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Behave yourself: Let your prefrontal cortex control your instincts


Scientists have identified neurons in the medial prefrontal cortex (mPFC) that project to the brainstem to prevent social animals from acting on impulsive instincts in certain contexts.

Being able to inhibit certain behaviours is an important aspect of the lives of a variety of social animals including humans, allowing us to maintain a functioning society.

“Instincts like fear and sex are important, but you don’t want to be acting on them all the time,” says Principal Investigator Dr Cornelius Gross, who led the recent work from the EMBL. “We need to be able to dynamically control our instinctive behaviours, depending on the situation.” But how do we do it?

The prime suspect: The prefrontal cortex

Since the famous case of Phineas Gage, who had a metal rod shot through his head in 1848, researchers have suspected a role for the prefrontal cortex (PFC) in our social inhibitions. The rod is believed to have damaged his PFC, causing acute personality changes. Other cases where patients have damaged their PFC through accidents or stroke have also pinpointed this region as having an important function in social behaviours. Various other studies also suggest that the mPFC uses information from past experiences to evaluate the most suitable response in a social situation. Additional experiments where researchers have manipulated the mPFC in mice through lesions or pharmacological agents show modifications in aggression between males, social hierarchy, and sex differences in social anxiety. However, the outputs via which the mPFC directly modulates social behaviour had not been identified.

The Pac-Man proposition

Scientists got a glimmer of what might be occurring in a study of people trying to avoid injury. In this study, participants were asked to play a Pac-Man-like game while an MRI scanner imaged their brains. The researchers found that while the players were trying to avoid being “eaten” their PFC was active, but in the moments before their character became a meal the PFC would shut down, and a region of the brainstem known as the periaqueductal grey (PAG) would become active. Thus, suggesting a link between the two areas.

Tracing the pathways of social inhibition

In a study seeking to investigate the link between the mPFC and PAG, recently published in Nature Neuroscience, researchers identified the exact neuronal projections that stop social animals, like humans, from acting out every impulse.

Using retrograde tracing, trans-synaptic rabies labelling, and ex vivo electrophysiology the research group showed that layer 5 glutamatergic mPFC neurons made monosynaptic links onto glutamatergic neurons in the dorsal PAG (dPAG). These projections were separate to other mPFC connections, like those that go to the nucleus accumbens (NAc), another area of the brain related to fear and impulsivity. The projections appear to exert an inhibitory effect on dPAG by suppressing PAG afferents, and thus inhibiting instinctual behaviour.

In mice who suffered from social defeat, caused by being repeatedly beaten in confrontations with other mice, the team found that the pathway between the mPFC and dPAG becomes weakened, and this results in the mice acting more scared. This effect could be mimicked by using drugs that selectively block the pathway.

Furthermore, they showed that social defeat did not affect activity in the hypothalamus, a region that controls emotions. This explains how we can stop ourselves from hitting someone while still feeling aggressive inside.

The implications of projections

The study has possible clinical applications in major depression, social anxiety disorder and schizophrenia, which have been linked to problems with the function and development of the prefrontal cortex.

Finally, the researchers found that a single dose of ketamine reversed the social avoidance induced by social defeat, suggesting that this pathway could be a target for antidepressants.

Further projections from the mPFC to the dorsal and lateral PAG suggests the mPFC plays a role in cortical modulations of behavioural adaptation to other environmental conditions. Further work will be needed to discover how social experience remodels the mPFC, dPAG circuit.

In Vitro Slice Electrophysiology

Acute coronal slices containing PAG were visualised on a SliceScope Pro 1000 by Dr Tiago Branco* and Dr Zina Perova* at the MRC Laboratory of Molecular Biology. They performed whole-cell patch-clamp recordings to measure light-evoked synaptic responses in dPAG neurons as a response to channelrhodopsin-2 (ChR2) activation in the mPFC.

Paper reference

Franklin T. B., Silva B. A., Perova Z., Marrone L., Masferrer M. E., Zhan Y., Kaplan A., Greetham L., Verrechia V., Halman A., Pagella S., Vyssotski A. L., Illarionova A., Grinevich V., Branco T., Gross C. T. Prefrontal cortical control of a brainstem social behavior circuit Nature Neuroscience (2017) doi: 10.1038/nn.4470

*Now at the Sainsbury Wellcome Centre

Image courtesy of EMBL/Livia Marrone

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