piRNAs in the Olfactory Bulb Related to Fear Conditioning can Migrate from the Brain to the Germline

Small RNAs have been shown to be crucial in the mechanisms of transgenerational memory. Precisely, piRNAs have previously been thought to only exist in the germline and are related to transgenerational memory. To determine if the offspring inherits memory due to piRNA transmission, we conducted odor fear-conditioning tests and identified a piRNA that increased in abundance. That piRNA is thought to be involved in memory formation of the fear-conditioning test. We then used a virus vector to manipulate a single nucleotide of that piRNA sequence to see if it can migrate from the olfactory bulb to the germline. The data should theoretically indicate whether the mutant piRNA has migrated from the olfactory bulb to the germline of the mice.

Increased Sociability in Mice Lacking Intergenic Dlx Enhancers

The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters (Dlx1/2, Dlx3/4, and Dlx5/6) with cis-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and Dlx5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams–Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i(–/–), I12b(–/–)). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2. The loss of the I56i enhancer resulted in a transient decrease in GABA+ cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development.

Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice

Background It is widely accepted that mitochondria have a direct impact on neuronal function and survival. Oxidative stress caused by mitochondrial abnormalities play an important role in the pathophysiology of lipopolysaccharide (LPS)-induced memory impairment. Elamipretide (SS-31) is a novel mitochondrion-targeted antioxidant. However, the impact of elamipretide on the cognitive sequelae of inflammatory and oxidative stress is unknown. Methods We utilized MWM and contextual fear conditioning test to assess hippocampus-related learning and memory performance. Molecular biology techniques and ELISA were used to examine mitochondrial function, oxidative stress, and the inflammatory response. TUNEL and Golgi-staining was used to detect neural cell apoptosis and the density of dendritic spines in the mouse hippocampus. Results Mice treated with LPS exhibited mitochondrial dysfunction, oxidative stress, an inflammatory response, neural cell apoptosis, and loss of dendritic spines in the hippocampus, leading to impaired hippocampus-related learning and memory performance in the MWM and contextual fear conditioning test. Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests. Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity. Conclusion These findings indicate that LPS-induced memory impairment can be attenuated by the mitochondrion-targeted antioxidant elamipretide. Consequently, elamipretide may have a therapeutic potential in preventing damage from the oxidative stress and neuroinflammation that contribute to perioperative neurocognitive disorders (PND), which makes mitochondria a potential target for treatment strategies for PND.

Combination of isoflurane and propofol, a means for general anesthesia in the surgery of perioperative cerebral hypoperfusion rats to avoid cognitive impairment

Background: Perioperative cerebral hypoperfusion often occurs. However, the underlying mechanism and targeted interventions remain mostly to be determined. Anesthetic isoflurane induces neuronal injury via endoplasmic reticulum (ER) stress, whereas sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common combination of anesthesia for patient, on ER stress and the associated cognitive function remain unknown. Methods: We therefore set out to determine the effects of isoflurane plus propofol on the ER stress and cognitive function in the rats insulted by cerebral hypoperfusion. The rats received isoflurane alone (1.9%), propofol alone (40 mg·kg -1 ·h -1 ) or a combination of isoflurane and propofol (1% and 20 mg·kg -1 ·h -1 or 1.4% and 10 mg·kg -1 ·h -1 ). Behavior studies (Fear Conditioning test) and biochemical analyses (Nissl staining and western blotting for the harvested rat brain tissues) were employed in the studies. Results: We found that the combination of 1% isoflurane plus 20 mg·kg -1 ·h -1 propofol attenuated the cerebral hypoperfusion-induced cognitive impairment and the ER stress. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and the combination of isoflurane and propofol was able to preserve cognitive function in the rats after cerebral hypoperfusion via prevention of ER stress. These findings have established a system to study the strategy in preventing and treating perioperative cerebral hypoperfusion, leading to promotion of the future larger scale studies.

Combination of isoflurane and propofol, a means for general anesthesia in the surgery of perioperative cerebral hypoperfusion rats to avoid cognitive impairment

Background: Perioperative cerebral hypoperfusion often occurs. However, the underlying mechanism and targeted interventions remain mostly to be determined. Anesthetic isoflurane induces neuronal injury via endoplasmic reticulum (ER) stress, whereas sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common combination of anesthesia for patient, on ER stress and the associated cognitive function remain unknown. Methods: We therefore set out to determine the effects of isoflurane plus propofol on the ER stress and cognitive function in the rats insulted by cerebral hypoperfusion. The rats received isoflurane alone (1.9%), propofol alone (40 mg·kg -1 ·h -1 ) or a combination of isoflurane and propofol (1% and 20 mg·kg -1 ·h -1 or 1.4% and 10 mg·kg -1 ·h -1 ). Behavior studies (Fear Conditioning test) and biochemical analyses (Nissl staining and western blotting for the harvested rat brain tissues) were employed in the studies. Results: We found that the combination of 1% isoflurane plus 20 mg·kg -1 ·h -1 propofol attenuated the cerebral hypoperfusion-induced cognitive impairment and the ER stress. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and the combination of isoflurane and propofol was able to preserve cognitive function in the rats after cerebral hypoperfusion via prevention of ER stress. These findings have established a system to study the strategy in preventing and treating perioperative cerebral hypoperfusion, leading to promotion of the future larger scale studies.