Interaction between theta-phase and spike-timing dependent plasticity simulates theta induced memory effects

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between pre- and post-synaptic neurons, known as spike-timing-dependent plasticity (STDP). STDP, together with theta-phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with synchronous and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the synchronous condition, as compared to the asynchronous conditions, and was specific to theta modulated inputs. Importantly, simulations with and without each mechanism suggest that both STDP and theta-phase-dependent plasticity are necessary to replicate the findings. Together, the results indicate a role for circuit-level mechanisms, which bridges the gap between slice preparation studies and human memory.

Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.

Telomerase increasing compound protects hippocampal neurons from amyloid beta toxicity by enhancing the expression of neurotrophins and plasticity related genes

The telomerase reverse transcriptase protein, TERT, is expressed in the adult brain and its exogenic expression protects neurons from oxidative stress and from the cytotoxicity of amyloid beta (Aβ). We previously showed that telomerase increasing compounds (AGS) protected neurons from oxidative stress. Therefore, we suggest that increasing TERT by AGS may protect neurons from the Aβ-induced neurotoxicity by influencing genes and factors that participate in neuronal survival and plasticity. Here we used a primary hippocampal cell culture exposed to aggregated Aβ and hippocampi from adult mice. AGS treatment transiently increased TERT gene expression in hippocampal primary cell cultures in the presence or absence of Aβ and protected neurons from Aβ induced neuronal degradation. An increase in the expression of Growth associated protein 43 (GAP43), and Feminizing locus on X-3 genes (NeuN), in the presence or absence of Aβ, and Synaptophysin (SYP) in the presence of Aβ was observed. GAP43, NeuN, SYP, Neurotrophic factors (NGF, BDNF), beta-catenin and cyclin-D1 expression were increased in the hippocampus of AGS treated mice. This data suggests that increasing TERT by pharmaceutical compounds partially exerts its neuroprotective effect by enhancing the expression of neurotrophic factors and neuronal plasticity genes in a mechanism that involved Wnt/beta-catenin pathway.

Primary Hippocampal Cell Culture and Its Application in Medical Researches

Studies in neuroscience can be performed in vitro and in vivo. In vivo studies will show significant results, but it is difficult to do and time-consuming. Primary hippocampal cell culture widely has used in neurobiological studies such as identifying the cellular mechanism of proteins, neuronal activity, and characteristics. The results of studies conducted on this cell culture will be very useful in discovering pathogenesis of a disease, the effect of a substance on the neuron, and neural basis of memory and learning. However, currently in Indonesia, primary hippocampal cell culture is still rare and difficult to do. The purpose of this study was to demonstrate that primary hippocampal cell culture can be done and developed in Indonesia and to review the application of it in medical researches. The study was an experimental study by obtaining neurons from animal’s hippocampus was conducted in 2015–2018 at Department of Cell Biology, Graduate School of Medicine Osaka University and Faculty of Medicine Universitas Padjadjaran. The experimental animal was mice embryo gathered 17.5-days postcoitus. Enzymatic and mechanical methods collected primary hippocampal cells. The cells counted and cultured, which later were observed to see neuron differentiation. The average number of culture cells from 3 embryonic’s hippocampus were 2.39×106. Neuron differentiation observed on the first day and more visible and numerous on the third day after plating. In conclusion, primary hippocampal cell culture using hippocampus from one hemisphere of embryonic mice brain showed a sufficient number of cells to carry out research and showed neuron differentiation. KULTUR SEL PRIMER HIPOKAMPUS DAN PENGGUNAANNYA DALAM RISET KEDOKTERANPenelitian dalam neurobiologi dapat dilakukan secara in vitro dan in vivo. Penelitian secara in vivo sangat berdampak hasilnya, namun sulit dan memakan waktu yang lama. Kultur sel primer hipokampus banyak digunakan dalam penelitian neurobiologi seperti melihat mekanisme protein seluler, serta aktivitas dan karakteristik neuron. Hasil penelitian yang dilakukan pada kultur sel ini akan sangat bermanfaat dalam menemukan proses suatu penyakit, efek suatu zat terhadap sel saraf, dan kemampuan belajar serta memori. Akan tetapi, saat ini di Indonesia kultur sel primer hipokampus masih jarang dan sulit dilakukan. Tujuan penelitian ini adalah menunjukkan bahwa kultur sel hipokampus primer dapat dilakukan dan dikembangkan di Indonesia, serta meninjau penerapannya dalam riset kedokteran. Penelitian ini merupakan studi eksperimental dengan mengoleksi neuron dari hipokampus hewan coba yang dilakukan pada tahun 2015–2018 di Department of Cell Biology, Graduate School of Medicine Osaka University dan Fakultas Kedokteran Universitas Padjadjaran. Hewan coba berupa embrio mencit hari ke-17,5 pascakoitus. Sel primer hipokampus dikoleksi untuk dihitung dan dikultur menggunakan metode enzimatik dan mekanik. Observasi neuron pada kultur dilanjutkan dengan mengamati diferensiasi neuron. Rerata jumlah sel kultur dari 3 hipokampus adalah 2,39×106. Diferensiasi neuron sudah tampak pada hari pertama dan makin jelas serta tampak pada hari ketiga pascapenanaman. Simpulan, kultur sel primer hipokampus menggunakan hipokampus dari salah satu sisi hemisfer otak menunjukkan jumlah sel yang cukup untuk melakukan suatu penelitian dan menunjukkan diferensiasi dari neuron.