Summary: 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 is altered in disorders such as schizophrenia.
The prefrontal cortex region of the human brain is responsible for a range 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, prefrontal cortex dysfunction is linked to several psychiatric illnesses, including schizophrenia and major depressive disorder.
Yale researchers and their Hungarian colleagues have found that cells in the hypothalamus, an area of the brain that controls functions such as hunger and body temperature, play a major role in shaping brain structure and function. prefrontal cortex in mice, a finding that could offer clues to how this region of the brain is altered by disease and open new avenues for treatment.
They reported their findings on July 29 in the newspaper 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 eating and non-eating behaviors such as reward seeking and offspring-parent bonding, among others.
When the researchers altered AgRP neurons in mice, they found that there were fewer neurons in the prefrontal cortex than in healthy animals.
“The remaining neurons were smaller than usual and behaved differently in response to signals from the body and signals from surrounding cells,” said Tamas Horvath, Jean and David W. Wallace Professor of Comparative Medicine at Yale and lead 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 areas – a region of the midbrain known as the ventral tegmental area – were hyperactive when AgRP neurons were impaired. These overactive neurons then released more dopamine, a neurotransmitter, into the prefrontal cortex than is typical 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 eating affect the cortex and behavior, says Horvath.
“When you’re hungry, you have to align all of your behaviors so you can find food and eat it,” he said. “And when you’re full, you need to change your behaviors to focus on what’s important at that time.”
After discovering the effects of altered AgRP cells on the cortex, researchers then tried to avoid them. They found that clozapine, a type of antipsychotic that blocks the action of dopamine and is used to treat schizophrenia, was able to prevent some of these problems, including neuron loss, when given at the right moment.
When it comes to these cortical changes, Horvath said, timing is critical. In the study, impairments began to appear during puberty when the brain is still developing and vulnerable. This is also when the administration of clozapine had an impact.
“And that tells us that if you mess with homeostatic functions during that specific time, such as dieting or overeating, you can have lasting effects on your cortical functions,” he said.
The importance of this developmental period may shed light on psychiatric illnesses, which can often appear in late adolescence, and why substance use during this period can have lasting effects on behavior, physiology and disease.
These results may also provide a new target for treatment. AgRP cells in the hypothalamus lie outside the blood-brain barrier, a feature of the brain that protects it from harmful substances and prevents many drugs from reaching brain tissue.
“That means these cells are readily available for intervention,” Horvath said. “Perhaps they can be harnessed to alter disorders in higher brain regions.”
The study also adds to a growing body of evidence that the function of the cortex is influenced by more primitive regions of the brain and other parts of the body. Horvath recently showed how AgRP cells can also affect the cortex via liver mediation.
“The fundamental message here is that in the brain there is very diffuse communication through different pathways,” Horvath said.
“Primitive areas like the hypothalamus influence higher cortical regions through countless communications, which include brain processes, but also peripheral tissues.
“We return 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 to favor the forgotten arguments of Camillo Golgi.
About this neuroscience research news
Author: Mallory Locklear
Contact: Mallory Locklear–Yale
Image: Image is credited to Yale
Original research: Free 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
Hypothalamic neurons expressing agouti-related peptide and neuropeptide Y (AgRP) play critical roles in feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulating impact on brain function .
Here, we show that constitutive deficiency of AgRP neurons or their peripubertal chemogenetic inhibition resulted 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 that could be reversed by administration of clozapine, a nonselective receptor antagonist dopamine. The observed effects of AgRP are transduced to mPFCs in part via dopaminergic neurons in the ventral tegmental region and may also be mediated 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 into adulthood.