How do the cellular properties of neurons, and circuit level interaction between neurons, support cognitive functions of the brain? We are addressing these questions by focusing on areas of the brain that are important for spatial cognition. These brain areas provide a model for understanding cognitive functions more generally as spatial activity of neurons during behavior is relatively robust and is accessible to experimental investigation. Our focus is on three areas: the organization of molecularly defined cell populations within circuits that support spatial cognition; how cells in these circuits implement computations that underlie spatial cognition; and how the cellular and molecular properties of neurons in these circuits determine their response to input signals that they receive. We are addressing these problems by combining in vitro and in vivo electrophysiology, optogenetics, transgenic and knockout mice, viral manipulations and computational modeling.
Circuit mechanisms for estimation of location
The hippocampus and entorhinal cortex contain neurons such as place cells and grid cells that encode representations of location. While the firing of these neurons during behavior has been well characterized, the mechanisms that generate these spatial firing fields and their roles in behavior remain unclear. We have recently begun to investigate the organization of circuitry in the entorhinal cortex and its inputs from the hippocampus and external structures such as the medial septum. By investigating circuitry at a molecular level we have discovered previously unanticipated complexity in the organization of entorhinal cortex circuits. For example, we have found that molecularly distinct populations of neurons separate input and output functions of deep layers (Sürmeli et al. 2015). We find that inputs to the entorhinal cortex also have a high level of specificity. For example, medial septal GABAergic inputs synapse exclusively with GABAergic interneurons (Gonzalez-Sulser et al, 2014). We are now combining targetted molecular manipulations with virtual reality-based behaviors to investigate how molecularly defined circuit components contribute to spatial behaviors.
Organization and tuning of synaptic information processing underlying spatial memory
How do responses to synaptic input determine neural computations important for navigation? Are these mechanisms tuned to information encoded? A typical neuron receives synaptic signals from thousands of upstream neurons. One of a neuron’s most important functions is to integrate these signals into a single output (Schmidt-Hieber & Nolan, 2017). Different neuron types demonstrate remarkable specificity and diversity in integration of synaptic signals, suggesting that the details of synaptic integration are critical to circuit computations and ultimately to behavior. Yet, we know very little about the molecular mechanisms that determine these rules, or about how these rules influence behavior or disease. We demonstrated that synaptic integration by stellate neurons in layer 2 is tuned according to the resolution of grid like firing fields (Garden et al., 2008). Our data suggest that this tuning is accounted for by a corresponding organization of leak potassium and HCN channels. HCN1 channels are likely to be of particular importance because of their dominant role in setting the integrative properties of layer 2 neurons (Dudman and Nolan, 2009; Nolan et al., 2007). These observations raise many new questions. For example, what are the molecular mechanisms that configure responses to synaptic input? Is tuning static or is it controlled by activity? We are now addressing these questions by combining physiological approaches with computational modeling, molecular and optogenetic tools.
Dudman, J.T., and Nolan, M.F. (2009). Stochastically gating ion channels enable patterned spike firing through activity-dependent modulation of spike probability. PLoS Comput Biol 5, e1000290.
Garden, D.L., Dodson, P.D., O’Donnell, C., White, M.D., and Nolan, M.F. (2008). Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields. Neuron 60, 875-889.
Gonzalez-Sulser A., Parthier D., Candela A., McClure C., Pastoll H., Garden G., Sürmeli G., and Nolan M.F. (2014). GABAergic projections from the medial septum selectively inhibit interneurons in the medial entorhinal cortex. Journal of Neuroscience 34, 16739-16743.
Nolan, M.F., Dudman, J.T., Dodson, P.D., and Santoro, B. (2007). HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex. J Neurosci 27, 12440-12451.
Schmidt-Hieber, C. & Nolan, M.F. (2017). Synaptic integrative mechanisms for spatial cognition. Nature Neuroscience, 20(11): 1483-1492.
Sürmeli G., Marcu D-C., McClure C., Garden D.L.F., Pastoll H. & Nolan M.F. (2015). Molecularly defined circuitry reveals input-output segregation in deep layers of the medial entorhinal cortex. Neuron 88(5):1040-1053.