Understanding how the brain changes with experience is a fundamental question in neuroscience. Our research projects attempt to address this question by characterizing how neuronal and synaptic circuit function changes by experience-driven neural activity.
Current ProjectsExperience-dependent modulation of synaptic circuits in the hippocampus
It is generally accepted that when we learn, our brain changes in order to store a memory. Much is known on the identification of brain regions and mechanisms important for the storage of memory. For instance, memories of facts and episodes (e.g. spatial memory) largely depend on the activity of the hippocampus. Similarly, synaptic plasticity, the experience-dependent change in synaptic function, is thought to be the cellular mechanism that underlies memory formation. Yet, we still lack a detailed understanding of the organization of memory traces at the level of neural and synaptic circuits. Our goal is to define how storing memories changes the function of neurons and their synaptic circuits in the hippocampus of mice that have been trained in a spatial task. We move toward this goal by way of an exciting interdisciplinary research collaboration with the laboratory of Dr. André A. Fenton (NYU). We investigate how learned experiences persistently modify the function of neurons in the CA1 area of the hippocampus by testing the electrophysiological properties of their intrahippocampal (CA3-CA1) and cortical (EC-CA1) synaptic circuits (Fig. 1). To identify neurons potentially recruited into the memory trace, we use a transgenic mouse that allows us to temporally restrict the expression of an immediate early gene-driven fluorescent protein during spatial learning (Fig. 2A-B). In addition to the electrophysiological analysis (Fig. 2C-F), we determine changes in mRNA expression and protein levels in single neurons (Fig. 2G-H). This combined analysis allows us to explore a connection between functional and molecular changes of neurons that putatively form a memory trace. Neural ensembles are speculated to support memory traces at the systems level. This project aims to bridge the scales of neural ensembles (connectome) and synaptic circuits (synaptome) by defining the changes of synaptic circuit function and mechanisms that underlie ensemble activity thought to generate a memory trace.
Decoding place cell firing-induced synaptic plasticity and cognitive mapping
The goal of this project is to characterize the core features of spike code that are important for the formation of synaptic plasticity. Synaptic plasticity is an experience-dependent change in the function of synapses and is hypothesized to be an important mechanism for learning and memory processes. When an animal moves through an environment, particular neurons in the hippocampus fire action potentials only at specific locations of the environment; these neurons are known as “place cells.”
A brainchild of the late Professor Robert L. Muller (SUNY Downstate), this study investigates how sequences of spike activity (action potentials), recorded from place cells, change the activity of synapses in a brain slice preparation. Our approach, developed by Isaac et al. (2009) and Froemke and Dan (2002), utilizes the time series of place cell spiking originally recorded from the freely moving animal as input stimulation to the pre and postsynaptic elements of CA1 pyramidal cells (Fig. 1). That is, we reproduce in a brain slice preparation the synaptic behavior of two synaptically connected place cells as we speculated it occurs in the behaving animal.
Our work is expected to aid in understanding aspects of spike coding information, such as frequency of spiking (rate spike coding) or timing of spiking (temporal spike coding), that are important for the formation of synaptic plasticity needed for the encoding of navigational information.
Compartmentalized synaptic plasticity
Neurons in the brain receive multiple streams of information from other neurons via synaptic connections. How do neurons integrate the multitude of incoming information arriving at their synapses is key to understand how processing of information occurs in the brain.
Synaptic plasticity is an experience-dependent modulation of the function of synapses and is thought to be an important mechanism for the process of learning and the formation of memory. During learning, it is speculated that multiple streams of learning-associated neural activity arrive and trigger synaptic plasticity mechanisms at distinct synapses of the neuron.
Our goal is to define how a neuron computes information when multiple forms of synaptic plasticity mechanisms are activated in two or more of its synapses. Our work is inspired by the synaptic tagging and capture hypothesis developed by Frey and Morris (1997, 1998). We investigate the computing capability of CA1 neurons of the mouse hippocampus that have been stimulated at separate synaptic inputs to induce different forms of synaptic plasticity (Fig. 1).
Our studies suggest that activation of synaptic plasticity mechanisms at a given synaptic input can change the properties of neighboring (unstimulated) synapses; a phenomenon that we call “compartmentalized synaptic plasticity” (Pavlowsky and Alarcon, 2012).
Our work investigates whether compartmentalization is an important process for the computing capability of neurons that is required to organize distinct learning-associated streams of information arriving to a neuron. We think these compartments work as units of computation for the association/separation and inclusion/dismissal of learning and memory information.
Molecular mechanisms underlying learning and memory
A long standing research collaboration with Dr. Ivan Hernandez’s laboratory, this project aims to investigate the mechanisms that underlie learning and memory processes. Physiological and molecular evidence indicate that synaptic plasticity, a cellular phenomenon known to modulate synaptic function, may be the cellular substrate of learning and memory processes. Indeed, the Synaptic Plasticity Hypothesis of Memory states that mechanisms supporting long-lasting synaptic plasticity are fundamental to the maintenance of memory.
Molecular neuroscience studies at Hernandez’s lab center on identifying a “master switch” mechanism able to control gene expression and protein synthesis relevant for the maintenance of synaptic plasticity and memory. Together, we observed that the requirement for poly(ADP)ribose polymerase (PARP) activity, an enzyme that regulates gene expression via chromatin relaxation, can distinguish populations of CA1 neurons of the hippocampus of mice trained in a spatial memory task versus those of untrained mice (Fig. 1). The identification of learning-associated molecular changes has initiated a line of research that is expected to bridge cell-specific molecular mechanisms and memory traces in cell networks.