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Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglial motility and significance for synapse stability, especially in the hippocampus during adulthood, remain widely unresolved. Here, we investigated the effect of neuronal activity on microglial motility and the implications for the formation and survival of dendritic spines on hippocampal CA1 neurons in vivo. We used repetitive two-photon in vivo imaging in the hippocampus of awake and anesthetized mice to simultaneously study the motility of microglia and their interaction with dendritic spines. We found that CA3 to CA1 input is sufficient to modulate microglial process motility. Simultaneously, more dendritic spines emerged in mice after awake compared to anesthetized imaging. Interestingly, the rate of microglial contacts with individual dendritic spines and dendrites was associated with the stability, removal, and emergence of dendritic spines. These results suggest that microglia might sense neuronal activity via neurotransmitter release and actively participate in synaptic rewiring of the hippocampal neural network during adulthood. Further, this study has profound relevance for hippocampal learning and memory processes.

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Background. Patients with Parkinson’s disease (PD) are highly vulnerable to develop cognitive dysfunctions, and the mitigating potential of early cognitive training (CT) is increasingly recognized. Predictors of CT responsiveness, which could help to tailor interventions individually, have rarely been studied in PD. This study aimed to examine individual characteristics of patients with PD associated with responsiveness to targeted working memory training (WMT). Methods. Data of 75 patients with PD (age: 63.99 ± 9.74 years, 93% Hoehn & Yahr stage 2) without cognitive dysfunctions from a randomized controlled trial were analyzed using structural equation modeling. Latent change score models with and without covariates were estimated and compared between the WMT group ( n = 37), who participated in a 5-week adaptive WMT, and a waiting list control group ( n = 38). Results. Latent change score models yielded adequate model fit (χ2-test p > .05, SRMR ≤ .08, CFI ≥ .95). For the near-transfer working memory composite, lower baseline performance, younger age, higher education, and higher fluid intelligence were found to significantly predict higher latent change scores in the WMT group, but not in the control group. For the far-transfer executive function composite, higher self-efficacy expectancy tended to significantly predict larger latent change scores. Conclusions. The identified associations between individual characteristics and WMT responsiveness indicate that there has to be room for improvement (e.g., lower baseline performance) and also sufficient “hardware” (e.g., younger age, higher intelligence) to benefit in training-related cognitive plasticity. Our findings are discussed within the compensation versus magnification account. They need to be replicated by methodological high-quality research applying advanced statistical methods with larger samples.

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca2+ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca2+ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.

Alzheimer's disease (AD) is characterized by cognitive decline and neuronal network dysfunction, but the underlying mechanisms remain unknown. In the hippocampus, microcircuit activity during learning and memory processes is tightly controlled by O-LM interneurons. Here, we investigated the effect of beta-amyloidosis on O-LM interneuron structural and functional connectivity, combining two-photon in vivo imaging of synaptic morphology, awake Ca2+ imaging, and retrograde mono-transsynaptic rabies tracing. We find severely impaired synaptic rewiring that occurs on the O-LM interneuron input and output level in a mouse model of AD. Synaptic rewiring that occurs upon fear learning on O-LM interneuron input level is affected in mice with AD-like pathology. This process requires the release of acetylcholine from septo-hippocampal projections. We identify decreased cholinergic action on O-LM interneurons in APP/PS1 mice as a key pathomechanism that contributes to memory impairment in a mouse model, with potential relevance for human AD.

Positron Emission Tomography (PET) bears a unique potential for examining the effects of physical exercise (acute or chronic) within the central nervous system in vivo, including cerebral metabolism, neuroreceptor occupancy, and neurotransmission. However, application of Neuro-PET in human exercise science is as yet surprisingly sparse. To date the field has been dominated by non-invasive neuroelectrical techniques (EEG, MEG) and structural/functional magnetic resonance imaging (sMRI/fMRI). Despite PET having certain inherent disadvantages, in particular radiation exposure and high costs limiting applicability at large scale, certain research questions in human exercise science can exclusively be addressed with PET: The 'metabolic trapping' properties of (18)F-FDG PET as the most commonly used PET-tracer allow examining the neuronal mechanisms underlying various forms of acute exercise in a rather unconstrained manner, i.e. under realistic training scenarios outside the scanner environment. Beyond acute effects, (18)F-FDG PET measurements under resting conditions have a strong prospective for unraveling the influence of regular physical activity on neuronal integrity and potentially neuroprotective mechanisms in vivo, which is of special interest for aging and dementia research. Quantification of cerebral glucose metabolism may allow determining the metabolic effects of exercise interventions in the entire human brain and relating the regional cerebral rate of glucose metabolism (rCMRglc) with behavioral, neuropsychological, and physiological measures. Apart from FDG-PET, particularly interesting applications comprise PET ligand studies that focus on dopaminergic and opioidergic neurotransmission, both key transmitter systems for exercise-related psychophysiological effects, including mood changes, reward processing, antinociception, and in its most extreme form 'exercise dependence'. PET ligand displacement approaches even allow quantifying specific endogenous neurotransmitter release under acute exercise interventions, to which modern PET/MR hybrid technology will be additionally fruitful. Experimental studies exploiting the unprecedented multimodal imaging capacities of PET/MR in human exercise sciences are as yet pending.

Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.

This study investigates the effects of fitness changes on hippocampal microstructure and hippocampal volume. Fifty-two healthy participants aged 59-74 years with a sedentary lifestyle were randomly assigned to either of two levels of exercise intensity. Training lasted for six months. Physical fitness, hippocampal volumes, and hippocampal microstructure were measured before and after training. Hippocampal microstructure was assessed by mean diffusivity, which inversely reflects tissue density hence, mean diffusivity is lower for more densely packed tissue. Mean changes in fitness did not differ reliably across intensity levels of training, so data were collapsed across groups. Multivariate modeling of pretest-posttest differences using structural equation modeling (SEM) revealed that individual differences in latent change were reliable for all three constructs. More positive changes in fitness were associated with more positive changes in tissue density (i.e., more negative changes in mean diffusivity), andmore positive changes in tissue density were associated with more positive changes in volume. We conclude that fitness-related changes in hippocampal volume may be brought about by changes in tissue density. The relative contributions of angiogenesis, gliogenesis, and/or neurogenesis to changes in tissue density remain to be identified. (C) 2015 Elsevier Inc. All rights reserved.

Summary Gating properties and surface trafficking of AMPA receptors (AMPARs) are modulated by auxiliary subunits. Here we studied the function of coexpressed auxiliary subunits belonging to two different classes. We focused on TARP γ-8 and CKAMP44 in dentate gyrus (DG) granule cells, since both subunits are highly expressed in this cell type. TARP γ-8 and CKAMP44 decrease the rate of deactivation but have an opposing influence on receptor desensitization, which accounts for their differential modulation of synaptic short-term plasticity. Furthermore, long-term plasticity (LTP) requires TARP γ-8 but not CKAMP44. The coexpression of both auxiliary subunits is necessary for the efficient targeting of AMPARs to the cell surface of DG granule cells. Finally, electrophysiological and biochemical evidence support the notion that CKAMP44 and TARP γ-8 can be contained in the same AMPAR complex. Video Abstract

Several important paradigm shifts have occurred in the field of schizophrenia treatment, including an increased focus on early detection, the development of preemptive interventions, and the view of schizophrenia as a neurodevelopmental disease characterized by decreased efficiency and abnormal connectivity in cortical and subcortical neural networks. In this review, we briefly describe some of the neural impairments that contribute to the development of schizophrenia, with an emphasis on the impact of stress and trauma on cognitively vulnerable neural systems. We then present current data on two behavioral interventions that target these critical risk factors and that aim to preempt the onset of schizophrenia in vulnerable individuals or improve the clinical course in recent-onset schizophrenia: cognitive therapy and computerized cognitive training.

According to the Hebb rule, the change in the strength of a synapse depends only on the local interaction of presynaptic and postsynaptic events. Studies at many types of synapses indicate that the early phase of long-term potentiation (LTP) has Hebbian properties. However, it is now clear that the Hebb rule does not account for late LTP; this requires an additional signal that is non-local. For novel information and motivational events such as rewards, this signal at hippocampal CA1 synapses is mediated by the neuromodulator, dopamine. In this Review, we discuss recent experimental findings that support the view that this “neoHebbian” framework can account for memory behavior in a variety of learning situations.

Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3–Aβ), has been described as a major constituent of Aβ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Aβ species by glutaminyl cyclase (QC;QPCT) and/or its isoenzyme (isoQC;QPCTL), pE3–Aβ aggregates rapidly and is known to seed additional Aβ aggregation. To directly investigate pE3–Aβ toxicityin vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Aβ. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Aβ and pE3–Aβ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3–Aβ neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3–Aβ formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3–Aβ levels. Hence, lowering the rate of QC-dependent posttranslational pE3–Aβ formation can, in turn, lower the amount of neurotoxic Aβ species in AD.

Non-pharmacological interventions have the potential to reduce cognitive decline and to improve psychosocial aspects in mild cognitive impairment and Alzheimer's dementia, and the absence of side effects makes them a favorable option also for preventive strategies. We provide an overview on recent studies involving cognitive training and reminiscence, stimulating and challenging experiences such as visual art and music, physical activities, and electromagnetic stimulation. We review findings on neuroplasticity in the aging brain and their relevance for cognitive improvement in patients with neurodegenerative diseases. We discuss cognitive reserve and possible mechanisms that drive neuroplasticity and new learning. Finally, we identify promising avenues for future intervention strategies and research, such as combinations of cognitive and pharmaceutical interventions, and individual strategies adapted to the disease stage and tailored to the needs, predispositions and preferences of patients.

An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards., Author Summary What are the physiological changes that take place in the brain when we solve a problem or learn a new skill? It is commonly assumed that behavior adaptations are realized on the microscopic level by changes in synaptic efficacies. However, this is hard to verify experimentally due to the difficulties of identifying the relevant synapses and monitoring them over long periods during a behavioral task. To address this question computationally, we develop a spiking neuronal network model of actor-critic temporal-difference learning, a variant of reinforcement learning for which neural correlates have already been partially established. The network learns a complex task by means of an internally generated reward signal constrained by recent findings on the dopaminergic system. Our model combines top-down and bottom-up modelling approaches to bridge the gap between synaptic plasticity and system-level learning. It paves the way for further investigations of the dopaminergic system in reward learning in the healthy brain and in pathological conditions such as Parkinson's disease, and can be used as a module in functional models based on brain-scale circuitry.

The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) is thought to underlie synaptic plasticity in both adult and developing CNS; however, its involvement in the thalamocortical synapse has not yet been directly demonstrated. 2. Whole-cell, thalamus-evoked synaptic currents were recorded from layer IV cells in slices of immature mouse somatosensory cortex. 3. Earlier than postnatal day 9 the majority of responses were monosynaptic and purely excitatory, with both non-NMDAR and NMDAR-mediated glutamatergic components. 4. In older animals, disynaptic inhibitory currents summated with the excitatory ones and lowered the reversal potential of the response to voltages at which the NMDAR conductance is mostly blocked. 5. These findings suggest a cellular basis for the transient plasticity observed in layer IV during early postnatal development.