Biophysics, Dendrites & Neural Computation
Our laboratory studies how the biophysical features of neurons, including ion channels, receptors, and membrane electrical properties, endow neural circuits with powerful processing capabilities, ultimately allowing them to perform the complex computations required to drive adaptive behavior. We focus on the role of dendrites, the elaborate tree-like structures where neurons receive the vast majority of afferent input. Due to the spatial arrangement of synaptic contacts on dendrites and the presence of particular biophysical mechanisms a complex array of interactions among synapses can take place. Elementary input-output operations that manifest as coincidence detection, pattern recognition, input comparison, and simple logical functions can all be carried out even in small dendritic subunits. Our hypothesis is that computations in neural circuits are built out of these fundamental integrative operations conducted at dendrites. The goal is to provide mechanistic explanations for how the neural circuits underlying sensory processing and navigation create complex, abstract representations of the environment and past experiences to ultimately guide behavior.
If neural circuits use integrative operations at single neurons as the building blocks for computations, then synaptic and cellular plasticity provide a potent means for either reinforcing or changing neural processing algorithms. Dendritic mechanisms governing input transformations likely impose plasticity induction rules distinct from the canonical spike-timing dependent plasticity framework, which currently dominates learning models. Using electrical and optical recording in behaving rodents as well as in vitro preparations we hope to understand the mechanisms and functional consequences of plasticity in dendrites to ultimately relate changes in synaptic and cellular function to the alterations in computations that occur during learning to modify behavior.
Many cognitive disorders, including Autism, are characterized by conspicuous changes in the number, distribution, and/or morphology of dendritic spines, the anatomical locus of the majority of excitatory synapses in the brain. However, there is limited functional data on how, or even if, these morphological changes effect neural circuit operation. We plan to address the relationship between anatomical aberrations observed in mouse models and the functional consequences for synaptic efficacy, plasticity, and integration to identify disease-associated mechanistic loci. Manipulation of these processes during behavior is hoped to causally link changes in synapse anatomy and cellular function with potentially ectopic computations in the relevant microcircuit and behavioral alterations in these animals. We hope this novel research plan will shed new light on these complicated and currently intractable disorders.
Beaulieu-Laroche L, Toloza EHS, van der Goes MS, Lafourcade M, Barnagian D, Williams ZM, Eskandar EN, Frosch MP, Cash SS, Harnett MT (2018). Enhanced dendritic compartmentalization in human cortical neurons. Cell 175(3):643-651
Beaulieu-Laroche L & Harnett MT (2018). Dendritic Spines Prevent Synaptic Voltage Clamp. Neuron 97(1):75-82
Shin Yim Y, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, Yeon Kim J, Kim S, Kim H, Waisman A, Littman DR, Wickersham IR, Harnett MT, Huh JR, Choi GB (2017). Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549(7673):482-487
Harnett MT, Magee JC, Williams SR (2015). Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons. Journal of Neuroscience 35(3):1024-37
Harnett MT, Xu N, Magee JC, Williams SR (2013). Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons. Neuron 79(3):516-29 *Preview article in Neuron by Dax Hoffman, p409
Marvin JS, Borghuis BG, Tian L, Cichon J, Harnett MT, Akerboom J, Gordus A, Renninger SL, Chen T, Bargmann CI, Orger MB, Schreiter ER, Demb JB, Gan W, Hires SA, Looger LL (2013). An optimized fluorescent probe for visualizing glutamate neurotransmission. Nature Methods 10(2):162-70
Xu N, Harnett MT, Williams SR, Huber D, O’Connor, DH, Svoboda K, Magee JC (2012). Nonlinear dendritic integration of sensory and motor input produces an object localization signal. Nature 492(7428):247-51
Harnett MT*, Makara J*, Kath W, Spruston N, Magee JC (2012). Synaptic amplification by dendritic spines enhances input cooperativity. Nature 491(7425):599-602