Leonid L. Moroz, Ph.D.
The Whitney Laboratory for Marine Bioscience
9505 Ocean Shore Blvd.
St. Augustine, FL 32080-8610
Key Words: Genome: Neurogenomics; Epigenomics; Memory; Cellular Bases of Behavior; Nervous System Evolution; Next Generation Sequencing; Genomic Bases of Neuronal Identity and Plasticity; Single-cell genomics; Epilepsy; Aging; Bioinformatics; Human Genomics & Epigenomics
The human brain is the most complex molecular machine known. It is composed of a hundred billion nerve cells, each of which is unique and makes innumerable connections (about 100 trillion!) with other nerve cells (connectome). Together these cells and all their connections allow us to move, think, dream, imagine and learn – they are our “free will”. Understanding brain complexity starts with the most fundamental questions: What makes a neuron? What is the molecular/genomic “toolkit” needed to make a neuron in the first place? Is there only one or are there many “toolkits” to support the origin and maintenance of neural organization?
Comparative neurobiology suggests that there are many ways to make a neuron. Astonishingly, our analysis reveals that neural centralization and formation of brains might have independently evolved at least seven to eleven times during the 550 million years of animal evolution. The hypothesis we are testing is that the complex brains we find in representatives of existing animal phyla are the result of parallel evolution of different ancestral cell lineages. We want to reconstruct how the descendents of these cell lineages “come together” to form a brain in the octopus, or honey bee, or human. We are working on a broad spectrum of animals representing different levels of neural organization and tissue complexity: from the simplest sponges to molluscs (e.g. the sea slugs, Nautilus and Octopus); from comb jellies to humans.
Another research goal is to understand the molecular mechanism of the formation and long-term maintenance of memories. Here, the sea slug Aplysia and related marine molluscs lead the way. Their giant nerve cells allow us to probe the critical molecular events of learning and memory in real time, all the way from genes to behaviors. In fact, we can follow the activity of all the genes in a single neuron as it learns and remembers! Most importantly, we successfully applied the developed genomic protocols to single mammalian (rodent) neurons in memory-forming circuits. Now, our next target is genomic organization in human circuits. Here, we are developing collaborations with neurosurgeons to probe one of the most mysterious and challenging cell populations – our neurons and neural circuits
In doing so we are asking questions which are difficult or impossible to address before. How does the activity of more than 20,000 genes within individual neurons of a given circuit lead to persistent changes in synaptic architecture and efficiency forming memories that last a lifetime? Is there only one way, or are there multiple ways to do this and why? This understanding has tremendous potential application for diseases of the human brain and the very origin of nervous system, cognition and intelligence in general.
Research Focus & Aims:
Leonid Moroz’s laboratory focuses on the mechanisms underlying the design of nervous systems and develops innovative approaches to study the genomic basis of neuronal identity and plasticity. We ask: (1) what makes a neuron a neuron and why do they differ so from each other, (2) how do they maintain such precise connections between each other, (3) how does this fixed wiring result in such enormous neuronal plasticity and (4) how does this contribute to learning and memory mechanisms?
The long-term objectives of Dr. Moroz’ research program are twofold: to understand fundamental aspects of (a) the origins and evolution of nervous systems and (b) mechanisms of integrative activity of the genome in eukaryotic cells generally and neurons in particular.
In cellular neuroscience oriented projects we are working to decipher (i) the genomic basis for the establishment and maintenance of unique neuronal identities within a given circuit (genomics of cellular memory), and (ii) genome-wide mechanisms of long-term cellular and nerve circuit plasticity (genomics of cellular plasticity). In both cases, the key question concerns how the activity of thousands of gene products is coordinated at the level of a given single neuron to maintain a uniquely polarized phenotype, with connections to its neighboring cells, and yet still allow this neuron to modify its functional characteristics and connectivity for weeks, months and even years in an experience-dependent manner to support long-term memory. Answers to this challenging task can be achieved only as a result of the highly interactive organization of interdisciplinary teams that will develop and implement imaging and sequencing technologies as well as systems approaches to probe the dynamic genome organization of individual living neurons and even their subcellular compartments in real time using the well-defined Aplysia model system. In some aspects of this program we have developed a fruitful collaboration with Columbia University (Drs. E.R. Kandel and J. Ju groups) as well as with the University of Illinois (Dr. Sweedler)
Although Aplysia is our primary model, we start to use the same genomic tools for deciphering the molecular organization of the memory-forming circuits in mammals (here we collaborate with Drs. T. Foster and J. Frazier). The use and rapid adoption of multiple next generation sequencing technologies enables us to cost-efficiently validate our data; a strong computational underpinning allows us to compile disparate data to generate new knowledge on neurobiological mechanisms.
At the same time, as part of our EvoDevo projects, we are interested in the origins and parallel evolution of neurons and nervous systems in different animal lineages and hope to identify the fundamental principles that govern the way nervous systems are built and function by examining the evolution of nervous systems. This aspect of my research program reflects a different view of the original question (the genomic bases of neuronal identity and plasticity) but uses an evolutionary perspective by looking at “experiments” on neural circuits already performed by nature over the past half billion years. Specifically, my group performs comparative studies of homologous neurons (or specific cell lineages), circuits and behaviors using gastropod and cephalopod molluscs as experimental models. We work to integrate analysis of genome operations in these neurons to decipher mechanisms of how novel neural circuits can emerge and/or how selected neural circuits maintain their cellular composition and high specificity of synaptic connections over hundreds of millions of years. The goal here is to identify genes, or more likely their regulatory regions and non-protein coding components, that lead to modification of the innate genetic program and eventually to formation of novel circuits. In parallel, we initiated studies of basal metazoans such as ctenophores that possess the earliest nervous systems in the animal kingdom. In addition, we expanded our program to look at representative basal deuterostome lineages, as well as other basal bilaterians, to reveal earlier stages of neuronal centralization and the origin of complex brains.