Research

Synaptic computation in sensory systems 

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 and the lateral line of fish.  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.  A 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. 

jose retina
Bipolar cells in the retina of a zebrafish expressing the glutamate reporter iGluSnFR. These allow us to image individual vesicles released at active zones.

Sensory systems continuously adjust their input-output relation according to the recent history of the stimulus.  A common alteration is a decrease in the gain of the response to a constant feature of the input, termed adaptation.  For instance, in the retina, many of the ganglion cells (RGCs) providing the output produce their strongest responses just after the temporal contrast of the stimulus increases, but the response declines if this input is maintained.  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. 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. 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. 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, which suggests a general framework for understanding the function of sensory circuits: plasticity of both excitatory and inhibitory synapses control dynamic changes in tuning and gain.

GCaMP6f in mouse visual cortex
Principal cells in Layer 2/3 of the mouse visual cortex expressing the calcium indicator GCaMP6f.

We are now studying the mechanisms of gain control in the primary visual cortex of awake mice, where responses to visual stimuli are modulated by a number of behavioural factors, such as the alertness and engagement in motor activity.  We are particularly interested in how activity in two particular subtype of interneuron, the VIPs and SSTs, alters responsivity of principal neurons according to the recent history of stimulation. We are also investigating changes occurring on a longer time-scale as the mouse learns a visual task as well was deficits in this circuit that accompany neurodegenerative changes (in collaboration with Janssen  Pharmaceutica).  Many of the questions and experimental and analytical methods that we use to study the retina relate directly to our work in the cortex.  We hope that by studying different neural circuits we might learn some general principles by which they operate.

Totos_X63_Series014_Scale_Label
Confocal images of mouse visual cortex showing pTau (red) and GFP (green)
Interneuron staining in mouse visual cortex
Confocal image of mouse visual cortex showing VIP interneuron boutons (green) and SST cells (red)

 

 

 

 

 

 

 

 

Hair cells
A neuromast of the lateral line. The kinocilia of the hair cells (green) project into the cupula, the surface of which is stained blue.

We have been focused 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.  But we are now also studying a mechanical sense – the lateral line of zebrafish which detects vibrations and pressure gradients in the animals hydrodynamic environment.  Here the primary receptors are hair cells on the animals surface, again allowing the experimenter direct control over the sensory input.   We are investigating how the mechanical stimulus is represented in synapses providing the output of hair cells and how the signals transmitted form the periphery are modulated by efferent activity to compensate for the fact that hair cells are activated whenever the fish swims.