Figure 1: Expression of the hM4D/CNO pharmacogenetic inhibition tool in cell bodies and projections of the VMH in Nr5a1::hM4D-2A-tomatoF transgenic mice as revealed by farnesylated tomato (red) reporter protein (B. Silva)
Figure 2: Microglia (green cells) visualised in the hippocampus of Cx3cr1GFP transgenic mice (cell nuclei labelled in blue, R. Paolicelli)
The Gross group uses pharmacological, histochemical, electrophysiological and behavioural genetic approaches to study the neural circuits underlying behaviour in mice.
Previous and current research
The laboratory is interested in understanding at a molecular and neural circuit level how early life events influence brain development in order to establish behavioural traits in adulthood, with a particular focus on fear and anxiety. We are currently pursuing two areas of research:
Neural circuits encoding fear and anxiety
Fear is a mental state that is elicited by exposure to threats or cues that signal those threats. Fear is part of an organism’s natural defense mechanism and the accompanying behavioural and physiological responses are essential for it to cope with potential bodily harm. However, in its pathological form, fear can become excessive or inappropriate – features associated with anxiety disorders. It is accepted that the amygdala plays a central role in processing fear. However, it is less widely appreciated that distinct amygdala outputs and downstream circuits are recruited in response to different types of fear (Gross and Canteras, 2012). We have recently shown that fear responses to painful stimuli, predators, and aggressive members of the same species, depend on distinct neural circuits that involve the amygdala, medial hypothalamus, and periaqueductal gray (Silva et al., 2013). These data demonstrate that independent fear circuits exist to respond to different classes of threat and imply that pathological fear may come in different flavours and be amenable to selective therapeutic treatment. Current work in the lab combines molecular genetic, electrophysiological, and genetically encoded neural manipulation tools (figure 1) with behavioural methods in mice to understand how amygdala, hypothalamic, and brainstem circuits support and adapt fear responses to diverse threats.
Developmental programming of brain wiring by microglia
Microglia are non-neuronal cells of the hematopoetic lineage that infiltrate the brain during development and are thought to play a role in brain surveillance. Recent studies from our group and others have shown that microglia are particularly abundant during the period of postnatal brain development when synapses are formed (figure 2) and that they play a key role in the elimination of synapses during this period, a phenomenon called ‘synaptic pruning’ (Paolicelli et al., 2011). Mice with deficient synaptic pruning show weak functional brain connectivity, poor social behaviour, and increased repetitive behaviour – all hallmarks of autism – suggesting that some features of this neurodevelopmental disorder may depend on a deficit in synaptic pruning (Yang, Paolicelli et al., 2014). We are currently using a variety of tools to identify the ‘eat me’ and ‘spare me’ signals that regulate pruning and understand the mechanisms by which synapse elimination remodels neural circuits during development.
Future projects and goals
Together these approaches are aimed at discovering the neural circuits and molecular mechanisms that support individual differences in behavioural traits in health and disease. A better understanding of the molecular signals that influence the formation and remodelling of these circuits will allow us to form specific hypotheses about how human behaviour is determined and lead to improved diagnostic and therapeutic tools for mental illness.