In the brain, a region called the hypothalamus is known to play a role in the control of hunger, while the hippocampus functions in learning and memory. Now researchers have found a link between those two areas. Reporting in Nature Neuroscience, the team learned more about how neurons change when molecules called NCOR1 and NCOR2 (NCOR1/2) are lost, and the resulting impact on memory in a mouse model. The work may help researchers understand neurological problems including autism spectrum disorder, intellectual disability, and neurodegenerative disease.
"It was not known how NCOR1/2 regulates memory or other cognitive functions, but there is evidence that NCOR1/2 plays a fundamental role in the activity of many hormones," said the corresponding author of the report Dr. Zheng Sun, an assistant professor of medicine and of molecular and cellular biology at Baylor College of Medicine.
The researchers used a mouse model for this work that carried mutations in the NCOR1/2 genes. "These mice clearly present with memory deficits," noted the study's co-first author Dr. Wenjun Zhou, a postdoctoral researcher in the Sun lab. "The signaling involving GABA, a key inhibitory neurotransmitter in the brain, was dysfunctional in hypothalamus neurons when NCOR1/2 was disrupted."
In this work, the scientists used electrophysiology to understand the memory defects in the NCOR1/2-deficient mice.
"What struck us the most was that the process by which NCOR1/2 regulates memory involves a new circuit that links two brain regions: the lateral hypothalamus, known as a feeding center of the brain, and the hippocampus, a place that stores memory," said study collaborator Dr. Yong Xu, an associate professor of pediatrics, molecular and cellular biology at Baylor. "It surprised us because the hypothalamus is not traditionally considered to be a major regulator of learning and memory."
The investigators used several techniques to validate their findings, including optogenetics, in which gene expression is modulated with a laser. "We applied both optogenetics and chemogenetics techniques," said the co-first author of the study Dr. Yanlin He, a postdoctoral associate in the Xu lab. "The protein complex NCOR1/2 is key to the hypothalamus-hippocampus circuit; when we knock it out the circuit becomes dysfunctional."
The researchers followed up on their findings in humans and were able to show that people with problems in their NCOR genes also have neurological issues.
"We describe here new genetic variants of NCOR1/2 in patients with intellectual disability or neurodevelopmental defects," explained the co-corresponding report author Dr. Pengfei Liu, an assistant professor of molecular and human genetics at Baylor and laboratory director of clinical research at Baylor Genetics.
"The gene NCOR1 is located on human chromosome 17, very close to the region that has been previously implicated in the Potocki-Lupski and Smith-Magenis syndromes," added Liu. "We have always suspected that mutations of this gene could cause intellectual disabilities or other deleterious neurological consequences. The mouse models in the current study provide the first evidence that this is indeed the case."
An increasing body of evidence is linking metabolic disorders to dementia and Alzheimer’s disease. This work may help begin to show how the problems are connected in the brain.
"Mechanisms underlying these associations are not completely clear," Sun said. "We think that the NCOR1/2-regulated neural circuit between the feeding and the memory centers of the brain we have discovered is worth exploring further in this context."
The video above from Mayo Clinic asks whether Alzheimer's disease is a third type of diabetes.