Neureka 2nd seminar with Tiago Branco

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Decision making is an essential part of our lives and is one of the main tasks the brain is in charge of. When making decisions our brain extracts important cues from the environment, computes them and, based on the net result, chooses a protocol of action. This requires complex neuronal circuitry that has to act reliably to ensure survival. Much of how this circuitry works is still a mystery. However, current research is giving us a clearer view on how this might be happening at least in simple instinctive decisions.

In our latest Neureka seminar, Dr. Tiago Branco from the MRC Laboratory of Molecular Biology in Cambridge discussed recent research in his laboratory where they study how specific neural circuits in the brain interpret external cues to choose instinctive behaviours. To do this Tiago and his colleagues focus on two antagonistic behaviours in mice: the escape response and feeding. Mice instinctively escape from danger cues associated with the presence of a predator, even if this means leaving precious food behind. However, under low-energy conditions they might take further risks and ignore these signals in order to secure food.

In order to characterise the brain circuitry behind these behaviours, they first looked at the Periaqueductal Gray (PAG), one of the main modulators of descending information travelling to the spinal cord. Using an optogenetic approach, they found that by inhibiting the excitatory glutamatergic neurons in the PAG, the escape response ceased completely. They later went on to characterise the sources of incoming signals into the PAG by using monosynaptic tracing. This experiment showed that two areas of interest were directly connected to the PAG: the superior colliculus, an area involved in early visual processing, and the hypothalamus, the neuroendocrinological centre of the brain and an area that could therefore interpret nutritional signals.

They saw that by optogenetically activating glutamatergic cells in the superior colliculus they were able to artificially trigger an escape response. Remarkably, this connection was quite weak, which from an ethological point of view could be a mechanism to ensure that escape only occurs when danger signals are strong enough, and might therefore compromise survival.

In parallel they also looked at two cell types of the hypothalamus involved in controlling eating behaviour, which also project to the PAG: Agouti-related Peptide (AgRP) cells and Pro-opiomelanocortin (POMC) cells. Activating AgRP neurons was sufficient to inhibit the escape response and the contrary happened when POMC cells were activated, with both sets of cells showing remarkable sensitivity to presynaptic input. AgRP neurons are known to regulate appetite and are activated in response to low-energy levels. Conversely, POMC neurons are normally activated in response to satiety. Thus, this data suggests that this binary circuitry may allow mice to subconsciously weigh the risk of visual danger signals, depending on their need for food.

After characterising the circuitry, Tiago’s lab decided to look at what made AgRP and POMC neurons so sensitive to presynaptic input. By using RNA sequencing they found an enriched expression of Nav1.7 voltage gated sodium channels, which is a channel known to affect excitability.

Overall, this very impressive work showed us how instinctive decision making can happen in mice, all they way from neuronal networks to specific ion channels. We are still far from understanding how we compute information in our brains, however studies at this level of resolution are taking valuable steps in the right direction and might be the key for understanding complex brain computations.

After the talk we enjoyed drinks with Tiago where the host Christopher Puhl asked him a question chosen by the Neureka Committee – What level of resolution should we seek in neuroscience? To which he answered – Depends on what you are satisfied with!

Alejandro Pan Vazquez


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