Neurogenesis-mediated forgetting minimizes proactive interference.

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Network Neuroscience Untethered: Brain-Wide Immediate Early Gene Expression for the Analysis of Functional Connectivity in Freely Behaving Animals

Studying how spatially discrete neuroanatomical regions across the brain interact is critical to advancing our understanding of the brain. Traditional neuroimaging techniques have led to many important discoveries about the nature of these interactions, termed functional connectivity. However, in animal models these traditional neuroimaging techniques have generally been limited to anesthetized or head-fixed setups or examination of small subsets of neuroanatomical regions. Using the brain-wide expression density of immediate early genes (IEG), we can assess brain-wide functional connectivity underlying a wide variety of behavioural tasks in freely behaving animal models. Here, we provide an overview of the necessary steps required to perform IEG-based analyses of functional connectivity. We also outline important considerations when designing such experiments and demonstrate the implications of these considerations using an IEG-based network dataset generated for the purpose of this review

New neurons in old brains: implications of age in the analysis of neurogenesis in post-mortem tissue

Abstract Adult neurogenesis, the proliferation and integration of newly generated neurons, has been observed in the adult mammalian hippocampus of many species. Numerous studies have also found adult neurogenesis in the human hippocampus, but several recent high-profile studies have suggested that this process is considerably reduced in humans, occurring in children but not in adults. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. These differences may represent biological species differences or could alternatively be explained by methodological differences in tissue handling and fixation. Here, we examine whether differences in the post-mortem interval between death and tissue fixation might impact subsequent detection of adult neurogenesis due to increased tissue degradation. Because there are fewer new neurons present in older subjects to begin with we hypothesized that, subject age might interact significantly with post-mortem interval in the detection of adult neurogenesis. We analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis

Repeated episodes of postictal hypoxia are a mechanism for interictal cognitive impairments

Abstract Comorbidities during the period between seizures present a significant challenge for individuals with epilepsy. Despite their clinical relevance, the pathophysiology of the interictal symptomatology is largely unknown. Postictal severe hypoxia (PIH) in those brain regions participating in the seizure has been indicated as a mechanism underlying several negative postictal manifestations. It is unknown how repeated episodes of PIH affect interictal symptoms in epilepsy. Using a rat model, we observed that repeated seizures consistently induced episodes of PIH that become increasingly severe with each seizure occurrence. Additionally, recurrent seizure activity led to decreased levels of oxygen in the hippocampus during the interictal period. However, these reductions were prevented when we repeatedly blocked PIH using either the COX-inhibitor acetaminophen or the L-type calcium channel antagonist nifedipine. Moreover, we found that interictal cognitive deficits caused by seizures were completely alleviated by repeated attenuation of PIH events. Lastly, mitochondrial dysfunction may contribute to the observed pathological outcomes during the interictal period. These findings provide evidence that seizure-induced hypoxia may play a crucial role in several aspects of epilepsy. Consequently, developing and implementing treatments that specifically target and prevent PIH could potentially offer significant benefits for individuals with refractory epilepsy

Retrograde amnesia for visual memories after hippocampal damage in rats

It is generally believed that the hippocampus is not required for simple discrimination learning. However, a small number of studies have shown that hippocampus damage impairs retention of a previously learned visual discrimination task. We propose that, although simple discrimination learning may proceed in the absence of the hippocampus, it plays an important role in this type of learning when it is intact. In order to test the role of the hippocampus in simple discrimination learning, we performed a series of experiments utilizing a two-choice picture discrimination task. Our experiments confirm that rats readily learn simple two-choice picture discriminations after hippocampus damage. However, if such discriminations are first learned while the hippocampus is intact, subsequent hippocampus damage causes severe retrograde amnesia for the discriminations. Furthermore, retrograde amnesia for simple picture discriminations was equally severe when the interval between training and damage was 1 d or 60 d; remote picture memories are not spared. Similarly, the rule or schema underlying a recently or remotely acquired picture discrimination learning set was lost after hippocampus damage. The severity of retrograde amnesia for simple picture discriminations is negatively correlated with the volume of spared hippocampus tissue. Thus, the hippocampus plays an essential role in long-term memories supporting simple picture discriminations

Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

Summary: The hypothalamus plays a crucial role in the modulation of social behavior by encoding internal states. The hypothalamic hypocretin/orexin neurons, initially identified as regulators of sleep and appetite, are important for emotional and motivated behaviors. However, their role in social behavior remains unclear. Using fiber photometry and behavioral analysis, we show here that hypocretin neurons differentially encode social discrimination based on the nature of social encounters. The optogenetic inhibition of hypocretin neuron activity or blocking of hcrt-1 receptors reduces the amount of time mice are engaged in social interaction in males but not in females. Reduced hcrt-1 receptor signaling during social interaction is associated with altered activity in the insular cortex and ventral tegmental area in males. Our data implicating hypocretin neurons as sexually dimorphic regulators within social networks have significant implications for the treatment of neuropsychiatric diseases with social dysfunction, particularly considering varying prevalence among sexes

Adult neurogenesis mediates forgetting of multiple types of memory in the rat

Abstract The formation and retention of hippocampus-dependent memories is impacted by neurogenesis, a process that involves the production of new neurons in the dentate gyrus of the hippocampus. Recent studies demonstrate that increasing neurogenesis after memory formation induces forgetting of previously acquired memories. Neurogenesis-induced forgetting was originally demonstrated in mice, but a recent report suggests that the same effect may be absent in rats. Although a general species difference is possible, other potential explanations for these incongruent findings are that memories which are more strongly reinforced become resilient to forgetting or that perhaps only certain types of memories are affected. Here, we investigated whether neurogenesis-induced forgetting occurs in rats using several hippocampus-dependent tasks including contextual fear conditioning (CFC), the Morris Water Task (MWT), and touchscreen paired associates learning (PAL). Neurogenesis was increased following training using voluntary exercise for 4 weeks before recall of the previous memory was assessed. We show that voluntary running causes forgetting of context fear memories in a neurogenesis-dependent manner, and that neurogenesis-induced forgetting is present in rats across behavioral tasks despite differences in complexity or reliance on spatial, context, or object memories. In addition, we asked whether stronger memories are less susceptible to forgetting by varying the strength of training. Even with a very strong training protocol in the CFC task, we still observed enhanced forgetting related to increased neurogenesis. These results suggest that forgetting due to neurogenesis is a conserved mechanism that aids in the clearance of memories