System for evaluating and treating Alzheimer's disease based on ventral hippocampus-prefrontal lobe loop

Abstract

The invention discloses a system for treating Alzheimer's disease based on ventral hippocampus-prefrontal lobe loop, the system comprises ventral hippocampus-prefrontal lobe loop activation equipment, the ventral hippocampus-prefrontal lobe loop activation equipment is used for activating neuronal cells in a ventral hippocampus area of a patient to be treated, and the ventral hippocampus-prefrontal lobe loop activation equipment is used for activating the ventral hippocampus area of the patient to be treated. Therefore, neuronal cells in the inner side prefrontal cortex are activated through the abdominal side hippocampus-prefrontal cortex loop, the Alzheimer disease focus in the abdominal side hippocampus region and the inner side prefrontal cortex is improved, and the spatial cognitive ability of a patient is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of brain neuroscience, and particularly relates to a system for evaluating and treating Alzheimer's disease based on a ventral hippocampus-frontal lobe circuit. BACKGROUND

[0002] Alzheimer's disease (AD) is characterized by progressive memory deficits and spatial cognitive impairment. Several important neuropathological features of AD have been revealed, including beta-amyloid (Aβ) and intracellular neurofibrillary tangles (NFT). It will destroy molecular pathways, neuronal plasticity and excitability, and local circuits in specific brain regions, as well as large-scale neural circuits. Many drugs have failed in clinical trials, and perhaps the focus should be shifted from targeting Aβ or tau to synaptic plasticity and neural circuit function specific to AD damage.

[0003] Positron emission tomography (PET) imaging as a staging tool for AD progression shows metabolic decline, Aβ plaque load and functional connectivity disruption in the posterior parietal cortex (PPC), hippocampus (HPC) and prefrontal cortex (PFC) in AD patients. In addition, studies have shown that Aβ deposition occurs early in the medial prefrontal cortex (mPFC) and ventral hippocampus in AD model mice. Currently, some studies have shown that the hippocampus is involved in cognitive impairment in AD mice, but the studies have mainly focused on the dorsal hippocampus. Since the hippocampus and mPFC are crucial in the progression of AD, the ventral hippocampus CA1 (vCA1) projects to the anterior limb region of the prefrontal cortex, which is a major circuit directly connecting the two key brain structures. However, current studies of the vCA1-mPFC circuit mainly focus on emotional function, and the function of this circuit in spatial cognition and its role in AD mice have not been elucidated. Therefore, there are many questions: is the vCA1-mPFC circuit important for spatial cognition, how does the vCA1-mPFC circuit change in AD mice, and can early intervention improve the cognitive function of AD mice. Therefore, there is an urgent need to study how the vCA1-mPFC circuit is involved in the cognitive impairment of AD, so as to more specifically improve spatial cognitive ability, and thus help diagnose and treat Alzheimer's disease. SUMMARY

[0004] The purpose of the present application is to provide a system for evaluating and treating Alzheimer's disease based on a hippocampus-frontal lobe circuit, which combines behavior to regulate neurons in the ventral hippocampus region, thereby activating neurons in the medial prefrontal cortex through the ventral hippocampus-frontal lobe circuit, and thus improving Alzheimer's lesions in the ventral hippocampus region and the medial prefrontal cortex, and improving the spatial cognitive ability of patients.

[0005] A first aspect of the present application provides a system for treating Alzheimer's disease based on the ventral hippocampal-frontal loop, comprising:

[0006] a ventral hippocampal-frontal loop activation device configured to activate neuronal cells in the ventral hippocampus of a patient to be treated, thereby activating neuronal cells in the medial prefrontal cortex through the ventral hippocampal-frontal loop, and further improving Alzheimer's disease lesions in the ventral hippocampus and the medial prefrontal cortex.

[0007] In another preferred embodiment, the activated neuronal cells in the medial prefrontal cortex are neurons that receive projections from neuronal cells in the ventral hippocampus.

[0008] In another preferred embodiment, the Alzheimer's disease lesions include β-amyloid plaques.

[0009] In another preferred embodiment, the improvement of Alzheimer's disease lesions in the ventral hippocampus and the medial prefrontal cortex includes a reduction in the number and area of β-amyloid plaques in the ventral hippocampus and the medial prefrontal cortex.

[0010] In another preferred embodiment, the patient's spatial cognitive ability is improved through the reduction in the number and area of β-amyloid plaques.

[0011] In another preferred embodiment, the ventral hippocampus refers to the anterior hippocampus of the patient.

[0012] A second aspect of the present application provides a system for treating Alzheimer's disease based on the ventral hippocampal-frontal loop, comprising:

[0013] a ventral hippocampal-frontal loop activation device configured to activate neuronal cells in the ventral hippocampus of a patient to be treated, thereby activating neuronal cells in the medial prefrontal cortex through the ventral hippocampal-frontal loop;

[0014] a behavioral training device configured to provide spatial cognitive training to the patient;

[0015] During the treatment of the patient, the ventral hippocampal-frontal loop activation device and the behavioral training device are operated simultaneously, so that the patient receives the spatial cognitive training and is stimulated by the ventral hippocampal-frontal loop activation device at the same time, thereby improving Alzheimer's disease lesions in the ventral hippocampus and the medial prefrontal cortex of the patient, and further improving the patient's spatial cognitive ability.

[0016] In another preferred embodiment, the ventral hippocampus refers to the anterior hippocampus of the patient.

[0017] In another preferred embodiment, the behavioral training device comprises a VR device.

[0018] In another preferred embodiment, the spatial cognition training comprises training of the spatial planning type or the spatial navigation type.

[0019] In another preferred embodiment, the patient to be treated is a human or animal model suffering from Alzheimer's disease, or a healthy human.

[0020] In another preferred embodiment, the patient to be treated is chronically modulated in the neurons of the ventral (anterior) hippocampus and / or the prefrontal cortex, so as to improve the spatial cognition of the patient to be treated, before the patient is found to have cognitive impairment, i.e. the system can also be used to prevent Alzheimer's disease.

[0021] In another preferred embodiment, the chronic modulation refers to a modulation (activation of the neuron cells in the ventral (anterior) hippocampus and / or the prefrontal cortex) performed for a predetermined time, preferably 2 weeks, 5 days a week, 20 minutes a day, with a stimulation intensity of 2 mA.

[0022] In another preferred embodiment, the ventral (anterior) hippocampus-prefrontal loop activation device is a transcranial direct current stimulation device arranged in the medial prefrontal cortex of the patient, so as to activate the neuron cells in the medial prefrontal cortex of the patient. Preferably, the activated neuron cells in the medial prefrontal cortex are neuron cells receiving projections from neuron cells in the ventral hippocampus.

[0023] In another preferred embodiment, the ventral hippocampus-prefrontal loop activation device comprises a neural electrode implanted in the ventral hippocampus of the patient.

[0024] In another preferred embodiment, the ventral (anterior) hippocampus-prefrontal loop activation device comprises a deep brain stimulation device, the electrodes of which are implanted in the ventral (anterior) hippocampus of the patient, so as to activate the neuron cells in the ventral (anterior) hippocampus by deep brain stimulation.

[0025] In another preferred embodiment, the spatial cognition refers to the ability to recognize, encode, store and retrieve spatial information.

[0026] In another preferred embodiment, the system further comprises a control device configured to control the ventral hippocampus-prefrontal loop activation device to send a stimulation signal to the neuron cells in the ventral hippocampus, so as to upregulate or downregulate the function of the neuron cells in the ventral hippocampus.

[0027] The third aspect of the present application provides an Alzheimer's disease condition assessment system, comprising:

[0028] a behavioral training device configured to provide spatial cognitive training to a patient to be assessed;

[0029] a data acquisition device configured to acquire data of a ventral hippocampal-frontal loop of the patient to be assessed when the patient is performing the spatial cognitive training;

[0030] an assessment device configured to assess the acquired data of the ventral hippocampal-frontal loop of the patient to be assessed, to give an assessment result of spatial cognitive impairment of the patient to be assessed, and to give an assessment result of subsequent cognitive impairment degree of the patient.

[0031] In another preferred embodiment, the ventral hippocampal region refers to the anterior hippocampal region of the patient.

[0032] In another preferred embodiment, the data of the ventral hippocampal-frontal loop comprises the number of neuron cells in the medial prefrontal cortex that receive projections from the ventral hippocampal region and / or the electrophysiological properties of the neuron cells in the medial prefrontal cortex that receive projections from the ventral hippocampal region.

[0033] In another preferred embodiment, the data of the ventral (anterior) hippocampal-frontal loop comprises the proportion of neuron cells in the medial prefrontal cortex that receive projections from the ventral (anterior) hippocampal region to all neuron cells in the medial prefrontal cortex.

[0034] In another preferred embodiment, the data of the ventral hippocampal-frontal loop comprises the number of neuron cells in the ventral hippocampal region of the patient that are connected to neuron cells in the medial prefrontal cortex of the patient.

[0035] In another preferred embodiment, in other words, the data of the ventral (anterior) hippocampal-frontal loop comprises the number of neuron cells in the ventral hippocampal region of the patient that are connected to neuron cells in the medial prefrontal cortex of the patient.

[0036] In another preferred embodiment, the data of the ventral (anterior) hippocampal-frontal loop comprises the number of activated neuron cells in the ventral (anterior) hippocampal region of the patient and the number of activated neuron cells in the medial prefrontal cortex of the patient.

[0037] In another preferred embodiment, the data of the ventral (anterior) hippocampal-frontal loop comprises functional magnetic resonance imaging (fMRI) of the patient, which shows the activity degree of the ventral (anterior) hippocampal and medial prefrontal brain regions of the patient when the patient is performing spatial cognitive training.

[0038] In another preferred embodiment, the patient to be evaluated is a human or animal model with Alzheimer's disease, or a healthy human.

[0039] It should be understood that, within the scope of the present application, each of the technical features of the present application described above and each of the technical features specifically described hereinafter (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0040] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. It should be understood that the drawings described below are only some of the embodiments of the present application, and those of ordinary skill in the art can also obtain other embodiments from these drawings without creative labor.

[0041] Figure 1 A schematic diagram showing that the vCA1-mPFC circuit is involved in the spatial cognitive behavior of WT mice is shown;

[0042] Wherein a shows the experimental paradigm of the novel object location test (NOLT) combined with c-Fos staining;

[0043] b shows a representative image of the c-Fos immunofluorescence staining result in the hippocampus, scale, 500 μm (top), 100 μm (bottom);

[0044] c shows a statistical graph of the number of c-Fos+ cells and the immunofluorescence intensity in the NOLT (novel object location test);

[0045] d shows the experimental paradigm of the Barnes maze (BM) combined with c-Fos staining;

[0046] e shows a statistical graph of the number of c-Fos+ cells and the immunofluorescence intensity in the BM;

[0047] f-k shows that optogenetic inhibition of the vCA1-mPFC circuit impairs the spatial cognitive ability of WT mice, f, the left and middle show the schematic diagram of virus injection and optical fiber embedding in the optogenetic inhibition experiment, scale, 500 μm (vCA1), 200 μm (mPFC); Right graph: experimental time axis of vCA1-mPFC circuit optogenetic inhibition;

[0048] g shows a heat map of NOLT and NOR (novel object recognition);

[0049] h-i shows that optogenetic inhibition of the vCA1-mPFC circuit impairs discrimination in NOLT (new location recognition) but not NOR (new object recognition);

[0050] j shows heat map of BM; k shows that optogenetic inhibition of the vCA1-mPFC circuit impairs performance of WT mice in BM;

[0051] Figure 2 shows schematic of reduced vCA1-mPFC circuit connectivity in 5xFAD mice, where a shows schematic of viral injection; b shows representative images of mPFC neurons receiving vCA1 projections in WT and 5xFAD mice; c shows statistics of the number of mPFC neurons receiving projections from vCA1 in WT and 5xFAD mice; d shows schematic of RV viral injection in mPFC, scale bar, 100 pm; e shows statistics of cell numbers in mPFC upstream projection brain regions;

[0052] Figure 3 shows schematic of impaired vCA1-mPFC circuit in 5xFAD mice, where a shows schematic of viral injection and in vitro electrophysiology; b shows significantly increased mEPSC event (miniature excitatory postsynaptic current event) inter-spike intervals of mPFC neurons receiving vCA1 projections in 5xFAD mice; c shows schematic of viral injection and principle of fiber photometry, scale bar, 500 pm; d shows experimental paradigm of NOLT and NOR combined fiber recording; e shows calcium responses of vCA1 neurons projecting to mPFC to new and old locations in WT mice; f shows calcium responses of vCA1 neurons projecting to mPFC to new and old objects in WT mice; g shows calcium responses of vCA1 neurons projecting to mPFC to new and old locations in 5xFAD mice; h shows calcium responses of vCA1 neurons projecting to mPFC to new and old objects in 5xFAD mice;

[0053] Figure 4Schematic diagram showing that chronic chemogenetic and optogenetic activation of vCA1-mPFC circuit improves spatial cognitive ability of 5xFAD mice; wherein a, left: chemogenetic virus injection scheme, middle: experimental timeline of chronic chemogenetic activation of vCA1-mPFC circuit, right: CNO (Clozapine-N-oxide) feeding schematic diagram; b shows the heatmap of NOLT and NOR in chemogenetic activation experiment; c shows that chemogenetic activation circuit improves the performance of NOLT in 5xFAD mice; d shows that chemogenetic activation circuit does not affect the performance of 5xFAD mice in NOR; e shows the heatmap of BM; f-g shows that chemogenetic activation of vCA1-mPFC circuit improves the performance of 5xFAD mice in BM; h, left: schematic diagram of virus injection and optical fiber embedding in optogenetic activation experiment; right: experimental timeline of chronic optogenetic activation of vCA1-mPFC circuit; i shows that optogenetic activation circuit improves the performance of 5xFAD mice in NOLT, but does not change the performance in NOR; j-k shows that optogenetic activation of vCA1-mPFC circuit improves the performance of 5xFAD mice in Barnes maze;

[0054] Figure 5 Schematic diagram showing that chronic chemogenetic and optogenetic activation of vCA1-mPFC circuit has long-term improvement effect, showing improvement in spatial memory and Aβ plaque after 1 month of chemogenetic and optogenetic activation; wherein a shows the experimental timeline of behavior and immunostaining of 5xFAD mice with chronic chemogenetic activation of vCA1-mPFC circuit at 6 months of age; b, c shows that chronic chemogenetic activation improves the performance of 5xFAD mice in BM at 6 months of age; d shows the immunofluorescence staining schematic diagram of Aβ plaque deposition in vCA1, scale bar, 500 μm (top), 200 μm (bottom); e shows the number and area of Aβ plaque deposition in 5xFAD mice at 6 months of age after chemogenetic activation; f shows the experimental timeline of behavior and immunostaining of 5xFAD mice with chronic optogenetic activation of vCA1-mPFC circuit at 6 months of age; g, h shows that chronic optogenetic activation improves the performance of 5xFAD mice in BM; i shows the Aβ immunofluorescence staining schematic diagram of 5xFAD mice in optogenetic activation experiment, scale bar, 500 μm (top), 200 μm (bottom); j shows that chronic optogenetic activation reduces the number and area of Aβ plaque in mPFC of 5xFAD mice;

[0055] Figure 6Schematic diagram showing that tDCS combined with behavior can improve the spatial cognitive ability of 5xFAD mice; Wherein a shows the c-Fos staining experiment paradigm of tDCS combined with behavior; B shows the schematic diagram of c-Fos immunofluorescence staining, red arrow indicates that mPFC neurons receive vCA1 projection, yellow arrow indicates co-standard cell, scale, 100 μm; C shows that tDCS combined with BM activates more c-Fos+ neurons, increases the co-labeling ratio of mPFC cells with vCA1 projection; D shows the experimental paradigm of tDCS combined with BM; E and f show that tDCS combined with behavior improves the performance of 5-month-old 5xFAD mice in BM;

[0056] Figure 7 Schematic diagram showing that tDCS combined with behavior has long-term improvement effect; Wherein a shows the experimental time line of 5xFAD mice in tDCS combined with BM behavior test and immunostaining at 6 months of age; B shows that tDCS combined with behavior improves the performance of 5-month-old 5xFAD mice in water maze; C shows that tDCS combined with behavior can better improve the performance of 6-month-old 5xFAD mice in water maze; D shows the schematic diagram of Aβ and Iba1 immunofluorescence staining, scale, 50 μm; E and f show that tDCS combined with BM group reduces the area of Aβ deposition and Iba1 cell; G and h show that tDCS reduces the number of Iba1 and the proportion of co-labeling with Aβ plaque;

[0057] Figure 8 Schematic diagram showing the cognitive related behavior performance of 5xFAD mice at 3 months and 5 months of age and the activation effect of CNO feeding; Wherein a, b show the experimental paradigm of new location recognition and new object recognition; C shows the experimental paradigm and DI index of NOLT and NOR of 3-month-old and 5-month-old 5xFAD mice; D shows the latency and error times of 3-month-old 5xFAD mice in BM; E shows the percentage of time in target quadrant of 3-month-old 5xFAD mice; F shows the daily liquid intake of mice in chronic chemical genetic activation experiment; G, h show the schematic diagram of in vitro electrophysiological experiment of CNO effect test; I shows the schematic diagram of c-Fos immunofluorescence staining of CNO combined with hm3D (human muscarinic acetylcholine receptor M3), blue arrow indicates hm3d labeled cell, white arrow indicates co-standard cell, scale, 200 μm (left), 20 μm (right); J shows that hm3D combined with CNO produces higher c-Fos fluorescence intensity; K shows the co-labeling ratio of c-Fos+ cells and hm3d labeled cells, CNO specifically activates hm3d labeled cells; L shows the schematic diagram of Aβ immunofluorescence staining in mPFC after optogenetic activation, white arrow indicates Aβ plaque;

[0058] Figure 9Schematic diagram of in vitro electrophysiology of non-vCA1-projecting mPFC cells; wherein a shows the viral injection scheme and in vitro electrophysiology schematic diagram, recording non-vCA1-projecting mPFC cells; b shows that the mEPSC event interval of non-vCA1-projecting neurons in the mPFC of 5xFAD mice has no obvious difference from WT; c shows the sEPSC amplitude of non-vCA1-projecting mPFC cells in 5xFAD mice and WT mice. DETAILED DESCRIPTION

[0059] The inventors first developed a system for evaluating and treating Alzheimer's disease based on the hippocampus-frontal lobe loop through extensive and in-depth research. The system regulates neurons in the ventral hippocampal region, activates neurons in the medial prefrontal cortex through the ventral hippocampus-frontal lobe loop, and improves Alzheimer's disease lesions in the ventral hippocampal region and the medial prefrontal cortex. The system also evaluates neurons in the ventral hippocampal region and the prefrontal cortex to assess the patient's spatial cognitive ability and provide an assessment of the patient's subsequent cognitive impairment.

[0060] Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Its typical pathological changes are extracellular amyloid plaque deposition (Amyloid protein, Aβ) and intracellular neurofibrillary tangles (neurofibrillar tangles, NFT), mainly in the prefrontal cortex (medial prefrontal cortex, mPFC) and hippocampus. The direct projection of the mouse mPFC from the hippocampus is mainly from the ventral hippocampus CA1 (ventral hippocampus, vCA1), and current vCA1-mPFC loop research mainly focuses on emotional function. The function of this loop in spatial cognition and its role in AD mice has not been elucidated.

[0061] Firstly, this application affects the spatial cognitive behavior of wild-type mice by inhibiting the vCA1-mPFC circuit, revealing that the circuit plays an important role in spatial cognition. Secondly, it is found that the number of cells in the mPFC of 5xFAD transgenic mice (AD disease model mice) receiving projections from the vCA1 brain area and excitability decrease, and in the new location recognition experiment, the fiber-optic calcium imaging recording shows that there is no significant difference in calcium signal between new and old locations in 5xFAD mice, further illustrating that the vCA1-mPFC circuit of AD mice is impaired. Next, early chronic chemical genetics and optogenetic methods are used to activate the vCA1-mPFC circuit, which improves the performance of mice in spatial cognition-related behavior, and this improvement not only has an immediate effect, but also has a certain long-term effect (still improved one month after regulation). Finally, a clinical neuroregulation technique: transcranial direct current stimulation (tDCS) is used, which is found to activate the neurons of the mPFC in combination with behavior, and better improve the performance of mice in spatial-related behavior than simple stimulation. In summary, the study finds that regulating the vCA1-mPFC circuit can improve the spatial cognition of AD mice, and has great enlightenment and important significance for the clinical treatment of AD.

[0062] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one skilled in the art that the present application can be practiced without some or all of these specific details. In other instances, well known process steps have not been described in detail in order not to unnecessarily obscure the present application.

[0063] Terminology

[0064] As used herein, "vCA1-mPFC circuit" refers to the ventral hippocampus-frontal lobe circuit.

[0065] As used herein, 5xFAD refers to a mouse with 5 gene mutations related to Familial Alzheimer's Disease (FAD);

[0066] As used herein, WT mouse refers to a wild-type mouse, whose genome is consistent with that of ordinary mice in nature, without any genetic modification or mutation;

[0067] As used herein, "AD" refers to "Alzheimer's disease".

[0068] As used herein, "hm3D" and "hm3d" both refer to "human muscarinic acetylcholine receptor M3".

[0069] As used herein, "ventral hippocampus" refers to "the anterior hippocampus region of the patient".

[0070] It should be noted that the relative terms such as first and second etc. in the patent application file of the present invention are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply that there is any such actual relationship or order between the entities or operations. Moreover, the terms "comprise", "contain" or any other variants thereof are intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such process, method, article or device. Without more limitations, the element defined by the statement "comprises one" does not exclude the presence of another identical element in the process, method, article or device including the element. In the patent application file of the present invention, if it is mentioned that a certain action is performed according to a certain element, it means that the action is performed at least according to the element, including two cases: the action is performed only according to the element, and the action is performed according to the element and other elements. The expressions of multiple, multiple times, multiple varieties, etc. include 2, 2 times, 2 varieties and more than 2, more than 2 times, more than 2 varieties.

[0071] In the present invention, all directional indications (such as up, down, left, right, front, back, etc.) are only used to explain the relative position relationship, motion condition, etc. between the components in a certain specific posture (as shown in the drawings), and the directional indications will change accordingly if the specific posture changes.

[0072] The present invention has at least one of the following advantages:

[0073] (a) The system for treating Alzheimer's disease based on ventral hippocampus-frontal lobe loop of the present invention can improve the spatial cognitive ability of the regulated object (treatment object) by activating the ventral hippocampus-frontal lobe loop;

[0074] (b) The system for treating Alzheimer's disease based on ventral hippocampus-frontal lobe loop of the present invention can better improve the spatial cognitive ability of the regulated object by combining the activation of the ventral hippocampus-frontal lobe loop and the behavior training device, and further treat Alzheimer's disease;

[0075] (c) The present invention can also diagnose Alzheimer's disease based on the data of the ventral hippocampus-frontal lobe loop;

[0076] (d) The present invention can better improve the spatial cognitive ability of the regulated object by combining chronic regulation of the ventral hippocampus-frontal lobe loop and the behavior training device, and the improvement of the spatial cognitive ability has a long-term effect.

[0077] A system for treating Alzheimer's disease based on the ventral (anterior) hippocampal-frontal loop

[0078] The present application provides a system for treating Alzheimer's disease based on the ventral (anterior) hippocampal-frontal loop, comprising a ventral (anterior) hippocampal-frontal loop activation device for activating neuron cells in the ventral (anterior) hippocampal region of a patient to be treated, so as to activate neuron cells in the medial prefrontal cortex through the ventral (anterior) hippocampal-frontal loop, and further improve Alzheimer's lesions in the ventral (anterior) hippocampal region and the medial prefrontal cortex.

[0079] Preferably, the activated neuron cells in the medial prefrontal cortex are neuron cells receiving projections from the neuron cells in the ventral (anterior) hippocampal region.

[0080] Preferably, the Alzheimer's lesions include β-amyloid plaques.

[0081] Preferably, the improvement of Alzheimer's lesions in the ventral hippocampal region and the medial prefrontal cortex includes the reduction of the number and area of β-amyloid plaques in the ventral hippocampal region and the medial prefrontal cortex. Preferably, the spatial cognitive ability of the patient is improved through the reduction of the number and area of β-amyloid plaques.

[0082] The ventral hippocampal region refers to the anterior hippocampal region of the patient.

[0083] A system for treating Alzheimer's disease based on the ventral hippocampal-frontal loop

[0084] The present application also provides a system for treating Alzheimer's disease based on the ventral hippocampal-frontal loop, comprising a ventral hippocampal-frontal loop activation device for activating neuron cells in the ventral hippocampal region of a patient to be treated, so as to activate neuron cells in the medial prefrontal cortex through the ventral hippocampal-frontal loop;

[0085] a behavioral training device configured to provide spatial cognitive training to the patient;

[0086] During the treatment of the patient, the ventral hippocampal-frontal loop activation device and the behavioral training device are operated simultaneously, so that the patient receives the spatial cognitive training and the stimulation of the ventral hippocampal-frontal loop activation device at the same time, and further improves the Alzheimer's lesions in the ventral hippocampal region and the medial prefrontal cortex of the patient, and further improves the spatial cognitive ability of the patient.

[0087] The ventral hippocampus of the patient refers to the anterior hippocampus of the patient.

[0088] In an embodiment, the behavior training device comprises a VR device. Preferably, the spatial cognition training comprises training of the spatial planning type or the spatial navigation type. Preferably, the patient to be treated is a human or animal model suffering from Alzheimer's disease, or a healthy human.

[0089] Preferably, the chronic regulation of neurons in the ventral (anterior) hippocampus and / or prefrontal cortex of the patient to be treated is performed before the patient is found to have cognitive impairment, so as to improve the spatial cognition of the patient to be treated, i.e., the system can also be used to prevent Alzheimer's disease.

[0090] Preferably, the chronic regulation refers to regulation (activation of neuron cells in the ventral (anterior) hippocampus and / or prefrontal cortex) for a predetermined time, preferably, the predetermined time lasts for 2 weeks, 5 days a week, 20 minutes a day, and the stimulation intensity is 2 mA.

[0091] In an embodiment, the ventral (anterior) hippocampus-prefrontal cortex loop activation device is a transcranial direct current stimulation device arranged in the medial prefrontal cortex of the patient, so as to activate neuron cells in the medial prefrontal cortex of the patient. Preferably, the activated neuron cells in the medial prefrontal cortex are neuron cells receiving projections from neuron cells in the ventral hippocampus.

[0092] In an embodiment, the ventral hippocampus-prefrontal cortex loop activation device comprises a neural electrode embedded in the ventral hippocampus of the patient.

[0093] In an embodiment, the ventral (anterior) hippocampus-prefrontal cortex loop activation device comprises a deep electrical stimulation device, and an electrode of the deep electrical stimulation device is embedded in the ventral (anterior) hippocampus of the patient, and neuron cells in the ventral (anterior) hippocampus are activated by the deep electrical stimulation.

[0094] Preferably, the spatial cognition refers to the ability to recognize, encode, store, and retrieve spatial information. In an embodiment, the system further comprises a control device configured to control the ventral hippocampus-prefrontal cortex loop activation device to send a stimulation signal to the neuron cells in the ventral hippocampus, so as to up-regulate or down-regulate the function of the neuron cells in the ventral hippocampus.

[0095] An Alzheimer's disease condition assessment system

[0096] The application also provides an Alzheimer's disease condition assessment system, comprising:

[0097] a behavioral training device configured to provide a spatial cognition training to a patient to be evaluated;

[0098] a data acquisition device configured to acquire data of a ventral hippocampal-frontal loop of the patient to be evaluated while the patient is performing the spatial cognition training;

[0099] an evaluation device configured to evaluate the acquired data of the ventral hippocampal-frontal loop of the patient to be evaluated, to give an evaluation result of the patient to be evaluated on spatial cognition impairment, and further to give an evaluation result of the patient on subsequent cognitive impairment.

[0100] wherein the ventral hippocampal region of the patient refers to the anterior hippocampal region of the patient.

[0101] Preferably, the data of the ventral hippocampal-frontal loop comprises the number of neuronal cells in the medial prefrontal cortex that receive projections from the ventral hippocampal region and / or the electrophysiological properties of the neuronal cells in the medial prefrontal cortex that receive projections from the ventral hippocampal region.

[0102] Preferably, the data of the ventral (anterior) hippocampal-frontal loop comprises the proportion of neuronal cells in the medial prefrontal cortex that receive projections from the ventral (anterior) hippocampal region to all neuronal cells in the medial prefrontal cortex.

[0103] Preferably, the data of the ventral hippocampal-frontal loop comprises the number of neuronal cells in the ventral hippocampal region of the patient that are connected to neuronal cells in the medial prefrontal cortex of the patient. In other words, the data of the ventral (anterior) hippocampal-frontal loop comprises the number of neuronal cells in the ventral hippocampal region of the patient that are connected to neuronal cells in the medial prefrontal cortex of the patient.

[0104] Preferably, the data of the ventral (anterior) hippocampal-frontal loop comprises the number of activated neuronal cells in the ventral (anterior) hippocampal region of the patient and the number of activated neuronal cells in the medial prefrontal cortex of the patient.

[0105] In an embodiment, the data of the ventral (anterior) hippocampal-frontal loop comprises a functional magnetic resonance imaging (fMRI) of the patient, which shows the extent of brain region activity of the ventral (anterior) hippocampus and the medial prefrontal cortex of the patient while the patient is performing the spatial cognition training.

[0106] Preferably, the patient to be evaluated is a human or animal model with Alzheimer's disease, or a healthy human.

[0107] In order to make the objectives, technical solutions and advantages of the present application clearer, the experimental methods used in the embodiments of the present application will be described in further detail below with reference to the drawings.

[0108] Experimental methods

[0109] To solve the existing technical problems, the present application first inhibits the vCA1-mPFC input by optogenetics, and finds that this loop is important for spatial cognition. Next, anterograde and retrograde viral tracing, in vitro electrophysiology and fiber photometry are used to observe the differences between vCA1-mPFC loops in 5xFAD mice and WT mice. It is found that the number and excitability of vCA1-mPFC functional projections in 5xFAD mice are reduced. Then, chronic chemical genetics and optogenetics are used to activate the vCA1-mPFC loop in early stage, and it is found that it can improve the spatial cognition of 5xFAD mice and has long-term effect. In order to further realize clinical application, transcranial direct current stimulation (tDCS) is used to activate mPFC cells receiving vCA1 projections in vivo of mice in combination with behavior, and it is found that it can improve the spatial cognition and pathology of AD mice. In summary, it is proved that regulating the vCA1-mPFC loop can improve the spatial cognition of AD mice, which has important significance and enlightenment for clinical treatment. The specific experimental methods and results are described as follows.

[0110] vCA1-mPFC loop participates in spatial memory of WT mice

[0111] The present application studies whether the vCA1-mPFC loop also plays a role in other cognitive-related behaviors. Figure 1 A schematic diagram showing that the vCA1-mPFC loop participates in the spatial cognitive behavior of WT mice is shown; first, the neuronal activity is examined by c-Fos staining combined with the novel place recognition test. The mice are divided into a new place group, a same place group and a home cage group. After contacting two objects, the new place group modifies the position of one object, while the same place group keeps its position. After the behavior test for 90 minutes, the brain is perfused for c-Fos staining (see Figure 1 a) of the drawings). The results show that c-Fos+ neurons can be activated by contacting objects whether in the new place group or the same place group. In order to further explore the activation state of c-Fos+ cells, the vCA1 and mPFC of the new place group have higher fluorescence intensity compared with the other two groups. When activating similar number of cells, changing the position leads to higher cell activity (see Figure 1 b and c of the drawings). The results show that vCA1 and mPFC participate in the novel place recognition test. The same results are found in the Barnes maze (BM), when WT mice perform BM, the number of c-Fos+ cells is more and the fluorescence intensity is higher (see Figure 1d and e) of FIG. 1. This indicates that vCA1 and mPFC brain regions are involved in cognitive-related behaviors.

[0112] To further investigate whether vCA1-mPFC projections regulate cognition in mice, AAV viruses expressing NpHR were injected into vCA1 and optical fibers were embedded into mPFC to enable terminal optogenetic inhibition. Cognitive behaviors were performed 4 weeks after viral expression. In the novel location recognition test (NOLT) and novel object recognition test (NOR), yellow light stimulation was continuously given during the test phase (see Figure 1 f) of FIG. 1. Because mice like to explore new things and have the ability to distinguish, WT mice will prefer new locations or new objects. Optogenetic inhibition of the vCA1-mPFC circuit showed impaired ability to distinguish new locations in the novel location recognition test, and the NpHR group preferred familiar locations. But optogenetic inhibition of the vCA1-mPFC circuit did not affect the performance of mice in NOR (see Figure 1 g, h and i) of FIG. 1. In the BM, GFP group mice (mice injected with control GFP virus) learned to find the correct hole much faster than the NpHR group, and the NpHR group showed learning deficits. In addition, optogenetic inhibition of vCA1-mPFC direct input shortened the percentage of time in the target quadrant and increased the number of error probe holes (see Figure 1 j and k) of FIG. 1. The results of the study indicate that the vCA1-mPFC circuit is essential for spatial cognition.

[0113] Impaired connectivity and function of the vCA1-mPFC circuit in 5xFAD mice

[0114] Previous studies have shown that 5xFAD mice can develop amyloidosis at 2 months of age, especially in the hippocampus and cortex, and cognitive memory impairment occurs at 4 to 5 months old. First, the cognitive-related behavior changes of 5xFAD mice at 3 months and 5 months old were examined. Figure 8 a-e of FIG. 2 show the cognitive-related behavior performance of 5xFAD mice at 3 months and 5 months old, and there was no significant difference between 3-month-old 5xFAD mice and wild-type mice for NOLT and NOR, but by 5 months old, 5xFAD showed significant impairment in discrimination and cognitive ability (see Figure 8 a-c) of FIG. 2. For BM, 5-month-old 5xFAD mice showed significant cognitive impairment, manifested as prolonged latency and increased number of errors, while there was no significant difference between 3-month-old 5xFAD mice and WT mice (see Figure 8 d and e) of FIG. 2. These results indicate that 5-month-old 5xFAD mice have already developed cognitive impairment, so 5-month-old mice are used to study the specific case of circuit impairment.

[0115] To observe the difference in the number of projection connections in the vCA1-mPFC circuit between 5xFAD and WT, anterograde tracing was performed using adeno-associated virus type 1 (AAV1) and retrograde tracing was performed using monosynaptic rabies virus (RV). For anterograde tracing, AAV1-EF1a-Cre virus was injected in vCA1 and AAV-EF1a-DIO-mCherry virus was injected in mPFC to achieve the somatic labeling of vCA1 projecting neurons in mPFC. The results showed that the number of cells in mPFC receiving direct projections from vCA1 was reduced in 5xFAD mice (see Figure 2 a-c). For retrograde tracing, AAV-TVA-mcherry-2A-Og and AAV-Ef1a-Cre virus were first injected in mPFC to provide TVA and G protein in Cre positive cells. Two weeks later, Rabies-EnVA-AG-GFP virus was injected into the same site. It was found that the number of connected cells upstream of mPFC was reduced in 5xFAD mice compared to WT mice, with a significant reduction of projections from vCA1 (see Figure 2 d and e). The above results showed that the number of projections from vCA1 to mPFC was reduced in 5xFAD mice, Figure 2 a schematic diagram showing the reduced number of vCA1-mPFC circuit connections in 5xFAD mice.

[0116] The above experiments showed that the number of circuit connections was reduced in 5xFAD mice, and further studies on its function were therefore carried out, so in vitro electrophysiology was performed. AAV1-EF1a-Cre virus was injected in vCA1 and AAV-EF1a-DIO-mCherry virus was injected in mPFC and mEPSCs of mPFC cells receiving vCA1 projections were recorded (see Figure 3 a, which shows the virus injection scheme and a schematic diagram of in vitro electrophysiology). The interval of mPFC neurons receiving vCA1 projections was significantly prolonged and the amplitude of 5xFAD was higher than that of WT mice. These results showed that the presynaptic excitability of mPFC neurons receiving vCA1 projections was reduced (see Figure 3 b, which shows that the mEPSC event interval of mPFC neurons receiving vCA1 projections in 5xFAD mice was significantly increased). In addition, non-vCA1 projecting cells in mPFC were recorded and there was no significant difference in the interval between 5xFAD and WT mice, see Figure 9 a and b, Figure 9Schematic of in vitro electrophysiology of non-vCA1-projecting mPFC cells; where a shows the viral injection protocol and schematic of in vitro electrophysiology to record non-vCA1-projecting mPFC cells; b shows that the mEPSC event inter-spike intervals of non-vCA1-projecting neurons in the mPFC of 5xFAD mice are not significantly different from WT, suggesting that the above frequency changes are loop-specific.

[0117] Next, in vivo optical fiber calcium imaging experiments were performed to record the calcium signals of vCA1 neurons projecting to the mPFC. The retroAAV-Cre virus was injected in the mPFC and the AAV-DIO-GCaMP6s virus was injected in the vCA1 (see Figure 3 c, which shows the viral injection protocol and schematic of fiber photometry, scale bar, 500 pm). The mice were recorded for their responses to new and old locations (or objects) in the NOLT and NOR tests (see Figure 3 d, which shows the experimental paradigm of NOLT and NOR combined fiber recording). First, it was found that the amplitude of calcium signals of 5xFAD mice was weaker than that of WT mice when exposed to objects, which is consistent with the electrophysiology indicating a decrease in presynaptic excitability. For the NOLT experiment, WT mice emitted more calcium signals to the old location, while 5xFAD mice did not show significant differences between the two locations (see Figure 3 e and g, e shows the calcium responses of vCA1 neurons projecting to the mPFC to new and old locations in WT mice, g shows the calcium responses of vCA1 neurons projecting to the mPFC to new and old locations in 5xFAD mice). Similarly, for the NOR experiment, WT mice had stronger calcium signals to the old object, while 5xFAD mice did not show significant differences between the two objects (see Figure 3 f and h, f shows the calcium responses of vCA1 neurons projecting to the mPFC to new and old objects in WT mice, h shows the calcium responses of vCA1 neurons projecting to the mPFC to new and old objects in 5xFAD mice). The results show that the responses of projecting neurons to locations (or objects) in the vCA1-mPFC loop of 5xFAD mice have changed.

[0118] In terms of quantity, the number of connections of the vCA1-mPFC loop in 5xFAD mice is reduced. In terms of quality, the function of the vCA1-mPFC loop in 5xFAD mice is impaired, i.e. Figure 3 Schematic showing the impairment of the vCA1-mPFC loop in 5xFAD mice.

[0119] Chronic chemogenetic and optogenetic activation improves cognitive impairment in 5xFAD mice

[0120] To investigate whether early manipulation of the vCA1-mPFC circuit can rescue the spatial memory deficits in AD mice. Chronic chemogenetic activation was used to modulate the vCA1-mPFC circuit in 5xFAD mice. AAV-CamkIIa-DIO-hm3D-mcherry virus was injected into vCA1 and retroAAV-EF1a-cre virus was injected into mPFC. After 4 weeks of CNO (Clozapine-N-oxide) feeding (see Figure 8 f), cognitive behaviors were performed at 5 months of age in mice (see Figure 4 a). To verify the activation effect of CNO, in vitro electrophysiological recordings were first performed on brain slices, and the addition of CNO was easier to stimulate action potentials than without and after clearing (see Figure 8 g and h, which show the schematic diagram of in vitro electrophysiological experiments for CNO effect test). In addition, the effect of CNO in vivo was also verified using c-Fos staining, and the results showed that after CNO feeding, the fluorescence intensity and number of c-Fos+ cells were much higher than those of the other two groups. In addition, hm3D-labeled cells were basically activated by CNO, see Figure 8 i-k, i shows the schematic diagram of c-Fos immunofluorescence staining combined with hm3D and CNO, blue arrows indicate hm3d-labeled cells, white arrows indicate co-labeled cells, scale bar, 200 μm (left), 20 μm (right); j shows that hm3D combined with CNO produces higher c-Fos fluorescence intensity; k shows the co-labeling ratio of c-Fos+ cells and hm3d-labeled cells, CNO specifically activates hm3d-labeled cells. The above results show that CNO feeding can effectively activate virus-infected cells. Figure 8 l also shows the schematic diagram of Aβ immunofluorescence staining in mPFC after optogenetic activation, white arrows indicate Aβ plaques.

[0121] Next, the cognitive level of 5xFAD mice after chronic chemogenetic modulation was observed, and 5-month-old 5xFAD mice had obvious new location cognitive impairment, and the ability to recognize new locations was improved after activation of the vCA1-mPFC circuit, which was significantly different from the WT group (see Figure 4 c, which shows that chemogenetic activation of the circuit improves the performance of NOLT in 5xFAD mice). However, there was no obvious effect on NOR behavior (see Figure 4 d, which shows that chemogenetic activation of the circuit does not affect the performance of 5xFAD mice in NOR). These results are consistent with the results of optogenetic inhibition. In addition, activation of the vCA1-mPFC circuit can improve the performance of 5xFAD mice in BM, which is reflected in the shortening of the latency of 5xFAD mice to find the target hole (see Figure 4(e.g.) In summary, chronic chemogenetic activation of the vCA1-mPFC loop in 5xFAD mice can improve spatial cognition. Figure 4 The figure shows a schematic diagram of how chronic chemogenetic activation of the vCA1-mPFC loop improves spatial cognitive ability in 5xFAD mice.

[0122] To further achieve peripheral regulation, chronic optogenetic activation was performed. AAV-CamkIIa-ChR2-eYFP virus was injected into vCA1 cells, and an optical fiber was embedded in the mPFC. After 4 weeks, light stimulation was applied for 20 minutes daily for 2 weeks, followed by behavioral measurements in 5-month-old 5xFAD mice. Figure 4 Consistent with the results of chronic chemogenetics, chronic optogenetic activation of the vCA1-mPFC circuitry improved cognitive function in mice in NOLT without affecting performance in NOR (see h). Figure 4 Furthermore, optogenetic activation significantly improved the abilities of 5xFAD mice in BM, primarily manifested in a shorter latency and a reduced number of errors during the testing phase. Figure 4 (j and k). Figure 4 The image shows a schematic diagram illustrating how optogenetic activation of the vCA1-mPFC loop improves spatial cognitive abilities in 5xFAD mice.

[0123] The above demonstrates that chronic chemogenetic and optogenetic activation of the vCA1-mPFC loop can effectively improve spatial cognition in 5xFAD mice. Figure 5 A schematic diagram is also shown showing how chronic chemogenetic and optogenetic activation of the vCA1-mPFC loop improves spatial cognitive abilities in 5xFAD mice.

[0124] Chronic activation of the vCA1-mPFC loop has long-term effects.

[0125] To investigate the long-term improvement effect after establishing a regulatory circuit in 5xFAD mice at 4 months of age, BM and β-amyloid (Aβ) staining were performed on the mice at 6 months of age (see [link to relevant documentation]). Figure 5 Figures a and f show the timelines of behavioral and immunostaining experiments in 5xFAD mice at 6 months of age, where a shows the timelines of behavioral and immunostaining experiments in 5xFAD mice at 6 months of age with chronic optogenetic activation of the vCA1-mPFC circuit. Chemogenetic regulation still had a beneficial effect on 6-month-old mice, primarily manifested in an increased percentage of time spent in the target quadrant by 5xFAD mice (see Figures a and f). Figure 5Figures b and c, b and c show that chronic chemogenetic activation improved BM performance in 6-month-old 5xFAD mice. For Aβ deposition, chronic chemogenetic activation effectively reduced the area of ​​Aβ in vCA1 without altering the amount of Aβ (see Figure b). Figure 5 Figures d and e show an immunofluorescence staining diagram of Aβ plaque deposition in vCA1, and figure e shows the number and area of ​​Aβ plaque deposition in 6-month-old 5xFAD mice after chemogenetic activation. Chronic optogenetic activation also has long-term effects, effectively improving BM cognitive abilities in 6-month-old 5xFAD mice (see Figure 2). Figure 5 g and h, g and h show that chronic optogenetic activation improves BM performance in 5xFAD mice. It also reduces Aβ deposition in mPFC and vCA1 in 5xFAD mice. Figure 5 i and j, i shows a schematic diagram of Aβ immunofluorescence staining in 5xFAD mice during optogenetic activation experiments, j shows that chronic optogenetic activation reduced the number and area of ​​Aβ plaques in the mPFC of 5xFAD mice).

[0126] In summary, early and chronic regulation of the vCA1-mPFC circuit has a long-term improvement effect. Figure 6 A schematic diagram is also shown showing the long-term improvement effect of chronic chemical activation and optogenetic activation of the vCA1-mPFC loop.

[0127] Behavioral stimulation combined with tDCS activation of the vCA1-mPFC circuit can improve spatial cognition in 5xFAD mice.

[0128] To explore a non-invasive method to activate vCA1-mPFC circuit as application. Repetitive anodal transcranial direct current stimulation (tDCS) has been shown to have unique neuroprotective effects in AD patients and AD model mice. In addition, anodal tDCS has long-term effects on tDCS improvement. This study innovatively used a portable device that allows mice to receive tDCS stimulation while being trained in behavior. Previous c-Fos staining showed that BM can effectively activate mPFC and vCA1 neurons, and multiple days throughout the BM training process, BM combined with tDCS was planned to activate the vCA1-mPFC circuit. As for the choice of brain regions, mPFC is more superficial and more suitable for the use of tDCS. To observe the activation of mPFC neurons by tDCS combined with behavior, c-Fos was used in combination with BM. First, AAV1-EF1a-Cre virus was injected into vCA1, and AAV-EF1a-DIO-mcherry virus was injected into mPFC to achieve cell body labeling of vCA1 projections in mPFC cells (i.e., label mPFC neuron cell bodies that receive projections from vCA1). Three weeks later, tDCS electrode implantation surgery was performed. Mice were divided into Barnes maze group and home cage group, and each group was further divided into tDCS group and Sham group (see Figure 6 Figure 1 shows the c-Fos staining experiment paradigm of tDCS combined with behavior). The results showed that BM can activate more mPFC cells, which is reflected in the number of c-Fos positive cells in the BM(sham) group and the BM(tDCS) group being higher than the other two groups. In addition, tDCS combined with BM can specifically activate the vCA1-mPFC circuit, which is reflected in the BM(tDCS) group having more co-labeled cells than the other groups Figure 6 Figure 1 shows the c-Fos staining experiment paradigm of tDCS combined with behavior). The results showed that BM can activate more mPFC cells, which is reflected in the number of c-Fos positive cells in the BM(sham) group and the BM(tDCS) group being higher than the other two groups. In addition, tDCS combined with BM can specifically activate the vCA1-mPFC circuit, which is reflected in the BM(tDCS) group having more co-labeled cells than the other groups

[0129] Next, one week after tDCS surgery, tDCS combined with BM training was performed, followed by behavior testing of 5-month-old mice. 5xFAD mice were divided into three groups: BM(tDCS) group, Home(tDCS) group, and BM(Sham) group, the BM(tDCS) group was trained during the BM test, the Home cage(tDCS) group received the same condition of tDCS stimulation in the cage, and the Sham group received tDCS surgery but was not powered on Figure 6d, which shows the experimental paradigm of tDCS combined with BM). The BM results show that tDCS combined with behavior can better improve the performance of BM, mainly reflected in the training process of BM. The BM(tDCS) group learns faster (see Figure 6 e) of FIG. 1. As for the BM test phase, both the BM(tDCS) group and the Home cage(tDCS) group reduced the latency and the number of errors. The BM(tDCS) group has a better improvement effect than the Home(tDCS) group in the time percentage of the target quadrant index (see Figure 6 f) of FIG. 1, Figure 7 e and f of FIG. 1 show that tDCS combined with behavior improves the performance of 5-month-old 5xFAD mice in BM. It is also interesting to see whether tDCS has a universal effect on similar behavior, so the water maze test is conducted. The BM(tDCS) group significantly shortens the time to reach the platform for the first time (see Figure 7 a and b of FIG. 2) These results show that tDCS can improve the spatial cognitive ability of 5xFAD mice, and tDCS combined with BM activation of the vCA1-mPFC loop can have a better improvement effect.

[0130] To explore whether tDCS has a long-term improvement effect, water maze experiments, Aβ and Iba1 staining were conducted on 6-month-old 5xFAD mice. Surprisingly, the cognitive improvement of 5xFAD mice by tDCS can last until 6 months of age, and tDCS combined with behavior shows a more significant improvement effect. The BM(tDCS) group not only increases the number of platform crossings and the time percentage in the target quadrant, but also shortens the time to reach the platform for the first time (see Figure 7 c of FIG. 3, which shows that tDCS combined with behavior can better improve the performance of 6-month-old 5xFAD mice in the water maze).

[0131] A large number of studies have shown that there is a connection between pathological Aβ deposition and microglia in AD. Therefore, Aβ and microglial Iba1 as AD pathological markers were immunofluorescently stained (see Figure 7 d of FIG. 4, which shows the schematic diagram of Aβ and Iba1 immunofluorescent staining). The BM(tDCS) group reduces the area of Aβ plaques and Iba1+ cells (see Figure 6 e and f of FIG. 4, e and f show that the tDCS combined with the BM group reduces Aβ deposition area and Iba1 cells). tDCS can reduce the number of microglia and the proportion of microglia co-labeled with Aβ (see Figure 7 g and h of FIG. 4, tDCS reduces the number and proportion of Iba1 co-labeled with Aβ plaques). The above results show that tDCS can improve the pathological markers of 5xFAD mice, and tDCS combined with behavior can produce a better improvement effect by activating the vCA1-mPFC loop. Among them ​A schematic diagram showing that tDCS combined with behavioral activation of mPFC neurons can improve the spatial cognitive ability of 5xFAD mice is also shown, ​ A schematic diagram showing that tDCS combined with behavior has a long-term improvement effect is also shown.

[0132] In summary, the following conclusions can be drawn from the above studies: (1) Chronic regulation of the vCA1-mPFC circuit can improve the spatial cognition and pathology of 5xFAD mice and has a long-term effect; (2) The role of vCA1-mPFC in spatial cognition is verified; (3) The improvement effect of tDCS combined with behavioral activation of brain regions can bring inspiration for clinical treatment.

[0133] A large number of technical features are described in the specification of the present application, which are distributed in various technical solutions. If all possible combinations of technical features (i.e. technical solutions) of the present application are listed, the specification will be too long. In order to avoid this problem, each technical feature disclosed in the above summary of the application, each technical feature disclosed in the following embodiments and examples, and each technical feature disclosed in the drawings can be freely combined to form various new technical solutions (these technical solutions are considered to have been described in the specification), unless such combination of technical features is technically infeasible. For example, features A+B+C are disclosed in one example, features A+B+D+E are disclosed in another example, features C and D are equivalent technical means that play the same role, and only one of them can be used technically, and feature E can be combined with feature C technically. Therefore, the scheme of A+B+C+D should not be considered as having been described because it is technically infeasible, and the scheme of A+B+C+E should be considered as having been described.

[0134] All documents mentioned in the present application are considered to be included in the disclosure of the present application as a whole, so that they can be used as a basis for modification if necessary. In addition, it should be understood that those skilled in the art can make various modifications or modifications to the present application after reading the above disclosure of the present application, and these equivalent forms also fall within the scope of the present application.

Claims

1. A system for treating Alzheimer's disease based on the ventral hippocampus-prefrontal loop, characterized in that, include: A ventral hippocampus-prefrontal loop activation device is used to activate neurons in the ventral hippocampus of a patient to be treated, thereby activating neurons in the medial prefrontal cortex through the ventral hippocampus-prefrontal loop, and thus improving Alzheimer's disease lesions in the ventral hippocampus and the medial prefrontal cortex.

2. The system as described in claim 1, characterized in that, The Alzheimer's disease lesions include β-amyloid plaques.

3. The system as described in claim 1, characterized in that, The improvement of Alzheimer's disease lesions in the ventral hippocampus and medial prefrontal cortex includes a reduction in the number and area of ​​β-amyloid plaques in the ventral hippocampus and medial prefrontal cortex.

4. The system as described in claim 3, characterized in that, By reducing the number and area of ​​β-amyloid plaques, the patient's spatial cognitive ability is improved.

5. A system for treating Alzheimer's disease based on the ventral hippocampus-prefrontal loop, characterized in that, include: A ventral hippocampus-prefrontal loop activation device is used to activate neurons in the ventral hippocampus of a patient to be treated, thereby activating neurons in the medial prefrontal cortex through the ventral hippocampus-prefrontal loop. A behavioral training device configured to provide spatial cognitive training to the patient; During the treatment of the patient, the ventral hippocampus-prefrontal loop activation device and the behavioral training device operate simultaneously. Thus, while the patient receives spatial cognitive training, they also receive stimulation from the ventral hippocampus-prefrontal loop activation device, thereby improving the Alzheimer's disease lesions in the ventral hippocampus and medial prefrontal cortex, and consequently improving the patient's spatial cognitive ability.

6. The system as described in claim 5, characterized in that, The ventral hippocampus-prefrontal loop activation device includes a neural electrode implanted in the patient's ventral hippocampus.

7. The system as described in claim 5, characterized in that, The system also includes a control device configured to control the ventral hippocampus-prefrontal loop activation device to send stimulation signals to neurons in the ventral hippocampus, thereby upregulating or downregulating the function of neurons in the ventral hippocampus.

8. An Alzheimer's disease assessment system, characterized in that, include: A behavioral training device configured to provide spatial cognitive training to a patient to be assessed; A data acquisition device configured to acquire data of the ventral hippocampus-prefrontal loop of the patient to be evaluated during the spatial cognitive training. An assessment device configured to evaluate data acquired from the ventral hippocampus-prefrontal loop of the patient to be assessed, provide an assessment result of the patient's spatial cognitive impairment, and further provide an assessment result of the degree of subsequent cognitive impairment of the patient.

9. The evaluation system as described in claim 8, characterized in that, The data from the ventral hippocampus-prefrontal loop include the number of neurons in the medial prefrontal cortex that receive projections from the ventral hippocampus and / or the electrophysiological characteristics of neurons in the medial prefrontal cortex that receive projections from the ventral hippocampus.

10. The evaluation system as described in claim 8, characterized in that, The data for the ventral hippocampus-prefrontal loop includes the number of connections between neurons in the patient's ventral hippocampus and neurons in the patient's medial prefrontal cortex.

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