Behavioral Effects of Deep Brain Stimulation of the Anterior Nucleus of Thalamus, Entorhinal Cortex and Fornix in a Rat Model of Alzheimer＇s Disease

Background：Recent clinical and preclinical studies have suggested that deep brain stimulation （DBS） can be used as a tool to enhance cognitive functions.The aim of the present study was to investigate the impact of DBS at three separate targets in the Papez circuit,including the anterior nucleus of thalamus （ANT）,the entorhinal cortex （EC）,and the fornix （FX）,on cognitive behaviors in an Alzheimer＇s disease （AD） rat model.Methods：Forty-eight rats were subjected to an intrahippocampal injection ofamyloid peptides 1-42 to induce an AD model.Rats were divided into six groups：DBS and sham DBS groups of ANT,EC,and FX.Spatial learning and memory were assessed by the Morris water maze （MWM）.Recognition memory was investigated by the novel object recognition memory test （NORM）.Locomotor and anxiety-related behaviors were detected by the open field test （OF）.By using two-way analysis of variance （ANOVA）,behavior differences between the six groups were analyzed.Results：In the MWM,the ANT,EC,and FX DBS groups performed differently in terms of the time spent in the platform zone （F（2.23） =6.04,P ＜ 0.01）,the frequency of platform crossing （F（2,23） =11.53,P ＜ 0.001）,and the percent time spent within the platform quadrant （F（2,23） =6.29,P ＜ 0.01）.In the NORM,the EC and FX DBS groups spent more time with the novel object,although the ANT DBS group did not （F（2,23） =10.03,P ＜ 0.001）.In the OF,all of the groups showed a similar total distance moved （F（1.42） =1.14,P =0.29）and relative time spent in the center （F（2,42） =0.56,P =0.58）.Conclusions：Our results demonstrated that DBS of the EC and FX facilitated hippocampus-dependent spatial memory more prominently thanANT DBS.In addition,hippocampus-independent recognition memory was enhanced by EC and FX DBS.None of the targets showed side-effects of anxiety or locomotor behaviors.

Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain

Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.

Icariin and differential protein expression in the entorhinal area of senescence-accelerated mouse prone 8 mice

The present study sought to explore the mechanism of action by which icariin, an active component of Epimedii Herba, treats Alzheimer＇s disease at the proteomics level. Two-dimensional gel electrophoresis was used to isolate total protein from the entorhinal cortex of senescence-accelerated mouse prone 8 （SAMP8） mice, and differential protein spots were obtained. Corresponding peptide mass fingerprinting was conducted through mass spectrography to identify differential protein spots. Twenty-six differential protein spots were found in the entorhinal area of SAMP8 mice at 8 weeks following intragastdc perfusion with icariin and double distilled water. Fourteen spots were identified, which were involved in mitochondrial energy metabolism, oxidative stress, and neuronal function. The results revealed that icafiin can regulate the expression of various proteins in the entorhinal cortex of SAMP8 mice, and treat Alzheimer＇s disease by improving mitochondfial function, suppressing oxidative stress, inhibiting neural cell apoptosis, and protecting neurons.

Brain imaging of mild cognitive impairment and Alzheimer's disease

The rapidly increasing prevalence of cognitive impairment and Alzheimer＇s disease has the potential to create a major worldwide healthcare crisis. Structural MRI studies in patients with Alzheimer＇s disease and mild cognitive impairment are currently attracting considerable interest. It is extremely important to study early structural and metabolic changes, such as those in the hippocampus, entorhinal cortex, and gray matter structures in the medial temporal lobe, to allow the early detection of mild cognitive impairment and AIzheimer＇s disease. The microstructural integrity of white matter can be studied with diffusion tensor imaging. Increased mean diffusivity and decreased fractional anisotropy are found in subjects with white matter damage. Functional imaging studies with positron emission tomography tracer compounds enable detection of amyloid plaques in the living brain in patients with Alzheimer＇s disease. In this review, we will focus on key findings from brain imaging studies in mild cognitive impairment and Alzheimer＇s disease, including structural brain changes studied with MRI and white matter changes seen with diffusion tensor imaging, and other specific imaging methodologies will also be discussed.

Lower serum expression of miR-181c-5p is associated with increased plasma levels of amyloid-beta 1-40 and cerebral vulnerability in normal aging

Background:Previous studies have shown that expression levels of miR-181c are downregulated by amyloid-β(Aβ)deposition and chronic cerebral hypoperfusion,both factors largely associated with the development of AD.Moreover,reduced 2-[18F]fluoro-2-deoxy-D-glucose(FDG)-PET brain metabolism and volume loss of regions of the medial temporal lobe have been generally recognized as hallmarks of AD.Based on this evidence,we have here investigated potential associations between serum levels of miR-181c-5p and these AD signatures in asymptomatic elderly subjects.Methods:Ninety-five normal elderly subjects underwent clinical,cognitive,structural MRI,and FDG-PET explorations.Serum expression levels of miR-181c-5p and plasma Aβ concentrations were further analyzed in this cohort.Regression analyses were performed to assess associations between serum miR-181c-5p levels and cognitive functioning,plasma Aβ,structural and metabolic brain changes.Results:Decreased serum expression of miR-181c-5p was associated with increased plasma levels of Aβ1–40,deficits in cortical glucose metabolism,and volume reduction of the entorhinal cortex.No significant associations were found between lower miR-181c-5p levels and cognitive deficits or cortical thinning.Conclusions:These findings suggest that deregulation of serum miR-181c-5p may indicate cerebral vulnerability in late life.

Global action against dementia call for innovations

With the fast-growing aging population, dementia has become a health priority.However, in the past, medicine was largely dealing with physical disorders, and not enough knowledge and experience have been accumulated for mental health. The main and first symptom of this disorder is the loss of memory; hence, understanding the hippocampal formation is the key to tackling dementia. In 2007, a milestone book titled "Hippocampus Book" was published. One of the authors/editors is the 2014 Nobel Laureate in Physiology and Medicine, Professor John O'Keefe. It is a MUST-READ encyclopedia about the hippocampal formation, for those who wish to commit themselves to helping the patients with dementia. The formation consists of the hippocampus,entorhinal cortex, subiculum, presubiculum, parasubiculum, and dentate gyrus. The hippocampus is further divided into CA1, CA2, and CA3. The entorhinal cortex is the gateway of receiving all sensory information from the neocortex, while the subiculum is the exit for the efferent projections to the neocortex. Memory is divided into short-term and long-term memory. The former does not require protein synthesis while the latter does. The electrophysiological activities of creating these memories are short-term potentiation and long-term potentiation respectively. In most cases, the entorhinal cortex is the first structure to be damaged, and even short-term memory cannot be created. However, all except spatial memory are stored in the neocortex. Damage to the hippocampal formation would not affect the storage and retrieval of memories. Hence, past memories may remain intact in the early phases of the disorder. This devastating progressive disease has no cure. However, the highly plastic hippocampal formation may offer us some hope. It is the responsibility of the pharmaceutical industries to develop new drugs. Clinicians should add their efforts to the endeavor. The author would suggest that they explore insulin-like growth factors,brain stimulation, cell transplantation, and animal-assisted therapy to find some innovative solutions to help patients with dementia. As the current status of neuroscience stands, the animal-assisted therapy seems to stand out among all methods. It alleviates symptoms and stabilizes the ailment.