Summary: AgRP neurons in the hypothalamus play an important role in shaping the structure and function of the prefrontal cortex in mice. Research is revealing how the prefrontal cortex is altered in disorders such as schizophrenia.
A source: Yale
The prefrontal cortex region of the human brain is responsible for a number of complex functions, from decision-making to certain types of memory.
When 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 disorders, including schizophrenia and major depressive disorder.
Yale researchers and their colleagues in Hungary found that cells in the hypothalamus, which control brain functions such as hunger and body temperature, play a major role in shaping the structure and function of the prefrontal cortex in mice. This could reveal how this region of the brain changes in disease and open new avenues for treatment.
They reported their findings to the journal on July 29 Molecular psychiatry.
For the study, the researchers focused on agouti-related peptide (AgRP) neurons located in the hypothalamus region of the brain. These neurons control hunger and regulate both feeding behavior and non-feeding behaviors such as reward seeking and offspring-parent bonding, among others.
When the researchers destroyed the AgRP neurons in the mice, they found that there were fewer neurons in the prefrontal cortex than in healthy animals.
“The neurons remained 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. Professor of Comparative Medicine at Yale. Wallace and senior author of the study.
AgRP neurons do not have strong direct connections with the cortex. But they project to other areas of the brain that connect to the prefrontal cortex.
Horvath and his colleagues found that neurons in one of these regions—a midbrain region called the ventral tegmental area—were overactive when AgRP neurons were damaged. These overactive neurons then released more dopamine, a neurotransmitter, into the prefrontal cortex than healthy mice, which in turn negatively affected the mice’s behavior.
For example, they observed that the mice moved much more and had abnormal startle responses.
These neurons, which control hunger and eating, affect the cortex and behavior, says Horvath.
“When you’re hungry, you have to map out all your behaviors to find food,” he said. “And when you’re not hungry, you have to change your behavior to focus on what’s important in that moment.”
After discovering the negative effects of AgRP cells on the cortex, researchers tried to prevent them. They found that clozapine, a type of antipsychotic drug that blocks the effects of dopamine and is used to treat schizophrenia, can prevent some of these problems, including the loss of neurons, if given in time.
When it comes to these cortical changes, Horvath says, timing is of the essence. In the study, the disorders began to appear during puberty, when the brain was still developing and vulnerable. Clozapine administration also had an effect.
“This tells us that if you play with homeostatic functions over a period of time, say by dieting or overeating, you can have long-lasting effects on your cortical functions,” he said.
The importance of this developmental period may shed light on psychiatric disorders, which often appear in late adolescence, and why substance use during this period has long-lasting effects on behavior, physiology, and disease.
These findings may also provide a new target for treatment. AgRP cells in the hypothalamus are located outside the blood-brain barrier, a feature of the brain that protects it from many harmful substances and prevents drugs from reaching brain tissue.
“This means that these cells are ready to intervene,” Horvath said. “Perhaps they can be used to reverse damage to higher brain regions.”
The research also adds to the growing body of evidence that cortical function is influenced by primitive brain regions and other parts of the body. Horvath recently demonstrated how AgRP cells can influence the cortex through a liver-mediated pathway.
“The main message here is that there is very diffuse communication in the brain through many different pathways,” Horvath said.
“Primitive areas such as the hypothalamus influence higher cortical areas through myriad connections involving brain processes as well as peripheral tissues.
“We are back to the debate between Camillo Golgi and Ramon y Cajal, who shared the Nobel Prize in 1906 but disagreed on the principles of how the brain works. Our results seem to favor the forgotten arguments of Camillo Goldi.
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Author: Mallory Locklear
A source: Yale
The connection: Mallory Locklear – Yale
Photo: Photo courtesy of Yale
Original research: Open access.
Bernardo Stutz et al. “AgRP neurons control the structure and function of the medial prefrontal cortex”. Molecular psychiatry
AgRP neurons control the structure and function of the medial prefrontal cortex
Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons play an important role in feeding and nonfeeding behavior in neonatal, adolescent, and adult mice, indicating their broad modulatory effects on brain function.
Here we show that constitutive disruption of AgRP neurons or their peripubertal chemogenetic inhibition results in numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice.
These changes were accompanied by altered oscillatory network activity in the mPFC, impaired sensorimotor gating, and altered ambulatory behavior, which could be reversed by administration of the nonselective dopamine receptor antagonist, clozapine. The observed effects of AgRP are partially transmitted to the mPFC through dopaminergic neurons in the ventral tegmental area and may also be transmitted by medial thalamic neurons.
Our results revealed a previously unsuspected role of hypothalamic AgRP neurons in controlling neural pathways that regulate higher-order brain functions during development and adulthood.