All Publications

  • Localized APP expression results in progressive network dysfunction by disorganizing spike timing. Neuron Viana da Silva, S., Haberl, M. G., Gaur, K., Patel, R., Narayan, G., Ledakis, M., Fu, M. L., de Castro Vieira, M., Koo, E. H., Leutgeb, J. K., Leutgeb, S. 2023


    Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.

    View details for DOI 10.1016/j.neuron.2023.10.001

    View details for PubMedID 37909036

  • Precisely timed theta oscillations are selectively required during the encoding phase of memory NATURE NEUROSCIENCE Quirk, C. R., Zutshi, I., Srikanth, S., Fu, M. L., Marciano, N., Wright, M. K., Parsey, D. F., Liu, S., Siretskiy, R. E., Huynh, T. L., Leutgeb, J. K., Leutgeb, S. 2021; 24 (11): 1614-1627


    Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

    View details for DOI 10.1038/s41593-021-00919-0

    View details for Web of Science ID 000703626100001

    View details for PubMedID 34608335

    View details for PubMedCentralID PMC8556344

  • Recurrent circuits within medial entorhinal cortex superficial layers support grid cell firing NATURE COMMUNICATIONS Zutshi, I., Fu, M. L., Lilascharoen, V., Leutgeb, J. K., Lim, B., Leutgeb, S. 2018; 9: 3701


    Specialized cells in the medial entorhinal cortex (mEC), such as speed cells, head direction (HD) cells, and grid cells, are thought to support spatial navigation. To determine whether these computations are dependent on local circuits, we record neuronal activity in mEC layers II and III and optogenetically perturb locally projecting layer II pyramidal cells. We find that sharply tuned HD cells are only weakly responsive while speed, broadly tuned HD cells, and grid cells show pronounced transient excitatory and inhibitory responses. During the brief period of feedback inhibition, there is a reduction in specifically grid accuracy, which is corrected as firing rates return to baseline. These results suggest that sharp HD cells are embedded in a separate mEC sub-network from broad HD cells, speed cells, and grid cells. Furthermore, grid tuning is not only dependent on local processing but also rapidly updated by HD, speed, or other afferent inputs to mEC.

    View details for DOI 10.1038/s41467-018-06104-5

    View details for Web of Science ID 000444368800001

    View details for PubMedID 30209250

    View details for PubMedCentralID PMC6135799

  • Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies CURRENT BIOLOGY Zutshi, I., Brandon, M. P., Fu, M. L., Donegan, M. L., Leutgeb, J. K., Leutgeb, S. 2018; 28 (8): 1179-+


    Biological oscillations can be controlled by a small population of rhythmic pacemaker cells, or in the brain, they also can emerge from complex cellular and circuit-level interactions. Whether and how these mechanisms are combined to give rise to oscillatory patterns that govern cognitive function are not well understood. For example, the activity of hippocampal networks is temporally coordinated by a 7- to 9-Hz local field potential (LFP) theta rhythm, yet many individual cells decouple from the LFP frequency to oscillate at frequencies ∼1 Hz higher. To better understand the network interactions that produce these complex oscillatory patterns, we asked whether the relative frequency difference between LFP and individual cells is retained when the LFP frequency is perturbed experimentally. We found that rhythmic optogenetic stimulation of medial septal GABAergic neurons controlled the hippocampal LFP frequency outside of the endogenous theta range, even during behavioral states when endogenous mechanisms would otherwise have generated 7- to 9-Hz theta oscillations. While the LFP frequency matched the optogenetically induced stimulation frequency, the oscillation frequency of individual hippocampal cells remained broadly distributed, and in a subset of cells including interneurons, it was accelerated beyond the new base LFP frequency. The inputs from septal GABAergic neurons to the hippocampus, therefore, do not appear to directly control the cellular oscillation frequency but rather engage cellular and circuit mechanisms that accelerate the rhythmicity of individual cells. Thus, theta oscillations are an example of cortical oscillations that combine inputs from a subcortical pacemaker with local computations to generate complex oscillatory patterns that support cognitive functions.

    View details for DOI 10.1016/j.cub.2018.02.061

    View details for Web of Science ID 000430694900039

    View details for PubMedID 29628373

    View details for PubMedCentralID PMC6488523