The brain continually processes streams of information that are coded at the neural level by temporal sequences of spiking activity. From this activity, the brain is able to extract behaviorally relevant data and form internal representations of the external world used, in turn, to create behavioral output. The brain also uses its internal state to make predictions about how external stimuli will change;these predictions play a critical role in executive behavioral planning. It is not known how this processing is accomplished in the brain. Establishing the relationship between activity sequences, plasticity and the neural coding of these internal representations will greatly inform our understanding of normal brain function and is necessary to understand the cognitive deficits associated with mental disorders. Since animals cannot self-report their cognitive state it is ver difficult to explore the high-level neural mechanisms of sequence learning using animal models. Generally speaking, the neocortex is organized according to a single common plan that imparts a characteristic local architecture and there is evidence suggesting that brain regions acquire functional differentiation as a result of their specific inputs. In this framework, visual cortex i """"""""visual"""""""" primarily because it connects to the retina and all regions of cortex are capable of solving similar information processing problems. This suggests that the same basic mechanisms used to learn sequences in """"""""higher"""""""" cortical regions should exist within """"""""lower"""""""" regions as well and leads to the hypothesis that primary sensory areas should contain the mechanisms necessary to locally encode sequence representations. A series of experiments testing this hypothesis demonstrate that it is possible to entrain visual sequences in primary visual cortex with both temporal and spatial precision.
This research aims to fully characterize and understand the mechanistic nature of this learning and its consequences for cortical processing. The proposed experiments are designed to test the hypothesis that visual sequence learning is encoded by NMDAR mediated synaptic plasticity between populations of neurons spread across the cortical layers locally within V1 using a combination of electrophysiological observation, 2- photon microscopy, pharmacological and optogenetic manipulation, and computational modeling.

Public Health Relevance

The brain is very good at storing, recognizing, and generating data with learned sequential organization;this is illustrated by how easy it is to say the alphabe and, conversely, how difficult it is to say it backwards. The neural basis of this ability is unknon and it is not easy to study using animals. This research proposal demonstrates that even low level cortical regions are capable of learning sequential relationships with temporal precision and proposes experiments to identify the neural mechanisms which may also be relevant in higher cortical processes. This research will help us understand a basic element of neural processing with relevance to perception, behavior and mental illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1-ERB-L (06))
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Desmond, Nancy L
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Massachusetts Institute of Technology
Internal Medicine/Medicine
Schools of Arts and Sciences
United States
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Cooke, Sam F; Komorowski, Robert W; Kaplan, Eitan S et al. (2015) Visual recognition memory, manifested as long-term habituation, requires synaptic plasticity in V1. Nat Neurosci 18:262-71
Gavornik, Jeffrey P; Bear, Mark F (2014) Higher brain functions served by the lowly rodent primary visual cortex. Learn Mem 21:527-33
Gavornik, Jeffrey P; Bear, Mark F (2014) Learned spatiotemporal sequence recognition and prediction in primary visual cortex. Nat Neurosci 17:732-7