Hippocampal injections of soluble amyloid-beta oligomers alter electroencephalographic activity during wake and slow-wave sleep in rats.

BACKGROUND: Soluble amyloid-beta oligomers (Aßo) begin to accumulate in the human brain one to two decades before a clinical diagnosis of Alzheimer's disease (AD). The literature supports that soluble Aßo are implicated in synapse and neuronal losses in the brain regions such as the hippocampus. This region importantly contributes to explicit memory, the first type of memory affected in AD. During AD preclinical and prodromal stages, people are also experiencing wake/sleep alterations such as insomnia (e.g., difficulty initiating sleep, decreased sleep duration), excessive daytime sleepiness, and sleep schedule modifications. In addition, changes in electroencephalographic (EEG) activity during wake and sleep have been reported in AD patients and animal models. However, the specific contribution of Aßo to wake/sleep alterations is poorly understood and was investigated in the present study. METHODS: Chronic hippocampal injections of soluble Aßo were conducted in male rats and combined with EEG recording to determine the progressive impact of Aß pathology specifically on wake/sleep architecture and EEG activity. Bilateral injections were conducted for 6 consecutive days, and EEG acquisition was done before, during, and after Aßo injections. Immunohistochemistry was used to assess neuron numbers in the hippocampal dentate gyrus (DG). RESULTS: Aßo injections did not affect the time spent in wakefulness, slow wave sleep (SWS), and paradoxical sleep but altered EEG activity during wake and SWS. More precisely, Aßo increased slow-wave activity (SWA; 0.5-5 Hz) and low-beta activity (16-20 Hz) during wake and decreased theta (5-9 Hz) and alpha (9-12 Hz) activities during SWS. Moreover, the theta activity/SWA ratio during wake and SWS was decreased by Aßo. These effects were significant only after 6 days of Aßo injections and were found with alterations in neuron counts in the DG. CONCLUSIONS: We found multiple modifications of the wake and SWS EEG following Aßo delivery to the hippocampus. These findings expose a specific EEG signature of Aß pathology and can serve the development of non-invasive and cost-effective markers for the early diagnosis of AD or other amyloid-related diseases.

Characterization of Sleep, Emotional, and Cognitive Functions in a New Rat Model of Concomitant Spinal Cord and Traumatic Brain Injuries.

Traumatic injuries to the spinal cord or the brain have serious medical consequences and lead to long-term disability. The epidemiology, medical complications, and prognosis of isolated spinal cord injury (SCI) and traumatic brain injury (TBI) have been well described. However, there are limited data on patients suffering from concurrent SCI and TBI, even if a large proportion of SCI patients have concomitant TBI. The complications associated with this "dual-diagnosis" such as cognitive or behavioral dysfunction are well known in the rehabilitation setting, but evidence-based and standardized approaches for diagnosis and treatment are lacking. Our goal was to develop and characterize a pre-clinical animal model of concurrent SCI and TBI to help identifying "dual-diagnosis" tools. Female rats received a unilateral contusive SCI at the thoracic level alone (SCI group) or combined with a TBI centered on the contralateral sensorimotor cortex (SCI-TBI group). We first validated that the SCI extent was comparable between SCI-TBI and SCI groups, and that hindlimb function was impaired. We characterized various neurological outcomes, including locomotion, sleep architecture, brain activity during sleep, depressive- and anxiety-like behaviors, and working memory. We report that SCI-TBI and SCI groups show similar impairments in global locomotor function. While wake/sleep amount and distribution and anxiety- and depression-like symptoms were not affected in SCI-TBI and SCI groups in comparison to the control group (laminectomy and craniotomy only), working memory was impaired only in SCI-TBI rats. This pre-clinical model of concomitant SCI and TBI, including more severe variations of it, shows a translational value for the identification of biomarkers to refine the "dual-diagnosis" of neurotrauma in humans.

Neuroligin-1 is altered in the hippocampus of Alzheimer's disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers.

Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aßo), but the exact synaptic components targeted by Aßo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aßo, and that it can modulate Aßo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aßo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aßo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aßo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aßo-driven neurodegeneration.

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis.

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.

Correction to: The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice.

Correction to: Molecular Brain (2018) 11:52 https://doi.org/10.1186/s13041-018-0394-3Following publication of the original article [1], the authors reported that the article was mistakenly submitted with the omission of two authors: Feng Cao and Zhengping Jia. The authors declare that this was an error made in good faith. The corrected author list and list of affiliations are used in this Correction. The changes made to the author list and list of affiliations are also listed below, as well as the revised 'Acknowledgements' section and 'Authors' contributions' section.

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice.

Sleep disorders are comorbid with most psychiatric disorders, but the link between these is not well understood. Neuroligin-2 (NLGN2) is a cell adhesion molecule that plays roles in synapse formation and neurotransmission. Moreover, NLGN2 has been associated with psychiatric disorders, but its implication in sleep remains underexplored. In the present study, the effect of Nlgn2 knockout (Nlgn2-/-) on sleep architecture and electroencephalographic (EEG) activity in mice has been investigated. The EEG and electromyogram (EMG) were recorded in Nlgn2-/- mice and littermates for 24 h from which three vigilance states (i.e., wakefulness, rapid eye movement [REM] sleep, non-REM [NREM] sleep) were visually identified. Spectral analysis of the EEG was performed for the three states. Nlgn2-/- mice showed more wakefulness and less NREM and REM sleep compared to wild-type (Nlgn2+/+) mice, especially during the dark period. This was accompanied by changes in the number and duration of individual episodes of wakefulness and sleep, indexing changes in state consolidation, as well as widespread changes in EEG spectral activity in all states. Abnormal 'hypersynchronized' EEG events have also been observed predominantly in Nlgn2-/- mice. These events were mainly observed during wakefulness and REM sleep. In addition, Nlgn2-/- mice showed alterations in the daily time course of NREM sleep delta (1-4 Hz) activity, pointing to modifications in the dynamics of sleep homeostasis. These data suggest that NLGN2 participates in the regulation of sleep duration as well as EEG activity during wakefulness and sleep.

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps.

Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aßo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aßo correlate with memory deficits in AD models and humans. The Aßo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aßo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aßo-induced memory deficits at the onset of AD. Since soluble Aßo aggregate relatively fast into insoluble Aß fibrils that correlate poorly with the clinical state of patients, soluble Aßo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aßo and continuous infusion of Aßo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aßo in pre-dementia patients.