely innervate higher-order areas that have been shown to be critical for memory, where they are enriched in layer 1.

Using acute slice recordings with optogenetics, transsynaptic anterograde tracing and in situ hybridization, I found that these projections connect selectively to inhibitory interneurons in cortex to disinhibit the local circuit.

Using freely behaving threat conditioning together with chemogenetics, I discovered that zona incerta afferents in auditory cortex are required for behavioral memory.

Using synaptic 2-photon calcium imaging combined with a fully head-fixed threat conditioning paradigm that I established during my Marie Curie fellowship, I found that zona incerta boutons encode both auditory stimuli and primary reinforcers, and furthermore undergo robust plasticity during learning that improves information transfer. In particular, a unique hallmark of these afferents is that memory encoding manifests as two distinct activity regimes, characterized by either positive or negative potentiation of stimulus responses in discrete subsets of incertocortical synaptic boutons. These two classes of boutons exhibit divergent temporal dynamics and response properties which emerge during memory acquisition, are boosted during consolidation and persist in recall. Notably, the rapid de novo appearance of negative responses – which has never been observed before in top-down excitatory projections to neocortex – constitutes the major driver of learning-related changes in stimulus representation.

Ultimately, this work reveals the distinctive contribution of long-range inhibitory projections from the zona incerta to the computational flexibility and memory encoding capacity of neocortical circuits.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The results of my Marie Curie project break new ground on several fronts:

1) It defines the organization, function and information content of zona incerta projections to neocortex, revealing this pathway as a major determinant of the role of this enigmatic brain region. This is particularly relevant since the zona incerta has recently been implicated in a wide range of behavioral capacities, and is moreover targeted therapeutically in human patients through deep brain stimulation. Understanding the function of this brain region therefore could influence how this treatment is used in patients in the future. I am currently discussing the results of my work with European neurosurgeons that are experts in this technique to help bridge the gap between my work in rodents, and their work in humans.

2) It provides the first functional dissection of how long-range inhibition shapes the computations of sensory neocortex, and reveals several unique features. Our work may thereby also enable future work on the contribution of additional long-range inhibitory systems to neocortical function.

3) It identifies a novel and distinct type of top-down control in neocortex. In addition to memory, these signals are likely critical for a number of additional functions including credit assignment and predictive coding.

The main manuscript for this Marie Curie was just resubmitted to Neuron, and I will continue working on this topic in the future.