Dissecting the functional organization of local hippocampal circuits underlying spatial representations

Project Abstract: The ability to remember past personal happenings to guide proper behavior and make correct decisions is essential to our everyday life. Memory transience observed in neurodegenerative disorders such as Alzheimer’s disease has severe afflicting implications. Hippocampal circuits have long been posited to mediate spatial information necessary for episodic memory processes. At the cellular level, a striking and behaviorally relevant form of spatial information can be found in the receptive fields of CA1 place cells which collectively produce a representation of the external world. However, it remains unknown how hippocampal circuits operate to give rise to these representations, coordinate their output at the population level and broadcast this information to the rest of the brain. Addressing these questions would serve as a major step towards a deeper mechanistic understanding of the hippocampus and allow for the development of targeted approaches to prevent the devastating consequences of hippocampal circuit dysfunctions in various brain disorders. In this proposal, I will leverage new electrophysiological, imaging, tracing and optogenetics methods to interrogate the functional organization of hippocampal circuits across multiple scales in awake behaving mice. The research plan is organized in three aims, split across a K99 training phase and a R00 independent phase. In the first aim (K99), I will initiate monosynaptic retrograde rabies tracing from a single CA1 neuron and record the activity of its inhibitory presynaptic partners with volumetric random-access 2-photon calcium imaging during behavior. This will allow me to directly test the contribution of local inhibition on sculpting the input/output function of individual pyramidal cells. In the second aim (K99), I will use patterned optogenetics manipulations with single- cell precision to produce network-wide circuit maps between principal neurons and distinct inhibitory cell types. I will use it to identify core circuit motifs shaping the CA1 network structure and regulating the circuit’s specialized operations. In the R00 portion of the award, I will characterize how the spatial code in CA1 is dispatched and integrated in downstream brain regions. I will focus on local circuits in dorsal subiculum, a region also involved with episodic memory processes and known to receive the densest innervation of CA1 inputs. This work will be conducted in the newly established Zuckerman Mind Brain Behavior Institute at Columbia University under the supervision of Drs. Attila Losonczy and Stefano Fusi. I will receive extensive training in research methods, particularly in advanced analytical and imaging tools, as well as career development to gain writing, project management, and leadership skills. I have also assembled a team of expert collaborators, including Drs. Liam Paninski, Darcy Peterka and Ashok Litwin-Kumar, who will ensure I am fully equipped to carry out the research and training plan, and thus enable me to establish a successful research program as an independent investigator.