Glutamatergic Neurons And GABAergic Neurons Of Medial Prefrontal Cortex Control Hoarding-like Behavior

Background and Objective : Hoarding disorder(HD)is a chronic disease that begins early in life and does not remission unless timely treated.A large number of factors affect the presentation of HD symptoms,including a strong possessive psychology of objects and neurocognitive functioning.Although previously considered one of the symptoms of obsessive–compulsive disorder(OCD),compared to other subtypes of OCD,hoarding behavior has been associated with relatively poor response in cognitive–behavioral therapy(CBT)and exhibits cognitive deficits in the value judgment of possessions,including difficulties in deciding to discard objects and classifying them.Furthermore,hoarding symptoms may be actually more common than OCD,with over 80% of hoarding adults not meeting the diagnosis criteria of OCD and showing fewer symptoms of anxiety.Thus,HD is distinct from OCD in the DSM‐5 and its etiology and pathology are still uncertain,and the neural mechanisms of excessive hoarding behavior in HD patients have been poorly studied.Hoarding is a systematic process of movement that involves going to the items source,picking,transporting,and dropping it down somewhere else.These schemas typically refer to many brain regions,such as the medial prefrontal cortex(mPFC)and the hippocampus.However,causal relationship between these areas and the underlying mechanism of hoarding is unclear.Method: To identify the neural mechanisms controlling hoarding-like behavior,we constructed a fasting-induce behavior mouse model.To investigate the specific brain regions involved in hoarding-like behavior,we searched for c-Fos protein expression in the mouse brain after 20-day hoarding training.To determine the activity of mPFC neurons in hoarding mice,whole-cell recordings were used in brain slices from mice with mPFC.Hoarding behavior is modulated by chemogenetic manipulation of neurons in the mPFC.Result: Here,we established a mouse model of hoarding-like behavior by fasting,which is analogous to the excessive hoarding behavior of HD patients.Based on this,our findings in hoarding mice demonstrate that the mPFC region is involved in hoarding-like behavior.In addition,we reveal that mPFC glutamatergic neurons activity is enhanced and GABAergic neurons activity is reduced in hoarding-like behavior.And chemogenetic specifically regulated these neuronal activity which could modulate hoarding-like behavior accordingly.Furthermore,we found that GABAergic neurons,which are mainly SST neurons rather than PV neurons,are involved in hoarding-like behavior.Conclusion: Using immunostaining,viral injections and brain slice electrophysiology recordings,we found that increased glutamatergic neuronal activity and decreased GABAergic neuronal activity in mPFC accelerated the hoarding-like behavior in mice.Contrastingly,chemogenetic manipulation of somatostatin(SST)-expressing GABAergic neurons,not parvalbumin(PV)-expressing GABAergic neurons,restored the behavioral response.These results reveal a critical role played by alterations in the activity of specific types of neurons in hoarding-like behavior,and that targeted therapies for HD may be possible by precisely modulating these types of neurons.