Dorsal dentate gyrus mediated enriched environment-induced anxiolytic and antidepressant effects in cortical infarcted mice.

Anxiety and depression are the most common mental health disorders worldwide, each affecting around 30% stroke survivors. These complications not only affect the functional recovery and quality of life in stroke patients, but also are distressing for caregivers. However, effective treatments are still lacking. Enriched environment (EE), characterized with novel and multi-dimensional stimulation, has been reported to exert therapeutic effects on physical and cognitive function. In addition, EE also had potential positive effects on emotional disorders after ischemic stroke; however, the underling mechanisms have not been well elucidated. This study aimed to explore the effectiveness of EE on emotional disorders after cerebral ischemia and its underling mechanism. Sensorimotor cortical infarction was induced by photothrombosis with stable infarct location and volume, resulting in motor dysfunction, anxiety and depression-like behaviors in mice, with decreased ALFF and ReHo values and decreased c-fos expression in the infarction area and adjacent regions. Seven days' EE treatment significantly improved motor function of contralateral forelimb and exhibited anxiolytic and antidepressant effects in infarcted mice. Compared to the mice housing in a standard environment, those subjected to acute EE stimulation had significantly increased ALFF and ReHo values in the bilateral somatosensory cortex (S1, S2), dorsal dentate gyrus (dDG), dorsal CA1 of hippocampus (dCA1), lateral habenular nucleus (LHb), periaqueductal gray (PAG), ipsilateral primary motor cortex (M1), retrosplenial cortex (RSC), parietal association cortex (PtA), dorsal CA3 of hippocampus (dCA3), claustrum (Cl), ventral pallidum (VP), amygdala (Amy), and contralateral auditory cortex (Au). Some of, but not all, the ipsilateral brain regions mentioned above showed accompanying increases in c-fos expression with the most significant changes in the dDG. The number of FosB positive cells in the dDG, decreased in infarcted mice, was significantly increased after chronic EE treatment. Chemogenetic activation of dDG neurons reduced anxiety and depressive-like behaviors in infarcted mice, while neuronal inhibition resulted in void of the anxiolytic and antidepressant effects of EE. Altogether, these findings indicated that dDG neurons may mediate EE-triggered anxiolytic and antidepressant effects in cortical infarcted mice.

Prefrontal projections modulate recurrent circuitry in the insular cortex to support short-term memory.

Short-term memory (STM) maintains information during a short delay period. How long-range and local connections interact to support STM encoding remains elusive. Here, we tackle the problem focusing on long-range projections from the medial prefrontal cortex (mPFC) to the anterior agranular insular cortex (aAIC) in head-fixed mice performing an olfactory delayed-response task. Optogenetic and electrophysiological experiments reveal the behavioral importance of the two regions in encoding STM information. Spike-correlogram analysis reveals strong local and cross-region functional coupling (FC) between memory neurons encoding the same information. Optogenetic suppression of mPFC-aAIC projections during the delay period reduces behavioral performance, the proportion of memory neurons, and memory-specific FC within the aAIC, whereas optogenetic excitation enhances all of them. mPFC-aAIC projections also bidirectionally modulate the efficacy of STM-information transfer, measured by the contribution of FC spiking pairs to the memory-coding ability of following neurons. Thus, prefrontal projections modulate insular neurons' functional connectivity and memory-coding ability to support STM.

Transient Delay-Period Activity of Agranular Insular Cortex Controls Working Memory Maintenance in Learning Novel Tasks.

Whether transient or sustained neuronal activity during the delay period underlies working memory (WM) has been debated. Here, we report that transient, but not sustained, delay-period activity in mouse anterior agranular insular cortex (aAIC) plays a dominant role in maintaining WM information during learning of novel olfactory tasks. By optogenetic screening over 12 brain regions, we found that suppressing aAIC activity markedly impaired olfactory WM maintenance during learning. Single-unit recording showed that odor-selective aAIC neurons with predominantly transient firing patterns encoded WM information. Both WM task performance and transient-neuron proportion were enhanced and reduced by activating and suppressing the delay-period activity of the projection from medial prefrontal cortex (mPFC) to aAIC. The ability of mice to resist delay-period distractors also correlated with an increased percentage of transient neurons. Therefore, transient, but not sustained, aAIC neuronal activity during the delay period is largely responsible for maintaining information while learning novel WM tasks.

In vitro evaluation of the ZX11 magnesium alloy as potential bone plate: Degradability and mechanical integrity.

Considering the excellent biocompatibility of magnesium (Mg) alloys and their better mechanical properties compared to polymer materials, a wrought MgZnCa alloy with low contents of Zn (0.7 wt%) and Ca (0.6 wt%) (ZX11) was developed by twin roll casting (TRC) technology as potential biodegradable bone plates. The degradability and cell response of the ZX11 alloy were evaluated in vitro, as well as the mechanical integrity according to tensile tests after immersion. The results revealed a slightly higher degradation rate for the rolled ZX11, in comparison to that of the annealed one. It was mainly caused by the deformation twins and residual strain stored in the rolled alloy, which also seemed to promote localized degradation, thereby leading to a relatively fast deterioration in mechanical properties, especially the fracture strain/elongation. In contrast, after the annealing treatment, the alloy showed relatively lower strength, yet a lower degradation rate and quite stable elongation during the initial weeks of immersion were observed. More importantly, the ZX11 alloy, regardless of the annealing treatment, showed good in vitro cytocomopatibility regarding human primary osteoblasts. The assessment indicates the rolled alloy as a good choice for implantation sites where relatively high mechanical strength is needed during the early implantation, while the annealed alloy is a potential candidate for the sites which demand stable mechanical integrity during service. STATEMENT OF SIGNIFICANCE: The development of magnesium alloys as bone implants demands low degradation rate to gain not only a slow hydrogen evolution, but also a stable mechanical integrity during service. The present study develops a micro-alloyed MgZnCa alloy via twin roll casting (TRC) technology. It exhibited limited cytotoxicity, fairly low degradation rate and comparable strength to the reported Mg-1Zn-5Ca alloy which has been used as bone screws in clinical trials, indicating the great potential application as biodegradable bone implants. Furthermore, it showed good mechanical integrity during immersion to support the defect healing. Our results can aid other researchers to evaluate the mechanical integrity of biodegradable materials and to pay more attention to the effect of degradation behaviour on mechanical integrity of materials.

Active information maintenance in working memory by a sensory cortex.

Working memory is a critical brain function for maintaining and manipulating information over delay periods of seconds. It is debated whether delay-period neural activity in sensory regions is important for the active maintenance of information during the delay period. Here, we tackle this question by examining the anterior piriform cortex (APC), an olfactory sensory cortex, in head-fixed mice performing several olfactory working memory tasks. Active information maintenance is necessary in these tasks, especially in a dual-task paradigm in which mice are required to perform another distracting task while actively maintaining information during the delay period. Optogenetic suppression of neuronal activity in APC during the delay period impaired performance in all the tasks. Furthermore, electrophysiological recordings revealed that APC neuronal populations encoded odor information in the delay period even with an intervening distracting task. Thus, delay activity in APC is important for active information maintenance in olfactory working memory.

Different effects of single protein vs. protein mixtures on magnesium degradation under cell culture conditions.

Bovine serum albumin (BSA) or fetal bovine serum (FBS), as the protein component, is usually added into solution to study the influence of proteins on Mg degradation. However, the specific character of proteins used and the interaction between organic molecules in FBS do not draw enough attention. This study investigated the influence of BSA, fibrinogen (Fib) and FBS on Mg degradation in Hanks' balanced salt solution without (HBSS) or with calcium (HBSSCa) and Dulbecco's modified eagle medium Glutamax-I (DMEM). The results reveal that the effect of BSA, Fib and FBS on the degradation rate of Mg is time- and media-dependent, as a result of the overlap of protein adsorption, binding/chelating to ions and interaction between organic molecules. The binding/chelating of proteins and/or the possible effect of proteins on the kinetics of products formation lead to the formation of different degradation precipitates on Mg surface in HBSS. The interaction between proteins and Ca2+/PO43- accelerates the formation of Ca-P salts in HBSSCa and DMEM, thereby impeding the degradation of Mg. Moreover, the interplay between organic molecules and the specific character of proteins are highlighted by the cooperative (in media + FBS) or competitive (in DMEM + BSA + Fib) effect of proteins in the presence of more kinds of proteins and the different effect of BSA and Fib on the degradation of Mg. Therefore, the addition of proteins to testing medium is necessary for in vitro tests and DMEM + 10% FBS is recommended as the in vitro testing medium to present an in vivo-like degradation for Mg. STATEMENT OF SIGNIFICANCE: The present study emphasizes the difference between proteins, and the difference between single protein and protein mixture in view of the effect on Mg degradation. The results highlight the importance of the interaction between proteins in media, which can increase or decrease the degradation of Mg compared to the single protein. It can aid other researchers to understand the effect of proteins on Mg degradation and to pay more attention to the interaction of organic molecules on Mg degradation when more kinds of organic molecules are used in medium, especially for FBS. The submitted work could be of significant importance to other researchers working in the related fields, thus appealing to the readers of Acta Biomaterialia.

Adsorption of Proteins on Degradable Magnesium-Which Factors are Relevant?

Although the adsorption of proteins on the Mg surface was ascribed to be the main reason for the effect of proteins on magnesium (Mg) degradation, few studies about the adsorption of proteins on the Mg surface were performed due to the labile circumstances during immersion. In the present study, the adsorption of bovine serum albumin (BSA) and fibrinogen (Fib) on the Mg surface during and after immersion was extensively investigated in different media for the first time. The results revealed that BSA and Fib showed a similar adsorption trend on the Mg surface during and after immersion, and they adsorbed more on the Mg surface in Hank's balanced salt solution (HBSS) than in Dulbecco's modified Eagle medium Glutamax-I (DMEM). The possible influence factors for protein adsorption, such as pH, surface roughness, and wettability, were considered to elucidate different adsorption in HBSS and DMEM. It was found that the participation of Ca2+ in the formation of degradation products largely affected the degradation rate of Mg, changed surface roughness, compactness, and surface charge during immersion, which largely suppressed the adsorption of proteins on the Mg surface.

Controllable degradation of medical magnesium by electrodeposited composite films of mussel adhesive protein (Mefp-1) and chitosan.

To control the degradation rate of medical magnesium in body fluid environment, biocompatible films composed of Mussel Adhesive Protein (Mefp-1) and chitosan were electrodeposited on magnesium surface in cathodic constant current mode. The compositions and structures of the films were characterized by atomic force microscope (AFM), scanning electron microscope (SEM) and infrared reflection absorption spectroscopy (IRAS). And the corrosion protection performance was investigated using electrochemical measurements and immersion tests in simulated body fluid (Hanks' solution). The results revealed that Mefp-1 and chitosan successfully adhered on the magnesium surface and formed a protective film. Compared with either single Mefp-1 or single chitosan film, the composite film of chitosan/Mefp-1/chitosan (CPC (chitosan/Mefp-1/chitosan)) exhibited lower corrosion current density, higher polarization resistance and more homogenous corrosion morphology and thus was able to effectively control the degradation rate of magnesium in simulated body environment. In addition, the active attachment and spreading of MC3T3-E1 cells on the CPC film coated magnesium indicated that the CPC film was significantly able to improve the biocompatibility of the medical magnesium.

Medial prefrontal activity during delay period contributes to learning of a working memory task.

Cognitive processes require working memory (WM) that involves a brief period of memory retention known as the delay period. Elevated delay-period activity in the medial prefrontal cortex (mPFC) has been observed, but its functional role in WM tasks remains unclear. We optogenetically suppressed or enhanced activity of pyramidal neurons in mouse mPFC during the delay period. Behavioral performance was impaired during the learning phase but not after the mice were well trained. Delay-period mPFC activity appeared to be more important in memory retention than in inhibitory control, decision-making, or motor selection. Furthermore, endogenous delay-period mPFC activity showed more prominent modulation that correlated with memory retention and behavioral performance. Thus, properly regulated mPFC delay-period activity is critical for information retention during learning of a WM task.

The protocadherin gene Celsr3 is required for interneuron migration in the mouse forebrain.

Interneurons are extremely diverse in the mammalian brain and provide an essential balance for functional neural circuitry. The vast majority of murine cortical interneurons are generated in the subpallium and migrate tangentially over a long distance to acquire their final positions. By using a mouse line with a deletion of the Celsr3 (Flamingo, or Fmi1) gene and a knock-in of the green fluorescent protein reporter, we find that Celsr3, a member of the nonclustered protocadherin (Pcdh) family, is predominantly expressed in the cortical interneurons in adults and in the interneuron germinal zones in embryos. We show that Celsr3 is crucial for interneuron migration in the developing mouse forebrain. Specifically, in Celsr3 knockout mice, calretinin-positive interneurons are reduced in the developing neocortex, accumulated in the corticostriatal boundary, and increased in the striatum. Moreover, the laminar distribution of cortical calbindin-positive cells is altered. Finally, we found that expression patterns of NRG1 (neuregulin-1) and its receptor ErbB4, which are essential for interneuron migration, are changed in Celsr3 mutants. These results demonstrate that the protocadherin Celsr3 gene is essential for both tangential and radial interneuron migrations in a class-specific manner.