Female rats prefer to forage food from males, an effect that is not influenced by stress.

As social beings, animals and humans alike make real life decisions that are often influenced by other members. Most current research has focused on the influence of same-sex peers on individual decision-making, with potential opposite sex effect scarcely explored. Here, we developed a behavioral model to observe food foraging decision-making in female rats under various social situations. We found that female rats preferred to forage food from male over female rats or from the no-rat storage side. Female rats were more likely to forage food from familiar males than from unfamiliar. This opposite-sex preference was not altered by the lure of sweet food, or with estrous cycle, nor under stress conditions. These results suggest that the opposite sex influences food foraging decision-making in female rats. The behavioral model established could facilitate future investigation into the underlying neurobiological mechanisms.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

Infralimbic YTHDF1 is necessary for the beneficial effects of acute mild exercise on auditory fear extinction retention.

Exposure therapy is the most effective approach of behavioral therapy for anxiety and post-traumatic stress disorder (PTSD). But fear is easy to reappear even after successful extinction. So, identifying novel strategies for augmenting exposure therapy is rather important. It was reported that exercise had beneficial effects on cognitive and memory deficits. However, whether exercise could affect fear memory, especially for fear extinction remained elusive. Here, our results showed that exposure to acute mild exercise 1 or 2 h before extinction training can augment recent fear extinction retention and 2 h for the remote fear extinction retention. These beneficial effects could be attributed to increased YTHDF1 expression in medial prefrontal cortex (mPFC). Furthermore, by using an AAV-shRNA-based approach to silence YTHDF1 expression via stereotactic injection in prelimbic cortex (PL) or infralimbic cortex (IL), respectively, we demonstrated that silence YTHDF1 in IL, but not in PL, blunted augmentation of exposure therapy induced by acute mild exercise and accompanied with decreased NR2B and GluR1 expression. Moreover, YTHDF1 modulated dendritic spines remodeling of pyramidal neuron in IL. Collectively, our findings suggested that acute mild exercise acted as an effective strategy in augmenting exposure therapy with possible implications for understanding new treatment underlying PTSD.

Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a risk factor for cognitive and memory dysfunction; however, the mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) was reported to have a positive effect on cognition and emotion regulation, but the study of its precursor, proBDNF, has been limited. This study aimed to elucidate the effects and associated mechanisms of hippocampal proBDNF in a lipopolysaccharide (LPS)-induced SAE mouse model. In this study, we found that the mice exhibited cognitive dysfunction on day 7 after LPS injection. The expression of proBDNF and its receptor, p75 NTR , was also increased in the hippocampus, while the levels of BDNF and its receptor, TrkB, were decreased. A co-localization study showed that proBDNF and p75 NTR were mainly co-localized with neurons. Furthermore, LPS treatment reduced the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, and NR2B in the hippocampus of SAE mice. Furthermore, an intrahippocampal or intraperitoneal injection of anti-proBDNF antibody was able to ameliorate LPS-induced cognitive dysfunction and restore the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, NR2B, and PSD95. These results indicated that treatment with brain delivery by an intrahippocampal and systemic injection of mAb-proBDNF may represent a potential therapeutic strategy for treating patients with SAE.

Expression of Cntn1 is regulated by stress and associated with anxiety and depression phenotypes.

In recent years, our understanding of neural circuits associated with depression has increased. Although inherited factors are known to influence individual differences in the risk for this disorder, it has been difficult to identify specific genes that moderate circuit functions affecting depression. Genome-wide association studies have identified genetic variants of Cntn1 that are linked to major depressive disorders. Cntn1, a subset of the neural cell adhesion protein and immunoglobulin supergene family, participates in cell contact formation and axonal growth control and plays a role in degenerative and inflammatory disorders. However, neuronal substrates that mediate Cntn1 action on depression-like phenotypes and involved mechanisms are unclear. Here, we exploited chronic unpredictable stress (CUS) exposure and found that CUS treatment significantly increased hippocampal Cntn1 messenger RNA and protein expression in both mice and rats, but not in the medial prefrontal cortex, which presented a region-specific regulation. Using an adeno-associated virus-based approach to directly overexpress Cntn1 via stereotactic injection, we demonstrated that Cntn1 overexpression in the hippocampus triggered anxiety- and depression-like phenotypes in addition to microglia activation or phagocytosis in the hippocampus, resulting in upregulation of pro-inflammatory cytokine (IL1α, IL6, and Ccl2) mRNA expression and downregulation of anti-inflammatory cytokine (IL4 and CD206) mRNA expression, determined using real-time quantitative PCR, thus impairing hippocampal immature neurons in the dentate gyrus, determined using immunohistochemical staining for doublecortin, a specific marker for immature neurons. Collectively, our results identified Cntn1 as a novel risk gene involved in regulating anxiety and depression via functional actions in the hippocampus that is correlated with microglial activation or phagocytosis and reduced hippocampal immature neurons. These results may provide a better understanding of the pathophysiological mechanisms underlying the risk of depression-related disorders.

The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice.

BACKGROUND: The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. OBJECTIVE: The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. METHODS: Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. RESULTS: ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. CONCLUSION: The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

Acute restraint stress alters food-foraging behavior in rats: Taking the easier Way while suffered.

Stress can influence decision-making in humans from many cognitive perspectives, while the underlying neurobiological mechanism remains incompletely understood. Food-foraging is a rodent behavior involving strategic possessing of nutritional supply in social context; experimental model of this behavior could help explore the effect of stress on decision-making and the brain mechanism thereof. In the present study, the influence of stress on food-foraging behavior was assessed in rats using an open field choosing paradigm wherein food collection (standard food or sweet food) were associated with social competition (with or without a rat in the cage). Acute restraint stress (ARS) was induced by placing the rat in a plastic restrainer for 2 h before food-foraging behavioral tests, with the effect of stress also determined biochemically and immunohistochemically. Restraint stressed rats showed anxiety-like behavior and elevation of serum corticosterone (CORT) and epinephrine (EPI) relative to controls. Both restraint and control animals preferred sugared food. However, the former group tended to forage food from a cage not occupied by a conspecific rat, whereas the control rats preferred to obtain food from the cage with a social competitor. Thus, the total amount of food foraged and eaten are reduced in the restrained rats than in controls. While the restraint animals had normal social interaction with other rats, they displayed enhanced social agonistic behavior. In brain examination, ARS attenuated the increase in immunolabeling and protein levels of c-fos, p-CREB, p-ERK1/2 in the anterior cingulate cortex (ACC) observed in control animals in association with food-foraging. These results indicate that restraint stressed rats tend to forage food by taking the advantage of a less competitive opportunity. Mechanistically, this decision-making alternative appears to be mediated through a neuronal deactivation in the ACC. The current findings provide novel insights into neuronal processing of decision-making behavior under the influence of stress.