The TD Drive: A Parametric, Open-Source Implant for Multi-Area Electrophysiological Recordings in Behaving and Sleeping Rats.

Intricate interactions between multiple brain areas underlie most functions attributed to the brain. The process of learning, as well as the formation and consolidation of memories, are two examples that rely heavily on functional connectivity across the brain. In addition, investigating hemispheric similarities and/or differences goes hand in hand with these multi-area interactions. Electrophysiological studies trying to further elucidate these complex processes thus depend on recording brain activity at multiple locations simultaneously and often in a bilateral fashion. Presented here is a 3D-printable implant for rats, named TD Drive, capable of symmetric, bilateral wire electrode recordings, currently in up to ten distributed brain areas simultaneously. The open-source design was created employing parametric design principles, allowing prospective users to easily adapt the drive design to their needs by simply adjusting high-level parameters, such as anterior-posterior and mediolateral coordinates of the recording electrode locations. The implant design was validated in n = 20 Lister Hooded rats that performed different tasks. The implant was compatible with tethered sleep recordings and open field recordings (Object Exploration) as well as wireless recording in a large maze using two different commercial recording systems and headstages. Thus, presented here is the adaptable design and assembly of a new electrophysiological implant, facilitating fast preparation and implantation.

Hypothalamic protein profiling from mice subjected to social defeat stress.

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples.

CBD lengthens sleep but shortens ripples and leads to intact simple but worse cumulative memory.

Cannabidiol (CBD) is on the rise as over-the-counter medication to treat sleep disturbances, anxiety, pain, and epilepsy due to its action on the excitatory/inhibitory balance in the brain. However, it remains unclear if CBD also leads to adverse effects on memory via changes of sleep macro- and microarchitecture. To investigate the effect of CBD on sleep and memory consolidation, we performed two experiments using the object space task testing for both simple and cumulative memory in rats. We show that oral CBD administration extended the sleep period but changed the properties of rest and non-REM sleep oscillations (delta, spindle, ripples). Specifically, CBD also led to less long (>100 ms) ripples and, consequently, worse cumulative memory consolidation. In contrast, simple memories were not affected. In sum, we can confirm the beneficial effect of CBD on sleep; however, this comes with changes in oscillations that negatively impact memory consolidation.

Increased cortical plasticity leads to memory interference and enhanced hippocampal-cortical interactions.

Our brain is continuously challenged by daily experiences. Thus, how to avoid systematic erasing of previously encoded memories? While it has been proposed that a dual-learning system with 'slow' learning in the cortex and 'fast' learning in the hippocampus could protect previous knowledge from interference, this has never been observed in the living organism. Here, we report that increasing plasticity via the viral-induced overexpression of RGS14414 in the prelimbic cortex leads to better one-trial memory, but that this comes at the price of increased interference in semantic-like memory. Indeed, electrophysiological recordings showed that this manipulation also resulted in shorter NonREM-sleep bouts, smaller delta-waves and decreased neuronal firing rates. In contrast, hippocampal-cortical interactions in form of theta coherence during wake and REM-sleep as well as oscillatory coupling during NonREM-sleep were enhanced. Thus, we provide the first experimental evidence for the long-standing and unproven fundamental idea that high thresholds for plasticity in the cortex protect preexisting memories and modulating these thresholds affects both memory encoding and consolidation mechanisms.

Defensive and offensive behaviours in a Kleefstra syndrome mouse model.

Kleefstra syndrome in humans is characterized by a general delay in development, intellectual disability and autistic features. The mouse model of this disease (Ehmt1±) expresses anxiety, autistic-like traits, and aberrant social interactions with non-cagemates. To investigate how Ehmt1± mice behave with unfamiliar conspecifics, we allowed adult, male animals to freely interact for 10 min in a neutral, novel environment within a host-visitor setting. In trials where the Ehmt1± mice were hosts, there were defensive and offensive behaviors. Our key finding was that Ehmt1± mice displayed defensive postures, attacking and biting; in contrast, wild-type (WT) interacting with other WT did not enact such behaviors. Further, if there was a fight between an Ehmt1± and a WT mouse, the Ehmt1± animal was the most aggressive and always initiated these behaviors.

Sleep scoring in rodents: Criteria, automatic approaches and outstanding issues.

There is nothing we spend as much time on in our lives as we do sleeping, which makes it even more surprising that we currently do not know why we need to sleep. Most of the research addressing this question is performed in rodents to allow for invasive, mechanistic approaches. However, in contrast to human sleep, we currently do not have shared and agreed upon standards on sleep states in rodents. In this article, we present an overview on sleep stages in humans and rodents and a historical perspective on the development of automatic sleep scoring systems in rodents. Further, we highlight specific issues in rodent sleep that also call into question some of the standards used in human sleep research.

Spindle-slow oscillation coupling correlates with memory performance and connectivity changes in a hippocampal network after sleep.

After experiences are encoded, post-encoding reactivations during sleep have been proposed to mediate long-term memory consolidation. Spindle-slow oscillation coupling during NREM sleep is a candidate mechanism through which a hippocampal-cortical dialogue may strengthen a newly formed memory engram. Here, we investigated the role of fast spindle- and slow spindle-slow oscillation coupling in the consolidation of spatial memory in humans with a virtual watermaze task involving allocentric and egocentric learning strategies. Furthermore, we analyzed how resting-state functional connectivity evolved across learning, consolidation, and retrieval of this task using a data-driven approach. Our results show task-related connectivity changes in the executive control network, the default mode network, and the hippocampal network at post-task rest. The hippocampal network could further be divided into two subnetworks of which only one showed modulation by sleep. Decreased functional connectivity in this subnetwork was associated with higher spindle-slow oscillation coupling power, which was also related to better memory performance at test. Overall, this study contributes to a more holistic understanding of the functional resting-state networks and the mechanisms during sleep associated to spatial memory consolidation.

The HexMaze: A Previous Knowledge Task on Map Learning for Mice.

New information is rarely learned in isolation; instead, most of what we experience can be incorporated into or uses previous knowledge networks in some form. Previous knowledge in form of a cognitive map can facilitate knowledge acquisition and will influence how we learn new spatial information. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze to test how mice learn a large spatial map over a longer time period-the HexMaze. Analyzing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge of the map accelerating both online learning and performance increases over offline periods when incorporating new information. We could identify the following three main phases: (1) learning the initial goal location; (2) faster learning after 2 weeks when learning a new goal location; and then (3) the ability to express one-session learning, leading to long-term memory effect after 12 weeks. Importantly, we are the first to show that buildup of a spatial map is dependent on how much time passes, not how often the animal is trained.

Sleep Leads to Brain-Wide Neural Changes Independent of Allocentric and Egocentric Spatial Training in Humans and Rats.

Sleep is important for memory consolidation and systems consolidation in particular, which is thought to occur during sleep. While there has been a significant amount of research regarding the effect of sleep on behavior and certain mechanisms during sleep, evidence that sleep leads to consolidation across the system has been lacking until now. We investigated the role of sleep in the consolidation of spatial memory in both rats and humans using a watermaze task involving allocentric- and egocentric-based training. Analysis of immediate early gene expression in rodents, combined with functional magnetic resonance imaging in humans, elucidated similar behavioral and neural effects in both species. Sleep had a beneficial effect on behavior in rats and a marginally significant effect in humans. Interestingly, sleep led to changes across multiple brain regions at the time of retrieval in both species and in both training conditions. In rats, sleep led to increased gene expression in the hippocampus, striatum, and prefrontal cortex. In the humans, sleep led to an activity increase in brain regions belonging to the executive control network and a decrease in activity in regions belonging to the default mode network. Thus, we provide cross-species evidence for system-level memory consolidation occurring during sleep.

The Object Space Task reveals increased expression of cumulative memory in a mouse model of Kleefstra syndrome.

Kleefstra syndrome is a disorder caused by a mutation in the EHMT1 gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized cumulative memory in the Ehmt1+/- mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model, and a trial-based classifier. Ehmt1+/- mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration, Ehmt1+/- show increased expression of cumulative memory, but a deficit in a more simple, control memory condition. Using our automatic classifier to differentiate between genotypes, we found that cumulative memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of the Ehmt1+/- mouse model.

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action.

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.