Research reveals the basis of neural circuits in the occurrence of psychiatric symptoms in Alzheimer's disease

On November 1, Li Jiali, a researcher at the Kunming Institute of Zoology, Chinese Academy of Sciences, published a research paper
entitled Hyper-excitability of corticothalamic PT neurons in mPFC promotes irritability in the mouse model of Alzheimer's disease in Cell Reports 。 This paper uses a mouse disease model to analyze the neural circuit mechanism
of irritability symptoms in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most important neurodegenerative diseases with complex etiology and pathogenesis that affect the health of the elderly population, with progressive decline in cognitive function as the most significant clinical manifestation, and its main neuropathological changes are the deposition of amyloid plaques in the brain and the tangles
of nerve fibers.
Clinically, in addition to cognitive dysfunction, patients are often accompanied by neuropsychiatric symptoms such as depression and anxiety, increased aggressive behavior, abnormal rhythm, auditory hallucinations, etc.
, which seriously affect the quality of life of patients and caregivers, and may accelerate cognitive decline in patients
.
However, the mechanism of neural circuits that occur and develop such symptoms is unclear
.
The medial prefrontal cortex (mPFC) plays an important role
in the progression of AD lesions.
Studies have found that pyramidal tract (PT) neurons projected into the extracerebral regions of the thalamus, upper thalamus and brainstem have important regulatory effects
on non-cognitive functions such as feeding, aggression, sleep, and emotion.
Therefore, PT neurons in the mPFC region of AD lesions are likely to mediate the occurrence
of neuropsychiatric symptoms in patients.
In addition, PT neurons can be divided into A-type and B-type
according to projection and expression characteristics.
At present, it is unclear whether these two types of neurons have different pathological changes in AD lesions and whether they play different roles
in the occurrence of neuropsychiatric symptoms.

In response to the above scientific questions, Li Jiali's team used AD mouse model as the research object to analyze the specific electrophysiological abnormalities of two types of PT neurons in diseases and their relationship
with aggressive behavior.
In this study, two types of PT neurons of PFC were labeled by reverse tracing virus, and then whole-cell recordings were recorded, and it was found that the intrinsic excitability abnormalities of the two types of neurons in AD mouse models were highly different
.
In model mice, A-type PT neurons headed by projecting to the thalamus showed increased intrinsic excitability and increased action potential release; However, B-type PT neurons, which are mainly projected to the brainstem, show a decrease in the ability to accommodate action potentials and a decrease
in action potential emissions.
Among them, the increase of excitability of A-type PT neurons led to the increase of the attack behavior of model mice, and the excitability of such neurons could be regulated by chemical genetic means in both directions
.

In addition, by comparing the differences in transcriptomics of the two types of neurons, the electrophysiological abnormalities of A-type PT neurons were located in the voltage-gated potassium channel Kv6.
3, and the decrease in the expression of Kv6.
3 in such neurons was determined by immunofluorescence, western blotting, single-cell qPCR, etc.
, and the electrophysiological abnormalities and increased
aggressive behavior of A-type PT neurons in model mice were reversed through the overexpression of Kv6.
3.
This study provides new insights into the mechanism of the occurrence of AD neuropsychiatric symptoms and provides a new basis
for the classification of PFC neurons.

The research work was supported
by the National Natural Science Foundation of China.
Peking University researchers participated in the research
.

Neural circuit mechanisms in the occurrence of irritable symptoms in Alzheimer's disease

Source: Kunming Institute of Zoology, Chinese Academy of Sciences