Laboratory of Cellular Neurobiology
Lab Director: Jennifer Luebke, Ph.D.
Dr Luebke‘s laboratory is interested in the electrophysiological and morphological properties of neocortical neurons in the rodent and primate prefrontal cortex across the lifespan. Our current work on neocortical pyramidal cells is divided into 5 research areas:
- Normative intrinsic membrane properties (e.g. action potentials and ionic currents).
- Normative glutamatergic and GABAergic synaptic response properties.
- Normative detailed morphological properties (e.g. dendritic architecture and spines).
- The effects of normal aging on the above properties in the rhesus monkey.
- The effects of protein mutations on the above properties in transgenic mouse models of Huntington’s disease and tauopathies.
Pyramidal Cells of the Prefrontal Cortex.
Working memory, which is essential for abilities such as abstract thinking, problem solving, and cognitive flexibility, is mediated in large part by pyramidal cells of the prefrontal cortex (PFC). We are interested in determining the basic properties of layer 2/3 and layer 5 pyramidal cells in both young and aged monkeys and in transgenic mouse models of Alzheimer’s disease. We employ whole-cell patch clamp and intracellular dye-filling techniques to examine the detailed properties of individual pyramidal cells in in vitro slices (see Images below).
We perform experiments on brain tissue obtained both from behaviorally characterized rhesus monkeys (as part of an integrated program project) and from transgenic mouse models of Alzheimer’s disease (such as the APP mutant Tg2576 and the tau mutant Tg4510). While we have experience in recording from many brain areas (hippocampus, brainstem areas, diverse neocortical areas), our research is currently focused on the prefrontal cortex- a brain area essential for higher cognitive function. The prefrontal cortex is removed from the experimental subject’s brain as a block and then cut into 400 micron thick living slices which are maintained in oxygenated artificial cerebrospinal fluid for up to 15 hours.
Whole-Cell Patch Clamp Recordings in In Vitro Brain Slices.
Using infrared differential interference contrast microscopy, we visualize living neurons in the in vitro slices and use whole-cell patch-clamp methodologies to record the electrophysiological and pharmacological response properties of identified neurons. We employ current-clamp techniques to examine action potential firing properties and intrinsic properties (such as resting membrane potential, input resistance and membrane time constant), and voltage-clamp techniques to examine ionic currents, responses to pharmacologic agents (primarily neurotransmitter agonists) and synaptic response properties. In addition, we provide single cells (from which recordings are obtained) to the Abraham laboratory for single cell PCR and microarray analyses, and filled neurons to the Peters laboratory for electronmicroscopy.
Morphometric Analyses of Neurons.
At the same time that recordings are obtained, we fill the neurons with intracellular dyes such as biocytin or Lucifer yellow. In addition, we fill neurons in fixed slices obtained from the same subjects. Dye-filled neurons are then scanned at ultra-high resolution using confocal laser scanning microscopy. Very detailed analyses of dendritic, somatic and axonal architecture are then undertaken. Dendritic spine morphology, number and density are also assessed. All morphological data are then correlated with electrophysiological data from the same neurons.
One of the electrophysiology rigs that we use to obtain data. This rig is comprised, in part, of a Nikon IR-DIC microscope upon the stage of which is the perfusion chamber which contains an in vitro slice of the prefrontal cortex (upper right panel). The lower right panel shows 2 visually identified layer 2/3 pyramidal cells from which recordings were obtained.
Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington’s Disease. Goodliffe JW, Song H, Rubakovic A, Chang W, Medalla M, Weaver CM, Luebke JI.n PLoS One. 2018 Aug 17;13(8):e0200626. doi: 10.1371/journal.pone.0200626. eCollection 2018. PMID: 30118496
Distinct Neocortical Progenitor Lineages Fine-tune Neuronal Diversity in a Layer-specific Manner. Guillamon-Vivancos T, Tyler WA, Medalla M, Chang WW, Okamoto M, Haydar TF, Luebke JI. Cereb Cortex. 2018 Feb 3. doi: 10.1093/cercor/bhy019. [Epub ahead of print] PMID:29415216
Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B. Nat Neurosci. 2018 Jan;21(1):72-80. doi: 10.1038/s41593-017-0022-z. Epub 2017 Nov 20. PMID:29273772
Strength and Diversity of Inhibitory Signaling Differentiates Primate Anterior Cingulate from Lateral Prefrontal Cortex. Medalla M, Gilman JP, Wang JY, Luebke JI. J Neurosci. 2017 May 3;37(18):4717-4734. doi: 10.1523/JNEUROSCI.3757-16.2017. Epub 2017 Apr 5. PMID:28381592
Pyramidal Neurons Are Not Generalizable Building Blocks of Cortical Networks. Luebke JI. Front Neuroanat. 2017 Mar 7;11:11. doi: 10.3389/fnana.2017.00011. eCollection 2017. Review. PMID:28326020
Comparative ultrastructural features of excitatory synapses in the visual and frontal cortices of the adult mouse and monkey. Hsu A, Luebke JI, Medalla M. J Comp Neurol. 2017 Jun 15;525(9):2175-2191. doi: 10.1002/cne.24196. Epub 2017 Mar 26. PMID:28256708
Automated evolutionary optimization of ion channel conductances and kinetics in models of young and aged rhesus monkey pyramidal neurons. Rumbell TH, Draguljić D, Yadav A, Hof PR, Luebke JI, Weaver CM.J Comput Neurosci. 2016 Apr 22. [Epub ahead of print]PMID: 27106692
Area-Specific Features of Pyramidal Neurons-a Comparative Study in Mouse and Rhesus Monkey. Gilman JP, Medalla M, Luebke JI. Cereb Cortex. 2017 Mar 1;27(3):2078-2094. doi: 10.1093/cercor/bhw062. PMID:26965903
Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Nat Neurosci. 2015 Nov;18(11):1584-93. doi: 10.1038/nn.4132. Epub 2015 Oct 5. PMID:26436904
Neural precursor lineages specify distinct neocortical pyramidal neuron types. Tyler WA, Medalla M, Guillamon-Vivancos T, Luebke JI, Haydar TF. J Neurosci. 2015 Apr 15;35(15):6142-52. doi: 10.1523/JNEUROSCI.0335-15.2015. PMID: 25878286
Diversity of glutamatergic synaptic strength in lateral prefrontal versus primary visual cortices in the rhesus monkey. Medalla M, Luebke JI. J Neurosci. 2015 Jan 7;35(1):112-27. doi: 10.1523/JNEUROSCI.3426-14.2015. PMID:25568107
Functional consequences of age-related morphologic changes to pyramidal neurons of the rhesus monkey prefrontal cortex. Coskren PJ, Luebke JI, Kabaso D, Wearne SL, Yadav A, Rumbell T, Hof PR, Weaver CM. J Comput Neurosci. 2015 Apr;38(2):263-83. doi: 10.1007/s10827-014-0541-5. Epub 2014 Dec 20. PMID:25527184
For more publications, see Dr. Luebke’s faculty page