Periodic Reporting for period 2 - DEVMEM (Learning to remember: the development of the neural mechanisms supporting memory processing.)
Periodo di rendicontazione: 2022-07-01 al 2023-12-31
The overall objective of this proposal is to identify the mechanisms within the brain that underlie our ability to learn and remember: we plan to do so by tracking the emergence of memory processing and neural activity during development. Humans (and many other mammals) are are not born with a fully functioning memory system. There are several accounts as to the source of this juvenile mnemonic deficit, each placing emphasis on impairments of specific processes (for example, the encoding of new memories, the strengthening of existing memories, or the ability to accurately retrieve previous memories). However, a general weakness in the study of memory development is the lack of data describing the memory-related activity of brain cells (neurons) during development. To directly address this problem, we are studying neural activity in the developing animals, simultaneously with behavioural testing of memory. We are focusing on a brain region called the hippocampus, as this structure is known to be critical for memory, but we also extend our investigations to brain-wide networks. Our experiments aim to understand how the development of different brain processes (for example, memory strengthening during sleep or interactions between different brain areas) relate to the emergence of memory. By discovering this, we will increase understanding both of how memory emerges during development, and also the brain supports memory across the whole life span.
The work in the project is organised around five objectives, each based on a different hypothesis for the causes of juvenile memory deficits. The five objectives, and the progress so far towards each of these, are outlined below.
1) The spatial hypothesis. The hippocampus contains neurons which respond to an animal’s current position and orientation: these neurons are thought to form the basis for spatial memory and navigation. We are testing the hypothesis that the juvenile spatial memory system is unstable and unanchored from the external world, which leads to deficits in the spatial aspect of memory. We have conducted experiments to test the effect of environment size and shape on neurons in the subiculum (the main output region of the hippocampus) and the entorhinal cortex (in major input region). We have found that environment shape has a consistent effect on the firing of subiculum neurons, even in younger animals, potentially explaining why square room walls act as an important navigational cue, even early in development. In the entorhinal cortex, we find that spatial firing takes longer to stabilise, especially in large environments, supporting the hypothesis that a lack of spatial stability may underlie immature memory function.
2) The consolidation hypothesis. During sleep, the hippocampus ‘replays’ similar patterns of firing to that seen in exploration. We aim to discover whether the emergence of these ‘replay’ events are linked to the emergence of memory. In previous work, we described the development of spontaneous ‘replay’ in animals: so far in this project, we have set up behavioural tests that allow us to detect whether memory of a particular place is linked to ‘replay’ of that place.
3) The planning hypothesis. During exploration, spatially-tuned neurons can sometimes appear to be responding to locations ahead of an animal’s actual position, a neural phenomenon thought to represent forward planning for decision making. We have developed behavioural tasks that allow us to assay the development of memory-based choice-making in young animals, and are now beginning to test neural responses, during the performance of these tasks.
4) The interference hypothesis. A specific sub-region of the hippocampus, the dentate gyrus (DG), is thought to help us distinguish between similar memories. However, the DG is unusual in maturing very late, compared to the rest of the brain. Does an immature DG network lead to ‘interference’ between similar memories, in young animals? We have tested the neural responses of developing DG neurons to places of varying similarity, with preliminary results showing immature DG networks may indeed be one reason why young animals can struggle to distinguish similar places and events.
5) Brain-wide network hypothesis. The hippocampus does not process memories in isolation, but as part of a wider network. We are exploring the role in memory of different parts of this wider network, initially focusing on the Parahippocampal Cortex, which contains neurons responding to associations of places and objects. We are now testing whether the emergence of these neural responses is related to specific object-place memory.
1) The spatial hypothesis. The hippocampus contains neurons which respond to an animal’s current position and orientation: these neurons are thought to form the basis for spatial memory and navigation. We are testing the hypothesis that the juvenile spatial memory system is unstable and unanchored from the external world, which leads to deficits in the spatial aspect of memory. We have conducted experiments to test the effect of environment size and shape on neurons in the subiculum (the main output region of the hippocampus) and the entorhinal cortex (in major input region). We have found that environment shape has a consistent effect on the firing of subiculum neurons, even in younger animals, potentially explaining why square room walls act as an important navigational cue, even early in development. In the entorhinal cortex, we find that spatial firing takes longer to stabilise, especially in large environments, supporting the hypothesis that a lack of spatial stability may underlie immature memory function.
2) The consolidation hypothesis. During sleep, the hippocampus ‘replays’ similar patterns of firing to that seen in exploration. We aim to discover whether the emergence of these ‘replay’ events are linked to the emergence of memory. In previous work, we described the development of spontaneous ‘replay’ in animals: so far in this project, we have set up behavioural tests that allow us to detect whether memory of a particular place is linked to ‘replay’ of that place.
3) The planning hypothesis. During exploration, spatially-tuned neurons can sometimes appear to be responding to locations ahead of an animal’s actual position, a neural phenomenon thought to represent forward planning for decision making. We have developed behavioural tasks that allow us to assay the development of memory-based choice-making in young animals, and are now beginning to test neural responses, during the performance of these tasks.
4) The interference hypothesis. A specific sub-region of the hippocampus, the dentate gyrus (DG), is thought to help us distinguish between similar memories. However, the DG is unusual in maturing very late, compared to the rest of the brain. Does an immature DG network lead to ‘interference’ between similar memories, in young animals? We have tested the neural responses of developing DG neurons to places of varying similarity, with preliminary results showing immature DG networks may indeed be one reason why young animals can struggle to distinguish similar places and events.
5) Brain-wide network hypothesis. The hippocampus does not process memories in isolation, but as part of a wider network. We are exploring the role in memory of different parts of this wider network, initially focusing on the Parahippocampal Cortex, which contains neurons responding to associations of places and objects. We are now testing whether the emergence of these neural responses is related to specific object-place memory.
Progress beyond the state of the art so far has included:
1) Describing how subiculum neurons are affected by the geometry of an animal’s local environment, in both adulthood and development. These results are important for models of how animals use boundary geometry to navigate, and may offer a neural mechanism for the phenomenon of ‘spatial reorientation’, i.e. the strong salience of square room geometry for spatial memory.
2) Uncovering the in vivo activity of dentate gyrus neurons during development, and testing their responses to differing spatial contexts. These results are an important test of the hypothesis that dentate gyrus immaturity leads to a lack of memory specificity during development, and furthermore will inform models of dentate gyrus function more generally, including in adulthood.
3) The development of several different behavioural tests for simultaneously assessing behavioural memory and neural responses, in developing animals. These tasks represent an important experimental resource for testing the relationship between the cognitive development of memory, and neural network activity.
Expected results until the end of the project:
1) Using behavioural testing, drawing correlative links between memory emergence and neural development.
2) When candidate neural mechanisms for memory development have been identified, using the correlative approach outlined above, we will proceed to causal testing, for example by supressing specific patterns of neural activity (e.g. ‘replay’) to test its causal necessity for memory development.
1) Describing how subiculum neurons are affected by the geometry of an animal’s local environment, in both adulthood and development. These results are important for models of how animals use boundary geometry to navigate, and may offer a neural mechanism for the phenomenon of ‘spatial reorientation’, i.e. the strong salience of square room geometry for spatial memory.
2) Uncovering the in vivo activity of dentate gyrus neurons during development, and testing their responses to differing spatial contexts. These results are an important test of the hypothesis that dentate gyrus immaturity leads to a lack of memory specificity during development, and furthermore will inform models of dentate gyrus function more generally, including in adulthood.
3) The development of several different behavioural tests for simultaneously assessing behavioural memory and neural responses, in developing animals. These tasks represent an important experimental resource for testing the relationship between the cognitive development of memory, and neural network activity.
Expected results until the end of the project:
1) Using behavioural testing, drawing correlative links between memory emergence and neural development.
2) When candidate neural mechanisms for memory development have been identified, using the correlative approach outlined above, we will proceed to causal testing, for example by supressing specific patterns of neural activity (e.g. ‘replay’) to test its causal necessity for memory development.