Abnormal gene expression or abnormal sensory experience during development has a profound and permanent impact on the construction of brain circuits. Many developmental diseases likely do not arise from a single defect that is present in all suffers, but rather from the systems-level impact of the interaction of any number of malfunctioning circuit elements. In order to understand how the elements of brain circuits interact during development and to shed light on how these processes go awry in diseases or injuries, it is important to investigate whole systems in the intact, living brain. This applicatin proposes studies of the circuit mechanisms underlying the experience-dependent development of motion selectivity in the ferret visual cortex. At the time of eye opening, ferret visual cortex exhibits orientation selectivity and orientation columns, but neurons are not yet selective for direction-of- motion, a property of most mature neurons in this species. Motion selectivity (that is, direction selectivity) arises in the days and weeks following eye opening, and requires visual experience.
The first aim addresses the degree to which the cortex derives its spatiotemporal selectivity from stimuli in the environment vs. being prewired to acquire motion selectivity. A visual stimulus "training" protocol will be used to expose the cortex to either 1) ambiguous motion stimuli (counter-phase gratings) or 2) arbitrary but repeating orientated flickering stimuli for several hours. Before and after this training, the response properties of dozens of single neurons will be monitored by 2-photon calcium imaging. If cortex develops pure motion selectivity in response to these training stimuli, then it is likely that the cortex is pre-wired t learn motion selectivity. If cortex develops selectivity for the specific counter-phase grating stimulus or arbitrary stimulus, then it is likely that cortex is flexible enough to derive its seletivity from patterns in the environment.
The second aim examines the contribution of different circuit elements to the development of direction selectivity. Neurons in the lateral geniculate nucleus, cortical layer 4, and cortical layer 2/3 will be monitored before and after training with a motion stimulus to examine how receptive field properties at each stage are altered. The fine structure of receptive fields will be examined to understand whether direction selectivity arises from expansion, contraction, or merely strengthening of the structure of spatio-temporal receptive fields.
The final aim directly examines the synaptic plasticity rules that underlie the developmen of motion selectivity. Light-activated channels and optical stimulation methods will be used to probe for spike-timing- dependent plasticity in thalamocortical and cortico-cortical connections. Concurrently with the aims, a computational model of the ferret visual cortex will be constructed to illuminate the possible combinations of synaptic plasticity rules and initial circuit structure hat could underlie the development of direction selectivity.

Public Health Relevance

It is likely that many neurological diseases, including sensory disorders such as amblyopia or social/cognitive disorders such as autism, do not arise from a single defect, but rather from interactions of any number of malfunctioning circuit elements at the systems level. Here, we propose to study the brain mechanisms underlying the development of motion selectivity - a process which requires visual experience - in an attempt to understand the brain circuit mechanisms that direct the normal development of the mammalian cortex so that we might ultimately shed light on how these processes go awry in developmental disease and injury.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022122-01A1
Application #
8436965
Study Section
Special Emphasis Panel (SPC)
Program Officer
Steinmetz, Michael A
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$370,626
Indirect Cost
$120,626
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Van Hooser, Stephen D; Escobar, Gina M; Maffei, Arianna et al. (2014) Emerging feed-forward inhibition allows the robust formation of direction selectivity in the developing ferret visual cortex. J Neurophysiol 111:2355-73
Ghiretti, Amy E; Moore, Anna R; Brenner, Rebecca G et al. (2014) Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo. J Neurosci 34:392-407