George Dragoi - US grants

Development of predictive coding networks for spatial navigation Summary: Mammalian navigation uses internal models to predict the spatial-temporal statistical regularity of the sequence of environmental locations. Predictive coding theories view the brain as Bayesian interpreter that computes the difference between the external stimuli and an internal model of the world. It is increasingly understood that sequential spatial information is represented by temporal sequences of ensemble neuronal firing in the hippocampus. Without exception, these ensemble patterns have been investigated exclusively in adult animals. A small handful of studies measured the activity of individual hippocampal neurons as pre- weanling or juvenile animals briefly explored open-field environments. However, spatial experience is believed to be internally represented by highly compressed temporal sequences of neuronal ensemble firing during awake and sleep states in the form of theta sequences, replay, and preplay, which are expressed within populations rather than single neurons. Our goal is to reveal the principles and stages of early-life development and maturation of attractor-based compressed temporal sequences as priors for encoding future navigation experiences (i.e., predictive coding), and the role age and early spatial experience play in these processes and in navigation learning. To achieve this goal, we develop new methods to: 1. Chronically record, at millisecond resolution, from large ensembles of neurons (up to 70 simultaneously) from the hippocampus in developing freely-behaving and sleeping rats from first day after eye opening; 2. Reveal and analyze predictive coding network properties; 3. Control and restrict animals? prior spatial experience. Successful completion of this proposal will provide unique resources to help understand the emergence and maturation of cortical networks for internally-generated representations and will provide links and predictive models to study perturbations in neuronal ensemble patterns underlying neurodevelopmental and psychiatric disorders like schizophrenia and autism spectrum disorder.

Project summary: Of the multiple memory systems operating in the brain, episodic memory, defined by the ability to remember where and when events occurred in the past, is a recently evolved, later developing and early deteriorating cognitive function. Early-life episodic memories are rapidly forgotten, a phenomenon known as infantile amnesia occurring in humans and non-human animals. The hippocampus, an evolutionarily ancient, highly organized part of the cortex, is essential for the relational binding of spatial locations and events into spatial and mental trajectories and memory episodes. The rapid encoding and consolidation of sequential spatial experiences into memory episodes is believed to be achieved by the representation of such trajectories within time-compressed hippocampal ?place cell? sequences during navigation and the sleep/rest periods preceding (i.e., preplay, supporting rapid encoding) and following (i.e., replay, supporting consolidation) the novel experiences. The hippocampus undergoes a developmental critical period and functionally matures around postnatal day 24 (P24) in the rat, an age when infantile amnesia ends in rodents. Our main goal is to explore and understand the dependence of memory development on intrahippocampal synaptic plasticity and early-life experience by studying the development of ensemble place cell coding in the hippocampus. We combine chronic electrophysiologic recording of large ensembles of neurons in awake-behaving and sleeping rats across three recently described developmental stages in postnatal life with intra-hippocampal infusion of enhancers of synaptic plasticity, rearing in enriched environments or early-life visual deprivation (dark rearing), and computational methods for decoding spatial trajectories. The successful completion of our proposed aims promises to uncover such developmental mechanism and factors in the rat, which should help understand the development and emergence of episodic memories in the human, where such invasive approaches are not possible. Our findings could more generally impact our understanding of developmental neuro-psychiatric brain diseases like autism, schizophrenia, and intellectual disabilities.