Cortical feedback circuits for sensory integration and control of synaptic plasticity

One of the great challenges in Neuroscience is understanding how learning and memory work. Long term memory is thought to be stored in the cerebral cortex. The cerebral cortex is particularly highly developed in humans. It is 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?

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 and 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. While feedback connections target apical dendrites, the feedforward connections favour the basal dendrites of the pyramidal cells. The pyramidal neurones in question are located in layers 2 and 3 (L2/3). We will study them in a relatively simple yet highly organised part of the mouse cerebral cortex (known as the barrel cortex) that receives tactile information from the whiskers. We will observe how feedback information from higher order cortical areas interacts with L2/3 neurones when the animal learns a tactile texture discrimination task, for example distinguishes between rough and smooth surfaces. We will test the hypothesis that feedback connections gate synaptic plasticity on the feedforward connections and thereby encode features of the stimulus advantageous for learning the discrimination. Furthermore, we will test 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) and 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, 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), allowing us to selectively stimulate feedback connections 1. in cortical slices to gate LTP in vitro or 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.

Our long-term aim is to understand learning and memory in the cortex. To this end, we aim to understand the operation of a cortical sub-circuit in layer 2/3 (L2/3) that gates plasticity at basal dendrites through excitatory interactions with apical dendritic inputs. We will test how the apical/basal interaction may be controlled through dendrite targeting somatostatin inhibitory interneurons. Further, we aim to understand the consequences for plasticity of mutations associated with mental health conditions such as schizophrenia (human DISC1 t(1;11) mutation), where we have found the basal dendrites remain underdeveloped causing remapping of feedforward connections onto more apical locations. To do so we will: 1. Probe the cortical circuit and its plasticity in slices of barrel cortex where the feedback connections express virally delivered ChR2 and can be activated optically. Preliminary studies show that S2 can gate LTP of L4 input to L2/3 cells. 2. Observe when feedback activity naturally occurs from S2 to S1 during a tactile texture discrimination (head-fixed) task using GCaMP and 2 photon imaging. In a related cohort, asses the effect of mistimed optical stimulation of feedback connections on texture learning. 3. In freely moving mice, test the effect of learning the texture discrimination on basal dendritic structural plasticity by imaging dendritic spines with in vivo 2 photon microscopy. 4. Interrogate the ability of dendritic targeting somatostatin inhibitory interneurones to control the apically gated LTP in vitro and the texture discrimination task learning in vivo. Conversely, test the role of VIP interneurones in facilitating such learning and plasticity. 5. Map feedforward, feedback and inhibitory interneurone connections to L2/3 cells in DISC1 mutants using laser scanning point stimulation of afferents expressing ChR2 (in TTX). We will test the mutation's effect on apically gated LTP and using the mapping results test how plasticity can be rescued.