Cells that control hunger affect brain structure and function

Overview: AgRP neurons in the hypothalamus play a critical role in shaping the structure and function of the prefrontal cortex in mice. The findings shed light on how the prefrontal cortex changes in conditions such as schizophrenia.

Source: Yalea

The prefrontal cortex region of the human brain is responsible for a range of complex functions, from decision-making to certain types of memory.

If something goes wrong in this part of the brain, it can be very detrimental to cognition and behavior. In fact, dysfunction in the prefrontal cortex has been linked to several psychiatric illnesses, including schizophrenia and major depressive disorder.

Yale researchers and their colleagues in Hungary have found that cells in the hypothalamus — an area of ​​the brain that regulates functions such as hunger and body temperature — play an important role in shaping the structure and function of the prefrontal cortex in mice, a finding which could provide clues about how this part of the brain changes in disease and open new avenues for treatment.

They reported their findings July 29 in the journal Molecular Psychiatry.

For the study, the researchers focused on agouti-related peptide (AgRP) neurons in the hypothalamus region of the brain. These neurons control hunger and regulate both feeding and non-feeding behaviors, such as reward seeking and bonding between offspring and parents.

When the researchers attacked AgRP neurons in mice, they found that there were fewer neurons in the prefrontal cortex than in healthy animals.

“The neurons that remained were smaller than normal and behaved differently in response to signals from the body and signals from surrounding cells,” said Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine at Yale and senior author of the study. .

AgRP neurons do not have strong direct connections to the cortex. But they do project to other brain regions connected to the prefrontal cortex.

Horvath and his colleagues found that the neurons in one of these areas — an area of ​​the midbrain known as the ventral tegmental area — were overactive when AgRP neurons were affected. Those overactive neurons then released more dopamine, a neurotransmitter, in the prefrontal cortex than is usual in healthy mice, which in turn negatively affected mouse behavior.

For example, they found that the mice moved much more and had abnormal startle responses.

It makes sense that these neurons that control hunger and feeding affect the cortex and behavior, Horvath says.

“When you’re hungry, you need to have all your behaviors lined up so you can find food and eat it,” he said. “And when you’re no longer hungry, you need to change your behavior to focus on what’s important in the moment.”

After uncovering the effects affected AgRP cells had on the cortex, the researchers then tried to avert them. They found that clozapine — a type of antipsychotic that blocks the action of dopamine and is used to treat schizophrenia — could prevent some of these problems, including loss of neurons, when given at the right time.

When it comes to these cortical changes, Horvath said, timing is crucial. In the study, disturbances began to appear during puberty, when the brain is still developing and vulnerable. Then the administration of clozapine also had an effect.

This is a diagram of the brain
Neurons in the hypothalamus (B) project to the ventral tegmental area (C), where cells send connections to the prefrontal cortex (A). Through this pathway, AgRP cells in the hypothalamus influence cortical structure and function. Credit: Yale University

“And this tells us that if you play around with homeostatic functions during that specific time period, such as dieting or overeating, you can have long-lasting effects on your cortical functions,” he said.

The importance of this period of development can shed light on psychiatric illness, which can often develop in late adolescence, and why substance use during that time can have long-lasting effects on behavior, physiology and disease.

These findings may also represent a new target for treatment. AgRP cells in the hypothalamus reside outside the blood-brain barrier, a feature of the brain that protects it from harmful substances and prevents many drugs from reaching brain tissue.

“This means that these cells are immediately available for intervention,” Horvath said. “Perhaps they can be exploited to alter disorders of higher areas of the brain.”

The study also adds to a growing body of evidence that the function of the cortex is influenced by more primitive brain regions as well as other parts of the body. Horvath recently showed how AgRP cells can also influence the cortex via liver mediation.

“The fundamental message here is that in the brain there is very diffuse communication through different pathways,” Horvath said.

Also see

This shows the eye of a man

“Primitive regions such as the hypothalamus affect higher cortical regions through myriad communications, including brain processes, but also peripheral tissues.

“We’re back to the debate between Camillo Golgi and Ramón y Cajal, who shared the Nobel Prize in 1906 but disagreed on the principles of how the brain works. Our results seem in favor of Camillo Golgi’s forgotten arguments.”

About this neuroscience research news

Author: Mallory Locklear
Source: Yalea
Contact: Mallory Locklear – Yalea
Image: The image is attributed to Yale

Original research: Open access.
“AgRP neurons regulate the structure and function of the medial prefrontal cortex” by Bernardo Stutz et al. Molecular Psychiatry


Abstract

AgRP neurons regulate the structure and function of the medial prefrontal cortex

Hypothalamic agouti-related peptide and neuropeptide Y expression (AgRP) neurons play a critical role in both feeding and non-feeding behavior of newborn, adolescent and adult mice, suggesting that they have a broad modulatory influence on brain functions.

Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice.

These changes were associated with a change in oscillatory network activity in mPFC, impaired sensorimotor gates, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are partially transduced to mPFC via dopaminergic neurons in the ventral tegmental area and may also be transmitted by medial thalamic neurons.

Our results revealed a previously unsuspected role for hypothalamic AgRP neurons in the control of neuronal pathways that regulate higher-order brain functions during development and adulthood.

Leave a Comment