Lagnado Lab


Synaptic Computation in the Visual System

How does a circuit of neurons process sensory information?  And how are transformations of neural signals altered by changes in synaptic strength? We investigate these questions in the context of the visual system. A distinguishing feature of our approach is the imaging of activity across populations of synapses - the fundamental elements of signal transfer within all brain circuits [1-5].  Our guiding hypothesis is that the plasticity of neurotransmission plays a major part in controlling the input-output relation of sensory circuits, regulating the tuning and sensitivity of neurons to allow adaptation or sensitization to particular features of the input [6-9].

We focus on computations carried out in the visual system because these are defined in sufficient detail to allow a quantitative analysis of the underlying circuitry and are also likely to have parallels in other brain regions [10-15].  How does a population of connected neurons detect the different temporal frequencies in a fluctuating input? Or the direction of motion of a moving object? Or the orientation of that object?  In parallel, we ask how these computations are modified in response to i) changes in the visual input that lead to adaptive changes in processing, and ii) neuromodulators that alter circuit function on longer time-scales.

1.  What are the synaptic mechanisms of gain control in the retina?

Sensory systems continuously adjust their input-output relation according to the recent history of the stimulus [16].  A common alteration is a decrease in the gain of the response to a constant feature of the input, termed adaptation [13, 17].  For instance, many of the retinal ganglion cells (RGCs) providing the retinal output produce their strongest responses just after the temporal contrast of the stimulus increases, but the response declines if this input is maintained [12].  The advantage of adaptation is that it prevents saturation of the response to strong stimuli and allows for continued signaling of future increases in stimulus strength [18]. But adaptation comes at a cost: a reduced sensitivity to a future decrease in stimulus strength. The retina compensates for this loss of information through an intriguing strategy: while some RGCs adapt following a strong stimulus, a second population gradually becomes sensitized [14]. We found that the underlying circuit mechanisms involve two opposing forms of synaptic plasticity in bipolar cells: synaptic depression causes adaptation and facilitation causes sensitization [4].  Facilitation is in turn caused by depression in inhibitory synapses providing negative feedback.  These opposing forms of plasticity can cause simultaneous increases and decreases in contrast-sensitivity of different RGCs [4, 14], which suggests a general framework for understanding the function of sensory circuits: plasticity of both excitatory and inhbitory synapses control dynamic changes in tuning and gain.

2. How do the mechanisms of adaptation in the retina, optic tectum and cortex compare?

Comparison between different neural circuits is key to identifying general mechanisms by which the brain processes sensory information [19, 20].  We will therefore examine the control of tuning and gain not only within the retina, but also in the optic tectum of zebrafish and primary visual cortex of mice. The optic tectum receives the major part of the retinal output and is involved in generating motor commands in response to visual stimuli [21].  The synapses of RGCs are tuned to one of three directions and two orientations [22].  How does the retinal output change in response to alterations in the distributions of orientations, speeds or directions of motion in the stimulus?  And how is processing in the optic tectum altered by the new distribution of inputs?  We are also beginning to analyze adaptation in the primary visual cortex [23]: how do the plasticity of excitatory and inhibitory synapses control the gain and tuning of neurons detecting stimulus orientation?

3. What are the specific roles of different classes of inhibitory interneuron?

Feedback and feedforward inhibition are fundamental mechanisms of gain control and temporal filtering in the brain ([9, 24-29]).  In the retina, these basic circuit motifs are used to process visual signals through about 20 parallel pathways, each applying different spatio-temporal filters to the visual input [30, 31].  How are these different filters constructed? It is hypothesized that the diversity reflects inhibitory amacrine cells with different connectivities and functional properties [29, 32].  To define how specific types of amacrine cell contribute to visual processing we will observe and manipulate their activity in different strata of the inner plexiform layer (IPL).  A similar approach will be used to investigate the role of inhibitory interneurons in the optic tectum and visual cortex. This combination of studies will allow us to test a general hypothesis: the gain and tuning of negative feedback pathways are also altered during adaptive changes in sensory circuits.

 4.  How do neuromodulators alter the processing of visual signals?

Neuromodulators such as amines and neuropeptides can profoundly reconfigure the operation of neural circuits [33]. They can be released by local interneurons, but also provide signals by which activity in one brain region can precisely regulate processing in another [7, 20, 33]. A common target of neuromodulators are GPCRs on presynaptic terminals which regulate synaptic strength [34]. For instance, we found that dopamine regulates signal flow through the retina by up-regulating presynaptic calcium channels in bipolar cells [3], while substance P inhibits them, eben blocking spikes that are generated in the synaptic terminal [38]. We will investigate how neuromodulators released by different amacrine cells regulate synaptic gain, initially concentrating on dopamine, substance P, and VIP.

Dopaminergic regulation of retinal processing is partly under control of the olfactory system in zebrafish, and we found that this reflects a selective action on the OFF pathway [3]. Olfactory stimuli act as part of an arousal system that also interacts with vision in the optic tectum, pretectum and thalamus [21].  We will image activity of both neurons and synapses in multiple brain areas with an initial focus on the dopaminergic projection from the pretectum to tectal neuropil, which is involved in prey-capture behaviour. How do olfactory inputs modulate processing of visual signals in circuits downstream of the retina?

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