The prefrontal cortex area of the human brain is responsible for a range of complex functions from decision-making to specific types of memory.
When something goes wrong in this part of the brain, it can be very harmful to cognition and behaviour. In fact, dysfunction in the prefrontal cortex is associated with several psychiatric illnesses, including schizophrenia and major depressive disorder.
Yale researchers and their colleagues in Hungary have discovered that cells in the hypothalamus — an area of the brain that controls functions such as hunger and body temperature — play a key role in shaping the structure and function of the prefrontal cortex in mice, a finding that could provide clues to how This area of the brain changes in disease and opens up new avenues for treatment.
They report their findings on July 29 in the journal Molecular Psychiatry.
For the study, the researchers focused on agouti-related peptide (AgRP) neurons located in the hypothalamus in the brain. These neurons control hunger and regulate both feeding and non-feeding behaviors such as reward-seeking and parent-child bonding, among others.
When the researchers weakened AgRP neurons in mice, they found fewer neurons in the prefrontal cortex than in healthy animals.
“The remaining neurons were smaller than normal and behaved differently in response to signals from the body and signals from surrounding cells,” said Tamas Horvath, professor of comparative medicine at Yale University and senior author of the study, Tamas Horvath.
AgRP neurons do not have strong direct connections with the cortex. But they do project to other areas of the brain that connect to the prefrontal cortex.
Horvath and colleagues found that neurons in one of these regions – an area of the midbrain known as the ventral tegmental area – were overactive when the AgRP neurons were inactivated. Those overactive neurons then released more dopamine, a neurotransmitter, into the prefrontal cortex than normal in healthy mice, which in turn negatively affected the mouse’s behavior.
For example, they found that mice were moving much more and had sudden, abnormal responses.
It makes sense, Horvath says, that these neurons that control hunger and feeding affect the cerebral cortex and behavior.
“When you are hungry, you need to put all your behaviors in order so that you can find and eat food,” he said. “And when you’re not hungry, you have to change your behaviors to focus on what’s important in that moment.”
After detecting the harmful effects of AgRP cells on the cortex, the researchers tried to avoid them. They found that clozapine — a type of antipsychotic that blocks dopamine from working and is used to treat schizophrenia — was able to prevent some of these problems, including neuronal loss, when given at the right time.
When it comes to these cortical changes, Horvath said, timing is critical. In the study, disabilities began to appear during puberty when the brain was still developing and weak. This is also when clozapine administration had an effect.
“And this tells us that if you play with the homeostatic functions in that specific time period, for example by dieting or overeating, you can have long-term effects on cortical function,” he said.
The importance of this period of development may shed light on mental illness, which can often appear in late adolescence, and why drug use during that period can have long-lasting effects on behavior, physiology, and disease.
These findings may also provide a new target for treatment. AgRP cells are located in the hypothalamus outside the blood-brain barrier, a feature of the brain that protects them from harmful substances and prevents many drugs from reaching brain tissue.
“This means that these cells are ready to intervene,” Horvath said. “Maybe it can be exploited to alter disorders of higher brain regions.”
The study also adds to a growing body of evidence that cortical function is affected by more primitive areas of the brain and other parts of the body. Horvath recently showed how AgRP cells can also influence the cortex through the mediation of the liver.
“The key message here is that in the brain, there is a very diffuse communication through different pathways,” Horvath said.
Primitive regions such as the hypothalamus affect the higher cortical regions through a myriad of connections, which include the processes of the brain, but also peripheral tissues.
“We’re back in the debate between Camilo Golgi and Ramon y Cajal, who shared the Nobel Prize in 1906, but differed on the principles of how the brain works. Our results seem to favor the forgotten arguments of Camilo Golgi.”
About this Neuroscience Research News
author: Mallory Locklear
Contact: Mallory Locklear – Yale
picture: Photo credited to Yale University
original search: open access.
“AgRP neurons control the structure and function of the medial prefrontal cortex” by Bernardo Stutz et al. Molecular Psychiatry
AgRP neurons control the structure and function of the medial prefrontal cortex
Peptide neurons and AgRP-expressing neurons play a critical role in both the feeding and non-nutritive behaviors of neonatal, adolescent and adult mice, indicating their broad modulatory effect on brain function.
Here we show that constitutive impairment of AgRP neurons or their chemogenetic inhibition surrounding puberty led to both numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of rats.
These changes were accompanied by altered oscillatory network activity in the mPFC, impaired sensory gating, and altered ambulatory behavior that could be reversed by administration of clozapine, a non-selective dopamine receptor antagonist. The observed effects of AgRP to the mPFC are partially transmitted via dopaminergic neurons in the ventral tegmental area and may also be transmitted by medial thalamic neurons.
Our results revealed a previously unexpected role for AgRP neurons in controlling neural pathways regulating higher brain functions during development and in adulthood.