The brain encodes sensory inputs as patterns of neuronal activity. While stimuli in the environment can vary over several orders of magnitude, neuronal responses cannot scale infinitely and span a limited range of outputs. Thus, a fundamental problem in sensory encoding lies in the trade-off between maintaining responsiveness to a wide range of intensities and resolving subtle variations in a stimulus. To overcome this challenge, sensory systems need to tune their output in order to match the average variation in input intensity. One way to achieve this is by proportionately changing the slope (gain) of the input-output function of individual neurons to increase or decrease the dynamic range of the outputs. This process is called gain control and has been shown to be implemented via normalization mechanisms in the auditory and visual systems. In the olfactory system, less is understood regarding how odors are reliably identified despite huge variations in their concentration. Several possible mechanisms have been suggested to contribute to olfactory gain control, ranging from local inhibition via interneurons that regulate the firing of he olfactory bulb's outputs, to feedback signals to the bulb from the olfactory cortex or the brainstem, or local processing in the cortex itself. In this proposal, we will study a particular class of neurons called short axon cells (SA cells) that are best suited anatomically and physiologically to implement gain control in this early olfactory circuit. We will test whether removing the contribution of these cells in the intact brain narrows the response spectrum of the output neurons of the bulb (mitral/tufted cells, M/T) across odors and concentrations. "To this end, we will first characterize responses of SA cells to a large set of odors and concentrations. We will use genetic targeting to express optical indicators of neuronal activity specifically in th SA cells and monitor odor triggered responses via wide-field and multiphoton imaging. "Then, using a similar approach, we will express light-gated (optogenetic) switches of neuronal activity in SA cells and use patterned optical illumination to suppress their activity in a controlled and reversible fashion. Simultaneously, we will present odor stimuli and monitor the response of M/T cells via electrophysiological recordings. We will compare M/T responses to increasing odor concentrations both in the presence and absence of SA inputs. Alterations in the concentration response curve of M/T cells upon light-induced inhibition of SA cells will directly reveal the contribution (if any) of SA cells. "Finally, we will begin to dissect the specific mechanisms by which SA cells modulate M/T activity. These cells are known to be the only source of the neurotransmitter dopamine in the bulb. We will determine the contribution of dopamine in mediating SA to M/T cell communication by using blockers of dopamine activity. We will determine whether blocking dopamine action can reverse the effects on M/T cell activity observed upon optogenetic manipulation of SA cells.
Brains have evolved to extract relevant information in dynamic environments via an intricate balance of excitation and inhibition in sensory networks. Loss of this balance is prevalent in psychiatric disorders like autism spectrum disorders. A clear understanding of network mechanisms underlying sensory processing is thus the first step towards identifying causal factors and intelligent design of therapies for such disorders. Further, understanding olfactory processing may have implications in the treatment of anosmia and other smell disorders that substantially impact human health and quality of life.