REM sleep behavior and olfactory dysfunction: Enhancing the utility and translation of animal models in the search for precision medicines for Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disease that belongs to the family of synucleiopathies, varying according to age, symptoms and progression. The hallmark of the disease is the accumulation of misfolded alpha-synuclein (α-Syn) protein in neuronal and non-neuronal brain cells. Over the past decades, the diagnosis and treatment of PD had a view centred on motoric endpoint and deficits in the nigrostriatal dopaminergic system, and consequently animal models of PD with predominantly motor behavior deficits have been used to study the disease.

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats.

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity.

Functional Neurophysiological Biomarkers of Early-Stage Alzheimer's Disease: A Perspective of Network Hyperexcitability in Disease Progression.

Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout.

Sleep, neuronal hyperexcitability, inflammation and neurodegeneration: Does early chronic short sleep trigger and is it the key to overcoming Alzheimer's disease?

Evidence links neuroinflammation to Alzheimer's disease (AD); however, its exact contribution to the onset and progression of the disease is poorly understood. Symptoms of AD can be seen as the tip of an iceberg, consisting of a neuropathological build-up in the brain of extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated aggregates of Tau (pTau), which are thought to stem from an imbalance between its production and clearance resulting in loss of synaptic health and dysfunctional cortical connectivity. The glymphatic drainage system, which is particularly active during sleep, plays a key role in the clearance of proteinopathies.

Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study.

The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer's disease (AD) patients, and age-matched healthy controls.

Odour Retrieval Processing in Mice: Cholinergic Modulation of Oscillatory Coupling in Olfactory Bulb-Piriform Networks.

Background/aims: Olfactory dysfunction can provide valuable insight into early pathophysiological processes of brain disorders. Olfactory processing of chemosensory and odour sensitivity relies on segregating salient odours from background odours cues. Odour-evoked fast oscillations in the olfactory bulb (OB) are hypothesized to be an important index of odour quality coding.

In Vivo Plasticity at Hippocampal Schaffer Collateral-CA1 Synapses: Replicability of the LTP Response and Pharmacology in the Long-Evans Rat.

Broad issues associated with non-replicability have been described in experimental pharmacological and behavioral cognitive studies. Efforts to prevent biases that contribute to non-replicable scientific protocols and to improve experimental rigor for reproducibility are increasingly seen as a basic requirement for the integrity of scientific research. Synaptic plasticity, encompassing long-term potentiation (LTP), is believed to underlie mechanisms of learning and memory.

Aging Alters Olfactory Bulb Network Oscillations and Connectivity: Relevance for Aging-Related Neurodegeneration Studies.

The aging process eventually cause a breakdown in critical synaptic plasticity and connectivity leading to deficits in memory function. The olfactory bulb (OB) and the hippocampus, both regions of the brain considered critical for the processing of odors and spatial memory, are commonly affected by aging. Using an aged wild-type C57B/6 mouse model, we sought to define the effects of aging on hippocampal plasticity and the integrity of cortical circuits.

Functional Alterations in the Olfactory Neuronal Circuit Occur before Hippocampal Plasticity Deficits in the P301S Mouse Model of Tauopathy: Implications for Early Diagnosis and Translational Research in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by neuronal loss and impaired synaptic transmission, ultimately leading to cognitive deficits. Early in the disease, the olfactory track seems most sensitive to tauopathy, while most plasticity studies focused on the hippocampal circuits. Functional network connectivity (FC) and long-term potentiation (LTP), considered as the plasticity substrate of learning and memory, were longitudinally assessed in mice of the P301S model of tauopathy following the course (time and location) of progressively neurodegenerative pathology (i.

The phosphodiesterase-4 and glycine transporter-1 inhibitors enhance in vivo hippocampal theta network connectivity and synaptic plasticity, whereas D-serine does not.

Dysfunctional N-methyl-D-aspartate receptors (NMDARs) and cyclic adenosine monophosphate (cAMP) have been associated with deficits in synaptic plasticity and cognition found in neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Therapeutic approaches that indirectly enhance NMDAR function through increases in glycine and/or D-serine levels as well as inhibition of phosphodiesterases that reduces degradation of cAMP, are expected to enhance synaptic strength, connectivity and to potentially impact cognition processes. The present in vivo study investigated effects of subcutaneous administration of D-serine, the glycine transporter 1 (GlyT1) inhibitor SSR504734 and the PDE4 inhibitor rolipram, on network oscillations, connectivity and long-term potentiation (LTP) at the hippocampi circuits in Sprague-Dawley rats.

Early Electrophysiological Disintegration of Hippocampal Neural Networks in a Novel Locus Coeruleus Tau-Seeding Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by loss of synapses and disrupted functional connectivity (FC) across different brain regions. Early in AD progression, tau pathology is found in the locus coeruleus (LC) prior to amyloid-induced exacerbation of clinical symptoms. Here, a tau-seeding model in which preformed synthetic tau fibrils (K18) were unilaterally injected into the LC of P301L mice, equipped with multichannel electrodes for recording EEG in frontal cortical and CA1-CA3 hippocampal areas, was used to longitudinally quantify over 20 weeks of functional network dynamics in (1) power spectra; (2) FC using intra- and intersite phase-amplitude theta-gamma coupling (PAC); (3) coherence, partial coherence, and global coherent network efficiency (Eglob) estimates; and (4) the directionality of functional connectivity using extended partial direct coherence (PDC).

Cholinergic Mechanisms of Target Oddball Stimuli Detection: The Late "P300-Like" Event-Related Potential in Rats.

Event-related potentials (ERPs) and oscillations (EROs) provide powerful tools for studying the brain's synaptic function underlying information processing. The P300 component of ERPs indexing attention and working memory shows abnormal amplitude and latency in neurological and psychiatric diseases that are sensitive to pharmacological agents. In the active auditory oddball discriminant paradigm, behavior and auditory-evoked potentials (AEPs) were simultaneously recorded in awake rats to investigate whether P300-like potentials generated in rats responding to rare target oddball tones are sensitive to subcutaneous modulation of the cholinergic tone by donepezil (1 mg/kg) and scopolamine (0.

Cortical high gamma network oscillations and connectivity: a translational index for antipsychotics to normalize aberrant neurophysiological activity.

Oscillatory activity in the gamma frequency range is a critical mechanism, which integrates neural networks within and across brain structures during cognitive processes. In schizophrenia, abnormalities in high gamma oscillations are ubiquitous and most likely reflect dysfunction in neuronal networks. In conscious rats, disturbed network oscillations associated with positive symptoms and cognitive deficits were modeled in different cortical areas by the dopaminergic agonist (amphetamine) and the N-methyl-D-aspartate (NMDA) receptor antagonists (PCP and MK801).

Emergence of early alterations in network oscillations and functional connectivity in a tau seeding mouse model of Alzheimer's disease pathology.

Synaptic dysfunction and disconnectivity are core deficits in Alzheimer's disease (AD), preceding clear changes in histopathology and cognitive functioning. Here, the early and late effects of tau pathology induction on functional network connectivity were investigated in P301L mice. Multichannel EEG oscillations were used to compute (1) coherent activity between the prefrontal cortex (PFC) and hippocampus (HPC) CA1-CA3 networks; (2) phase-amplitude cross frequency coupling (PAC) between theta and gamma oscillations, which is instrumental in adequate cognitive functioning; (3) information processing as assessed by auditory evoked potentials and oscillations in the passive oddball mismatch negativity-like (MMN) paradigm.

Ketamine: differential neurophysiological dynamics in functional networks in the rat brain.

Recently, the N-methyl-d-aspartate-receptor (NMDAR) antagonist ketamine has emerged as a fast-onset mechanism to achieve antidepressant activity, whereas its psychomimetic, dissociative and amnestic effects have been well documented to pharmacologically model schizophrenia features in rodents. Sleep-wake architecture, neuronal oscillations and network connectivity are key mechanisms supporting brain plasticity and cognition, which are disrupted in mood disorders such as depression and schizophrenia. In rats, we investigated the dynamic effects of acute and chronic subcutaneous administration of ketamine (2.

Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k, k and residence time (RT) were determined. The PAMs showed various kinetic profiles; k values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range.

Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer's disease.

Despite a great deal of research into Alzheimer's disease (AD) over the last 20 years, an effective treatment to halt or slow its progression has yet to be developed. With many aspects of the disease progression still to be elucidated, focus has shifted from reducing levels of amyloid β (Aβ) in the brains of AD patients towards tau, another pathology, which initiates much earlier in deeper brainstem networks and is thought to propagate via cell-to-cell processes prior to the onset of amyloid pathology and cognitive impairments. In-vitro, ex-vivo molecular biology/biochemistry read-outs, and various transgenic animal models have been developed, yet clinical failures have highlighted a clear disconnect and inadequate use of such animal models in translational research across species.

Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM).

Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs.

Simultaneous Changes in Sleep, qEEG, Physiology, Behaviour and Neurochemistry in Rats Exposed to Repeated Social Defeat Stress.

Depression is a heterogeneous disorder characterized by alterations at psychological, behavioural, physiological, neurophysiological, and neurochemical levels. Social stress is a prevalent stress in man, and the repeated social defeat stress model in rats has been proposed as being the rodent equivalent to loss of control, which in subordinate animals produces alterations that resemble several of the cardinal symptoms found in depressed patients. Here, rats followed a resident-intruder protocol for 4 consecutive days during which behavioural, physiological, and electroencephalographic (EEG) parameters were simultaneously monitored in subordinate rats.

Off-target potential of AMN082 on sleep EEG and related physiological variables: Evidence from mGluR7 (-/-) mice.

The metabotropic glutamate receptor type 7 (mGluR7), a most abundant presynaptic G protein-coupled receptor in the brain provides an attractive mechanism to fast fine-tune abnormal excitatory neurotransmission and synaptic plasticity associated with emotional and cognitive impairments in neuropsychiatric and neurodegenerative disorders. Preclinical studies using AMN082, the mGluR7 allosteric agonist, produced conflicting results, so that results of further in-vivo studies are needed. Here, we investigated effects of subcutaneous administration at the lights onset of AMN082 on sleep-wake architecture and spectral contents in rats.

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications.

Current research on the effects of pharmacological agents on human neurophysiology finds its roots in animal research, which is also reflected in contemporary animal pharmaco-electroencephalography (p-EEG) applications. The contributions, present value and translational appreciation of animal p-EEG-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. After the pioneering years in the late 19th and early 20th century, animal p-EEG research flourished in the pharmaceutical industry in the early 1980s.

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications.

The contemporary value of animal pharmaco-electroencephalography (p-EEG)-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. While p-EEG in humans and animals has been shown to be closely related in terms of underlying neuronal substrates, both translational and back-translational approaches are being used to address extrapolation issues and optimize the translational validity of preclinical animal p-EEG paradigms and data. Present applications build further on animal p-EEG and pharmaco-sleep EEG findings, but also on stimulation protocols, more specifically pharmaco-event-related potentials.

Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats.

Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.

Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice.