Fitzpatrick, David

The physical architecture of neural circuits is thought to underlie the computations that give rise to higher order feature sensitivity in the neocortex. Recent technological breakthroughs have allowed the structural and functional investigation of the basic computational units of neural circuits; individual synaptic connections. However, it remains unclear how cortical neurons sample and integrate the thousands of synaptic inputs, supplied by different brain structures, to achieve feature selectivity. Here, I first describe how visual cortical circuits transform the elementary inputs supplied by the periphery into highly diverse, but well-organized, feature representations. By combining and optimizing newly developed techniques to map the functional synaptic connections with defined sources of inputs, I show that the intersection between columnar architecture and dendritic sampling strategies can lead to the selectivity properties of individual neurons: First, in the canonical feedforward circuit, the basal dendrites of a pyramidal neuron utilize unique strategies to sample ON (light increment) and OFF (light decrement) inputs in orientation columns to create the distinctive receptive field structure that is responsible for basic sensitivity to visual spatial location, orientation, spatial frequency, and phase. Second, for long-range horizontal connections, apical dendrites unbiasedly integrate functionally specialized and spatially targeted inputs in different orientation columns, which generates specific axial surround modulation of the receptive field.

Individual neurons in the primary visual cortex respond selectively to different
features of visual stimuli, such as spatial orientation or direction of motion. A longstanding
goal in systems neuroscience has been to understand the transformations single
cells perform as they integrate synaptic inputs to generate spiking output. Recent
technological developments have facilitated these lines of investigation by enabling direct
measurement of the functional properties of single synaptic inputs to neurons in the
neocortex. It remains an outstanding question as to whether the tuning of single
neocortical neurons can be predicted by their excitatory synaptic inputs. Here, I show
that excitatory synaptic inputs exhibit significant functional diversity with respect to
orientation and direction selectivity. I show that cells can use at least two strategies to
overcome this functional diversity to achieve selective responses in the face of broadly
tuned excitatory input: enhancing responses to the preferred stimuli and suppressing
responses to the non-preferred stimuli. In the case of orientation selectivity, synaptic inputs cluster according to orientation preference and evoke local dendritic nonlinearities,
thereby enhancing somatic responses to the preferred direction. For direction selectivity,
cells receive excitatory synaptic inputs tuned to the preferred and null directions, but
selectively suppress inputs tuned for the null direction to enhance direction selectivity.
This suppression comes from direction-tuned GABAergic interneurons that make longrange,
intercolumnar projections to enhance direction selectivity.

The visual cortex of higher mammals, including humans, is arranged as to achieve a
continuously varying map of features such as the orientation of contours in the environment.
Previous studies used intrinsic signal and two-photon imaging to examine the functional
composition of these cortical maps, but lacked the functional resolution to resolve the underlying
synaptic architecture. Here, we exploited recent advances in genetically encoded calcium
indicators to perform in vivo two photon imaging of dendrites and dendritic spines in an animal
with a mapped visual cortex. We found sharp orientation and direction tuning when we presented
drifting gratings and imaged synaptic calcium transients from large numbers of dendritic spines
in single neurons, obtaining synaptic maps of orientation preference. In addition, we
implemented a newly developed two-photon microscope that uses acousto-optical deflectors to
rapidly steer a pulsed laser in three dimensions. This technology allowed us to image 320 single
cells in an 800x800x200 micron three-dimensional volume, which yielded a three-dimensional
orientation map with single-cell resolution. In the future, we will perform fast, three-dimensional
imaging of a single cell and its entire dendritic tree to monitor functional properties of a cell’s
inputs and its somatic spiking output. These experiments will yield important insight into
synaptic integration and sensory processing in cortical maps and how such organizing principles
might be disrupted in disease states.