Mice model shows how the signalling molecule somatostatin acts to dampen neural circuits in the prefrontal cortex and stimulate exploratory behaviour

Somatostatin, a signalling molecule produced by many inhibitory neurons in the brain, broadly dampens communication among a variety of cell types in the prefrontal cortex and promotes exploratory and risk-taking-like behaviour in mice, according to a Penn State-led research team.

Their new paper describes the signalling mechanism of somatostatin in the prefrontal cortex, a brain region thought to be essential for executive functions like planning, memory, decision making and social behaviour.

The research is an early step in deciphering somatostatin’s function in the human brain and how its signalling may go awry with several neuropsychiatric disorders, according to the researchers.

Nikki Crowley, Huck Early Career Chair in Neurobiology and Neural Engineering, assistant professor of biology in the Eberly College of Science and of biomedical engineering in the College of Engineering at Penn State, and the leader of the research team, said: “Somatostatin has been heavily implicated in a number of different neuropsychiatric disorders.

“It is clinically implicated in individuals with conditions such as depression, schizophrenia, bipolar disorder, and cognitive decline, as well as alcohol drinking, but also general processes such as fear learning and avoidance behaviour, but we don’t really know why.

“So, we set out to characterise its function in the prefrontal cortex of mice with the ultimate goal of finding ways to therapeutically target it to improve human health.”



Different signalling molecules


Somatostatin is a neuropeptide, which is a small protein released by inhibitory neurons as a chemical messenger.

Once released, it works by binding to receptor molecules expressed on other neurons, and potentially other cell types in the brain, which sets off a cascade of molecular changes in the cell. Neuropeptide signalling complements the signalling of classic neurotransmitters, like GABA, which is typically co-expressed in somatostatin neurons, and others such as dopamine and serotonin.

The two types of signalling molecules use different pathways to communicate between cells and are released through different stimulation scenarios.

Crowley said: “The activity of neuropeptides can be much more difficult to measure.

“Signalling in the brain heavily relies on electrical communication. That is what is happening when we talk about the ‘firing’ of neurons.

“Neurotransmitters generally work through a combination of receptors, some of which allow electrical current to move in and out of neurons.

“We can measure this electrical activity relatively easily and have done so for over 50 years – but neuropeptide signalling does not directly produce an electrical signal.

“Only in more recent years have we had really good tools that allowed us to measure neuropeptide activity to begin to understand what they are doing.”


Pyramidal neurons dampened


The research team first characterised the effect that somatostatin signalling has on neurons within the prefrontal cortex.

They measured the activity of these pyramidal neurons before and after artificially introducing the neuropeptide.

They did this by directly applying a solution that contained somatostatin and, separately, by driving release of the neuropeptide through light-activation of somatostatin-releasing neurons.

In both cases, the researchers saw the activity of the pyramidal neurons dampened.

Crowley said: “Somatostatin appears to function like a car’s brake, slowing the activity of neural circuitry in specific brain regions.

“We then wanted to know if this had a behavioural consequence.”

The researchers first tested if the somatostatin-releasing neurons were activated in two exploratory behavioural tests in mice.

In one test, mice are placed on an elevated maze where they can choose to explore riskier, open arms of the maze that don’t have side walls or stick to safer arms with walls.

In the second ‘open-field’ test, mice can explore the centre of an open field – simulating how mice might naturally be exposed to dangers – or stay in the relative safety of the edges.

Crowley said: “We saw that somatostatin neurons were most active just before entering the open arms of the maze or the centre of the open field and while they explored these ‘riskier’ areas.

“This suggests that these neurons are involved in the decision to take risks.”


Increased risk-taking


Next, the researchers artificially increased or decreased somatostatin signalling in the brains of mice and measured their behaviour in these same mazes.

Interestingly, Crowley noted, when somatostatin activity was increased, male mice showed increased exploratory, risk-taking behaviour, but female mice did not.

When the signalling was decreased, there was no significant change in behaviour.

Crowley said: “The difference in behaviour between males and females in exploratory behaviour after we artificially increased somatostatin signalling is fascinating and something that we plan to explore in further research.

“Peptides can interact with many things, including potentially other hormones, and we’re looking at this now.”

Based on their experiments, the researchers suggest that somatostatin is fine-tuning the circuits in the prefrontal cortex to promote certain behaviours – specifically risk-taking, exploration, and decision-making – over others.

Crowley concluded: “We know that this region of the brain drives higher-order behaviours and decision-making in humans as well, and that somatostatin is related to several human neuropsychiatric disorders.

“As we continue to explore the function of somatostatin, we hope a better understanding of its role will help drive the development of new ways to treat these diseases where its expression might be reduced.”

The study is published in Cell Reports.

Image 1: New research shows that somatostatin, a signalling molecule produced by many inhibitory neurons in the brain, broadly dampens communication among a variety of cell types in the prefrontal cortex and promotes exploratory and risk-taking-like behaviour in mice. The researchers used patch-clamp electrophysiology, shown here, to understand how somatostatin influences cortical circuits. Credit: Kelby Hochreither/ Penn State. CC BY-NC-ND.

Image 2: Activity of pyramidal neurons in the prefrontal cortex before (left) and after (right) application of somatostatin. Inhibitory neurons (pink) release somatostatin, a neuropeptide, that binds to receptors on the surface of pyramidal neurons (purple) and other cells in the brain. Representative traces from whole-cell current clamp recordings (black lines) show that the activity of pyramidal cells is reduced following both bath applied somatostatin, and light-evoked somatostatin release. Credit: Crowley Laboratory/ Penn State. CC BY-NC-ND.

Research Aether / Health Uncovered