Skip to main content
Northwestern University Feinberg School of Medicine
John Disterhoft Lab

Research

The Disterhoft Lab employs in vivo and in vitro techniques in the investigation of aging and learning in the brain. Explore the research areas to which our lab has been making significant contributions below.

Current Projects

 Behavior

Our laboratory focuses on characterizing the mechanisms by which neuronal networks and individual neurons process and store new information during and after learning. Eyeblink conditioning is our primary model paradigm to assess associative learning. This Pavlovian task offers excellent stimulus control, ease of precise behavioral measurement, robust associative learning and the capacity to test both human and non-human animal subjects.

We use rabbit, rat, mouse or human subjects depending upon the question being investigated. We also use a broad set of additional techniques, including fear conditioning and spatial navigation in the Morris water maze, to assess other types of behavior to evaluate the specificity of experimental manipulations on mechanisms of associative learning. An important focus of our research is on the network and cellular mechanisms that are altered by aging or neurodegenerative diseases such as Alzheimer’s. For more information about the full behavioral repertoire of behavioral tests employed, please visit the Behavioral Phenotyping Core website.

Representative Publications:

 In Vitro Biophysics

Our program focuses on characterizing the ways in which neurons store new information during associative learning at the cellular and subcellular levels. Experiments focus on the hippocampus, a paleocortical region involved in transferring information during learning from the short- to long-term memory store. We make biophysical measurements from hippocampal brain slices taken from eyeblink-trained animals to define what ionic mechanisms underlie the changes in neuronal excitability recorded in the intact animal. We have observed conditioning-specific alterations in postsynaptic intrinsic currents (calcium-activated potassium currents) likely to enhance cellular excitability and are performing current and whole-cell patch clamp recordings to characterize them and their relation to acquisition and consolidation of the eyeblink-conditioned response. An important focus of our research is on cellular mechanisms for altered learning in aging. We are using a combination of behavioral and biophysical approaches to address this question.

Recently, we have incorporated calcium-imaging techniques using both a charge-coupled device (CCD) camera system and a two-photon laser scanning microscopy (2P-LSM) system to investigate learning- and aging-related changes in calcium properties in CA1 pyramidal neurons. In addition, we have added the capacity to investigate calcium transients in dendritic spines by using two-photon glutamate uncaging. Thus, these latest, powerful tools will be used to complement our traditional biophysical measures in pursuing the cellular mechanism(s) that underlie learning- and aging-related changes in the hippocampal neurons.

Representative Publications:

 In Vivo Single-Neuron Recording

Electrophysiological recording experiments in the conscious animal enable direct correlation of neural activity with behavior, especially when the activity is a measure or reflection of a cognitive process such as learning or memory.

Our lab conducts multiple single-neuron recording experiments using chronically implantable microdrives in rabbits, rats and mice as they perform eyeblink conditioning, an associative memory task. We are also beginning to use miniature microscopes (miniscopes) to monitor calcium activity of hundreds of simultaneously recorded neurons during behavior.

We use these techniques to test hypotheses about the neurophysiological properties and the functional role of neurons from brain regions that are involved in associative memory such as the prefrontal cortex, hippocampus, thalamus and the basal ganglia.

Representative Publications:

 Molecular Neuroscience

This is the newest branch of the Disterhoft Laboratory. We have established a number of methods that include quantitative Western blotting, immunohistochemistry, q-RT-PCR and in vivo shRNA viral vector “gene therapy." We are equipped to perform many standard techniques that include cloning, in situ hybridization, RT-PCR and ELISA.

We are primarily interested in a translational approach where molecular targets associated with learning, neuronal excitability and lifespan may be identified and manipulated for potential therapeutic utility for cognitive disorders and aging-associated dementia.

Current Projects:
  • Amelioration of aging-related learning and memory deficits by overexpressing CREB in dorsal CA1 region of aged rats
  • Measurement and quantification of various voltage-gated calcium channels that regulate the afterhyperpolarization in young and aging animals during learning
  • Design and delivery of therapeutic shRNAs directed against multiple signaling targets in animal models of Alzheimer’s and aging-associated dementia
  • Assay biochemical pathways that participate in the expression of normal and aging-associated learning and memory
Representative Publications:
  • Yu XW, Curlik DM, Oh MM, Disterhoft JF. CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats. ELife. 2017 Jan 4;6. pii: e19358. doi: 10.7554/eLife.19358. PubMed PMID: 28051768; PMCID: PMC5214885.
  • Yu XW, Oh MM, Disterhoft JF. CREB, cellular excitability, and cognition: Implications for aging. Behav Brain Res. 2016 Jul 28. pii: S0166-4328(16)30477-6. doi:10.1016/j.bbr.2016.07.042. [Epub ahead of print] PubMed PMID: 27478142.
Research conducted by the Disterhoft Lab is funded by NIH grants R37 AG008796 and RF1 AG017139.