People in the early stages of Alzheimer’s disease often experience a decline in their ability to recognize and remember smells. A recent study published in the journal Molecular Psychiatry suggests that this sensory loss is due to a breakdown in communication between memory-storing cells in two specific brain regions. By using light to stimulate these neural pathways in mice, the researchers were able to temporarily restore olfactory memory function.
Diagnosing Alzheimer’s disease before widespread cognitive decline occurs is a continuing challenge in neurology. Neurodegeneration often begins years before normal memory loss becomes apparent. Changes in a person’s sense of smell may be a strong predictor of future cognitive decline. The research team is trying to map exactly how early neurodegeneration disrupts the brain networks responsible for processing odors.
The study was led by researchers Yan Yan from Shenzhen MSU-BIT University and Zhifang Dong from Chongqing Medical University. They wanted to understand the structural connections between the piriform cortex, which processes odors, and the infralimbic cortex, a prefrontal cortex involved in memory storage and retrieval. Together, these two regions form a network that connects specific odors with past experiences.
Memories are thought to be stored in physical networks of neurons known as engrams. When the brain learns something new, certain groups of engram cells are activated at the same time. To retrieve that memory later, the same engram cells must be reactivated in the correct order. The researchers suspected that the connections between piriform and infralimbic engram cells may be disrupted during the early stages of cognitive decline.
To investigate structural changes in living humans, the research team analyzed functional magnetic resonance imaging scans from public databases. They compared brain scans from 183 people with mild cognitive impairment to scans from 182 healthy adults. Imaging data showed that connectivity between the piriform cortex and the infralimbic cortex was significantly reduced in patients with mild cognitive impairment.
In an effort to understand the cellular mechanisms behind this weakened bond, the researchers turned to a genetically engineered mouse model of Alzheimer’s disease. These mice are engineered to accumulate amyloid plaques, a hallmark of neurodegenerative conditions. The researchers trained mice to associate the smell of limonene with a mild shock to the foot, creating an olfactory memory of fear.
The day after training, the researchers placed the mice in a new environment and exposed them to the scent without shocking them. Age-matched normal mice immediately froze in place, anticipating a negative event. Mice genetically engineered with Alzheimer’s disease mutations showed normal fear responses at three months of age, but did not flinch when tested at four months of age.
This behavioral change suggests that 4-month-old Alzheimer’s mice are able to encode olfactory memories, but struggle to retrieve them the next day. The researchers then used genetic tools to place fluorescent tags on specific engram cells that fired during initial olfactory training. By monitoring these fluorescent tags during memory recall tests, the team was able to observe individual neurons in real time.
Imaging studies revealed that the activity of tagged engram cells in both the piriform and infralimbic cortex was much lower in Alzheimer’s disease mice than in normal mice. To test whether this lack of activity was the cause of memory impairment, the research team used optogenetics. The technique involves modifying targeted neurons so that they can be turned on or off with precisely timed flashes of light through tiny implanted fibers.
In healthy mice, using light to suppress the activity of targeted engram cells prevented the mice from remembering odor associations. In mice with Alzheimer’s disease, the researchers tried the opposite approach. They sent high-frequency pulses of light to the nerve fibers that connect target cells in the piriform cortex to the infralimbic cortex, effectively forcing the cells to fire.
This targeted light stimulation caused Alzheimer’s disease mice to freeze when exposed to the odor. The results showed that when the brain circuits were stimulated artificially, the mice were able to successfully recall memories. It turns out that stimulating piriform cortex cells is enough to activate connected engram cells in the sublimbic cortex.
To find out why natural memory signals were unable to bridge the gap between the two brain regions, scientists analyzed the genetic activity of individual engram cells. They identified an abnormality in the way cells process glutamate. Glutamate is the main excitatory neurotransmitter in the brain, responsible for sending activation signals from one neuron to the next through tiny gaps called synapses.
When a healthy brain forms new memories, it engages in long-term potentiation, a process that physically strengthens the synapses within the engram network. This enhancement typically relies on the influx of biological structures known as AMPA receptors. These specialized proteins are located at the receiving end of the synapse and capture incoming glutamate molecules.
The researchers found that in healthy mice, the learning process succeeded in increasing the number of functional AMPA receptors in the sublimbic cortex. This daily reinforcement mechanism did not occur in Alzheimer’s disease mice. As a result, the chemical signals sent from the piriform cortex were too weak to properly activate memory memory cells in the infralimbic cortex.
High-frequency light stimulation compensated for this chemical weakness. The researchers artificially induced sudden synaptic strengthening by manually forcing presynaptic neurons to fire rapidly. This influx of activity temporarily repaired the communication failure, allowing memory signals to travel normally through brain circuits.
Animal models of Alzheimer’s disease primarily mimic distinct pathological features of Alzheimer’s disease. This means that the timeline of memory loss in mice does not fully reflect the human experience. Photostimulation techniques used in the laboratory require highly invasive surgical and genetic modifications. Such methods are primarily experimental and cannot be used as treatments for human patients.
Future research may explore non-invasive neuromodulation methods that can stimulate targeted memory circuits. Mapping the functional connectivity between these specific olfactory areas via brain scans could serve as an auxiliary diagnostic tool. Tracking early communication deficits in the olfactory system may ultimately help clinicians detect neurodegenerative diseases long before severe cognitive symptoms appear.
The study, “Dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer’s disease,” was authored by Yan Yan, Da Song, Guangfei Li, Junjie Li, Yuanhong Tang, Danyang Li, Jian Mao, Hui Li, Xiaoyun Liu, Ding Yu, Fangfang Ma, Yayan Pang, Yue Jin, and Yujun. Deng, Yunjie Qiu, Zhenzhen Quan, Junjun Ni, Yong Cheng, Zhe Wang, Zhifang Dong, and Qing Hong.
