Periodic Reporting for period 1 - IN VIVO MOSSY (Is the hippocampal mossy fiber synapse a detonator in vivo?)
Reporting period: 2016-04-01 to 2018-03-31
A commonly repeated maxim is that an individual cortical neuron receives synaptic input from tens of thousands of presynaptic partners, with each individual connection carrying only minor weight. In that case, concerted firing by many presynaptic neurons is required to cause an action potential in the postsynaptic neuron. However, there is circumstantial evidence that the mossy fiber synapse (the second connection in Cajal’s heavily studied “trisynaptic circuit” of the hippocampus) is powerful enough to translate a single presynaptic spike into a postsynaptic spike - termed “detonation”. If true, this would have substantial implications for our understanding of learning and memory, spatial navigation, and pattern recognition. Thus, the results will likely be of general interest.
The overall objective is to image the activity of CA3 pyramidal neurons in awake mice navigating along a linear track, and also to image activity in presynaptic mossy fiber terminals. Together this may conclusively confirm or rule out the detonation hypothesis. This approach allows to distinguish between detonator, conditional detonator, and subdetonator synapses, and more generally to quantify the number of simultaneously active mossy fiber boutons necessary to cause CA3 spiking during behavior. Such results would have substantial implications for established models of associative memory and spatial navigation, and more generally for information transfer in the hippocampus.
The overall objective is to image the activity of CA3 pyramidal neurons in awake mice navigating along a linear track, and also to image activity in presynaptic mossy fiber terminals. Together this may conclusively confirm or rule out the detonation hypothesis. This approach allows to distinguish between detonator, conditional detonator, and subdetonator synapses, and more generally to quantify the number of simultaneously active mossy fiber boutons necessary to cause CA3 spiking during behavior. Such results would have substantial implications for established models of associative memory and spatial navigation, and more generally for information transfer in the hippocampus.
For this study, the region of interest – CA3 – lies deep within the hippocampus, making it difficult to obtain images from neurons at this location and to measure calcium transients at high resolution. Thus, the majority of our work has focused on improving on existing state-of-the-art techniques, in order to obtain suitable images. We adopted an iterative process, and considered all aspects of the experimental system, including the microscope, the imaging implant, techniques for expressing fluorescent indicators in the brain, and post-processing software routines.
These efforts have produced dividends: we have succeeded in obtaining high-quality images from the CA3 region in awake, behaving mice, and are using this approach to quantify the population activity of CA3 pyramidal neurons during spatial navigation. These results have been accepted for presentation at a large conference.
These efforts have produced dividends: we have succeeded in obtaining high-quality images from the CA3 region in awake, behaving mice, and are using this approach to quantify the population activity of CA3 pyramidal neurons during spatial navigation. These results have been accepted for presentation at a large conference.
How the brain works is a question of great general interest to the public, both to satisfy innate curiosity and in hope that even partial answers may ameliorate human suffering in disease. By the end of this study, the expected results have the potential to shed light, at multiple levels, on fundamental mechanisms of memory and synaptic transmission. The targeted brain circuits are not only instrumental in the healthy brain, but also implicated in a broad range of brain disorders. Our technical advances have been developed in a small mammalian model system, but may one day contribute to therapeutic interventions.