Cortical feedback circuits for sensory integration and control of synaptic plasticity

Understanding how learning and memory works - one of the greatest challenges in Neuroscience.

About

Long term memory is thought to be stored in the cerebral cortex. The cerebral cortex is particularly highly developed in humans being involved in almost every aspect of behaviour and cognition. From sensory processing and planning for action, through to logical reasoning and imaginative thought. How therefore is learning and memory organised in such a diverse structure?

Aims

Our aim in this programme of work is to understand a component of the cortical circuit that forms a recurring module throughout most cortical areas. This may provide a common substrate for learning and long-term memory across the great variety of modalities that compose the cortical repertoire.

We will study:

• pyramidal neurones that receive both feedback connections from higher order cortical areas and ascending feedforward connections carrying sensory information using the simple yet organised part of the mouse cerebral cortex (known as the barrel cortex) that receives tactile information from the whiskers.
• how feedback information from higher order cortical areas interacts with level 2/3 neurones when the animal learns a tactile texture discrimination task, for example distinguishes between rough and smooth surfaces.
• the hypothesis that feedback connections gate synaptic plasticity on the feedforward connections and thereby encode features of the stimulus advantageous for learning the discrimination.
• the idea that a subset of inhibitory interneurones that target the apical dendrites are able to control the interaction between the feedback and feedforward connections and thereby exert control over synaptic plasticity.

The programme of work comprises experiments where:

1. we probe the nature and operation of the cortical circuit in some detail using in vitro brain slices and measure the plasticity by observing a synaptic process known as long-term potentiation (LTP)
2. we test how the components of the circuit behave in whole animals (in vivo) when they learn to distinguish between two tactile textures in a discrimination task to gain a reward
3. we measure structural plasticity in the L2/3 cells during learning with and without the correct feedback.

Preliminary studies show that our texture discrimination task depends on barrel cortex, which can be learned by mice over a few days and causes structural plasticity in the L2/3 neurones. The feedback connections from higher order cortical areas can be made to express artificial ion channels that can be activated by light (optogenetics). This allows us to selectively stimulate feedback connections in:

1. cortical slices to gate LTP in vitro
2. during tactile learning in vivo to bias choices toward one texture or the other.

Our studies probe what we believe is a fundamental component of the long-term memory system. Its correct operation relies on the separation of connections on apical and basal dendrites. However, in a mutation that is known to cause mental health conditions in people (DISC1 t(1;11)), we have found that the balance between apical and basal dendrites of pyramidal cells is altered (in barrel cortex and prefrontal cortex). Connections normally directed to basal dendrites are found to excite apical dendrites, due to developmental atrophy of the basal dendrites.

To understand the extent of this mis-wiring and its consequences for plasticity we will map excitatory and inhibitory inputs in the mutants using optogenetics methods and determine the ability of inhibition to control apical gating of plasticity. This aspect of the study could help explain how cognitive deficits arise in mental health conditions like schizophrenia.

Funding

This project has received funding of £1,803,575.60 from the Medical Research Council.

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