Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an ?-synuclein (?Syn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with human ?-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-?SynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-?SynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages. Altogether results show that H-?SynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD.

Perspective article on the role of systemic inflammation in modulating the effect of lifestyle on cognitive performance.

Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB.1/, knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB.1/ HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and d-containing GABAA receptor (d-GABAAR), we profiled d subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR d subunit in the hippocampus of the GABAB.1/ KO alcohol-naïve mice that was associated with increased G2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal d-GABAAR occurring in the GABAB.1/ KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB.1/ KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB.1/ KO mice but elicited an expected increase in the hippocampal level of progesterone and 3a,5a-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB.1/ subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB.1/ KO mice. In addition, we documented that GABAB.1/ deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.

'Dysbiosis' of the adult gut microbiota, in response to challenges such as infection, altered diet, stress, and antibiotics treatment has been recently linked to pathological alteration of brain function and behavior. Moreover, gut microbiota composition constantly controls microglia maturation, as revealed by morphological observations and gene expression analysis. However, it is unclear whether microglia functional properties and crosstalk with neurons, known to shape and modulate synaptic development and function, are influenced by the gut microbiota. Here, we investigated how antibiotic-mediated alteration of the gut microbiota influences microglial and neuronal functions in adult mice hippocampus. Hippocampal microglia from adult mice treated with oral antibiotics exhibited increased microglia density, altered basal patrolling activity, and impaired process rearrangement in response to damage. Patch clamp recordings at CA3-CA1 synapses revealed that antibiotics treatment alters neuronal functions, reducing spontaneous postsynaptic glutamatergic currents and decreasing synaptic connectivity, without reducing dendritic spines density. Antibiotics treatment was unable to modulate synaptic function in CX3CR1-deficient mice, pointing to an involvement of microglia-neuron crosstalk through the CX3CL1/CX3CR1 axis in the effect of dysbiosis on neuronal functions. Together, our findings show that antibiotic alteration of gut microbiota impairs synaptic efficacy, suggesting that CX3CL1/CX3CR1 signaling supporting microglia is a major player in in the gut-brain axis, and in particular in the gut microbiota-to-neuron communication pathway.

Young age is often characterized by high consumption of processed foods and fruit juices rich in fructose, which, besides inducing a tendency to become overweight, can promote alterations in brain function. The aim of this study was therefore to (a) clarify brain effects resulting from fructose consumption in juvenile age, a critical phase for brain development, and (b) verify whether these alterations can be rescued after removing fructose from the diet. Young rats were fed a fructose-rich or control diet for 3 weeks. Fructose-fed rats were then fed a control diet for a further 3 weeks. We evaluated mitochondrial bioenergetics by high-resolution respirometry in the hippocampus, a brain area that is critically involved in learning and memory. Glucose transporter-5, fructose and uric acid levels, oxidative status, and inflammatory and synaptic markers were investigated by Western blotting and spectrophotometric or enzyme-linked immunosorbent assays. A short-term fructose-rich diet induced mitochondrial dysfunction and oxidative stress, associated with an increased concentration of inflammatory markers and decreased Neurofilament-M and post-synaptic density protein 95. These alterations, except for increases in haptoglobin and nitrotyrosine, were recovered by returning to a control diet. Overall, our results point to the dangerous effects of excessive consumption of fructose in young age but also highlight the effect of partial recovery by switching back to a control diet.

Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.

Summary Flexible navigation relies on a cognitive map of space, thought to be implemented by hippocampal place cells: neurons that exhibit location-specific firing. In connected environments, optimal navigation requires keeping track of one's location and of the available connections between subspaces. We examined whether the dorsal CA1 place cells of rats encode environmental connectivity in four geometrically identical boxes arranged in a square. Rats moved between boxes by pushing saloon-type doors that could be locked in one or both directions. Although rats demonstrated knowledge of environmental connectivity, their place cells did not respond to connectivity changes, nor did they represent doorways differently from other locations. Place cells coded location in a global reference frame, with a different map for each box and minimal repetitive fields despite the repetitive geometry. These results suggest that CA1 place cells provide a spatial map that does not explicitly include connectivity.

Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that enable accurate neuronal modeling, there are now a large number of different models of many cell types available in the literature. These models were usually built to capture a few important or interesting properties of the given neuron type, and it is often unknown how they would behave outside their original context. In addition, there is currently no simple way of quantitatively comparing different models regarding how closely they match specific experimental observations. This limits the evaluation, re-use and further development of the existing models. Further, the development of new models could also be significantly facilitated by the ability to rapidly test the behavior of model candidates against the relevant collection of experimental data. We address these problems for the representative case of the CA1 pyramidal cell of the rat hippocampus by developing an open-source Python test suite, which makes it possible to automatically and systematically test multiple properties of models by making quantitative comparisons between the models and electrophysiological data. The tests cover various aspects of somatic behavior, and signal propagation and integration in apical dendrites. To demonstrate the utility of our approach, we applied our tests to compare the behavior of several different rat hippocampal CA1 pyramidal cell models from the ModelDB database against electrophysiological data available in the literature, and evaluated how well these models match experimental observations in different domains. We also show how we employed the test suite to aid the development of models within the European Human Brain Project (HBP), and describe the integration of the tests into the validation framework developed in the HBP, with the aim of facilitating more reproducible and transparent model building in the neuroscience community.

Women are more prone than men to develop age-related dementia, such as Alzheimer's disease (AD). This has been linked to the marked decrease in circulating estrogens during menopause.

How are distinct memories formed and used for behavior? To relate neuronal and behavioral discrimination during memory formation, we use in vivo 2-photon Ca imaging and whole-cell recordings from hippocampal subregions in head-fixed mice performing a spatial virtual reality task. We find that subthreshold activity as well as population codes of dentate gyrus neurons robustly discriminate across different spatial environments, whereas neuronal remapping in CA1 depends on the degree of difference between visual cues. Moreover, neuronal discrimination in CA1, but not in the dentate gyrus, reflects behavioral performance. Our results suggest that CA1 weights the decorrelated information from the dentate gyrus according to its relevance, producing a map of memory representations that can be used by downstream circuits to guide learning and behavior.

Coupling among neural rhythms is one of the most important mechanisms at the basis of cognitive processes in the brain. In this study, we consider a neural mass model, rigorously obtained from the microscopic dynamics of an inhibitory spiking network with exponential synapses, able to autonomously generate collective oscillations (COs). These oscillations emerge via a super-critical Hopf bifurcation, and their frequencies are controlled by the synaptic time scale, the synaptic coupling, and the excitability of the neural population. Furthermore, we show that two inhibitory populations in a master-slave configuration with different synaptic time scales can display various collective dynamical regimes: Damped oscillations toward a stable focus, periodic and quasi-periodic oscillations, and chaos. Finally, when bidirectionally coupled, the two inhibitory populations can exhibit different types of ?-? cross-frequency couplings (CFCs): Phase-phase and phase-amplitude CFC. The coupling between ? and ? COs is enhanced in the presence of an external ? forcing, reminiscent of the type of modulation induced in hippocampal and cortex circuits via optogenetic drive.

GABAergic transmission regulates neuronal excitability, dendritic integration of synaptic signals and oscillatory activity, thought to be involved in high cognitive functions. By anchoring synaptic receptors just opposite to release sites, the scaffold protein gephyrin plays a key role in these tasks. In addition, by regulating GABA(A)receptor trafficking, gephyrin contributes to maintain, at the network level, an appropriate balance between Excitation (E) and Inhibition (I), crucial for information processing. An E/I imbalance leads to neuropsychiatric disorders such as epilepsy, schizophrenia and autism. In this article, we exploit a previously published computational method to fit spontaneous synaptic events, using a simplified model of the subcellular pathways involving gephyrin at inhibitory synapses. The model was used to analyze experimental data recorded under different conditions, with the main goal to gain insights on the possible consequences of gephyrin block on IPSCs. The same approach can be useful, in general, to analyze experiments designed to block a single protein. The results suggested possible ways to correlate the changes observed in the amplitude and time course of individual events recorded after different experimental protocols with the changes that may occur in the main subcellular pathways involved in gephyrin-dependent transsynaptic signaling.

Background: Clinical evidence indicates that patients affected by Alzheimer's Disease (AD) fail to form new memories although their memories for old events are intact. This amnesic pattern depends on the selective vulnerability to AD-neurodegeneration of the hippocampus, the brain region that sustains the formation of new memories, while cortical regions that store remote memories are spared.

The dentate gyrus of the hippocampus is one of two brain areas generating throughout life new neurons, which contribute to the formation of episodic/associative memories. During aging, the production of new neurons decreases and a cognitive decline occurs. Dietary factors influence neuronal function and synaptic plasticity; among them the phenolic compound hydroxytyrosol (HTyr), present in olive oil, displays neuroprotective effects. As age impacts primarily on the hippocampus-dependent cognitive processes, we wondered whether HTyr could stimulate hippocampal neurogenesis in vivo in adult and aged wild-type mice as well as in the B-cell translocation 1 gene (Btg1) knockout mouse model of accelerated neural aging. We found that treatment with HTyr activates neurogenesis in the dentate gyrus of adult, aged, and Btg1-null mice, by increasing survival of new neurons and decreasing apoptosis. Notably, however, in the aged and Btg1-null dentate gyrus, HTyr treatment also stimulates the proliferation of stem and progenitor cells, whereas in the adult dentate gyrus HTyr lacks any proliferative effect. Moreover, the new neurons generated in aged mice after HTyr treatment are recruited to existing circuits, as shown by the increase of BrdU(+)/c-fos(+) neurons. Finally, HTyr treatment also reduces the markers of aging lipofuscin and Iba1. Overall, our findings indicate that HTyr treatment counteracts neurogenesis decline during aging.

Dimethyl fumarate (DMF) is the only available approved drug for first line treatment of multiple sclerosis (MS), a lethal condition impairing central nervous system (CNS). To date, however, little is known of its mechanisms of action. Only recently, it has been suggested that DMF exerts neuroprotective effects acting as an immunomodulator and that it may alter the activation state of microglia cells, crucial in MS pathogenesis. However, DMF effects on microglia functions are still not well determined. Here, we examine the effects of DMF treatment on microglia functional activities, as phenotype, morphology, processes motility and rearrangement, migration, ATP response and iron uptake in mouse primary microglia culture and acute hippocampal slices. We found that DMF treatment reduces microglia motility, downregulating functional response to ATP, increases ferritin uptake and pushes microglia towards an anti-inflammatory phenotype, thus reducing its proinflammatory reactivity in response to tissue damage. These results highlight the effects of this compound on microglia functions and provide new insights on the mechanism of action of DMF in MS treatment.

Dietary fats and sugars were identified as risk factors for overweight and neurodegeneration, especially in middle-age, an earlier stage of the aging process. Therefore, our aim was to study the metabolic response of both white adipose tissue and brain in middle aged rats fed a typical Western diet (high in saturated fats and fructose, HFF) and verify whether a similarity exists between the two tissues. Specific cyto/adipokines (tumor necrosis factor alpha (TNF-?), adiponectin), critical obesity-inflammatory markers (haptoglobin, lipocalin), and insulin signaling or survival protein network (insulin receptor substrate 1 (IRS), Akt, Erk) were quantified in epididymal white adipose tissue (e-WAT), hippocampus, and frontal cortex. We found a significant increase of TNF-? in both e-WAT and hippocampus of HFF rats, while the expression of haptoglobin and lipocalin was differently affected in the various tissues. Interestingly, adiponectin amount was found significantly reduced in e-WAT, hippocampus, and frontal cortex of HFF rats. Insulin signaling was impaired by HFF diet in e-WAT but not in brain. The above changes were associated with the decrease in brain derived neurotrophic factor (BDNF) and synaptotagmin I and the increase in post-synaptic protein PSD-95 in HFF rats. Overall, our investigation supports for the first time similarities in the response of adipose tissue and brain to Western diet.

Recent theories of episodic memory (EM) posit that the hippocampus provides a spatiotemporal framework necessary for representing events. If such theories hold true, then does the development of EM in children depend on the ability to first bind spatial and temporal information? And does this ability rely, at least in part, on normal hippocampal function? We investigated the development of EM in children 2-8 years of age (Study 1) and its impairment in Williams Syndrome, a genetic neurodevelopmental disorder characterized by visuospatial deficits and irregular hippocampal function, (Study 2) by implementing a nonverbal object-placement task that dissociates the what, where, and when components of EM. Consistent with the spatiotemporal-framework view of hippocampal EM, our results indicate that the binding of where and when in memory emerges earliest in development, around the age of 3, and is specifically impaired in WS. Space-time binding both preceded and was critical to full EM (what + where + when), and the successful association of objects to spatial locations seemed to mediate this developmental process.

Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+/Mg(2+)ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron-microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.

Brain injuries causing chronic sensory or motor deficit, such as stroke, are among the leading causes of disability worldwide, according to the World Health Organization; furthermore, they carry heavy social and economic burdens due to decreased quality of life and need of assistance. Given the limited effectiveness of rehabilitation, novel therapeutic strategies are required to enhance functional recovery. Since cell-based approaches have emerged as an intriguing and promising strategy to promote brain repair, many efforts have been made to study the functional integration of neurons derived from pluripotent stem cells (PSCs), or fetal neurons, after grafting into the damaged host tissue. PSCs hold great promises for their clinical applications, such as cellular replacement of damaged neural tissues with autologous neurons. They also offer the possibility to create in vitro models to assess the efficacy of drugs and therapies. Notwithstanding these potential applications, PSC-derived transplanted neurons have to match the precise sub-type, positional and functional identity of the lesioned neural tissue. Thus, the requirement of highly specific and efficient differentiation protocols of PSCs in neurons with appropriate neural identity constitutes the main challenge limiting the clinical use of stem cells in the near future. In this Review, we discuss the recent advances in the derivation of telencephalic (cortical and hippocampal) neurons from PSCs, assessing specificity and efficiency of the differentiation protocols, with particular emphasis on the genetic and molecular characterization of PSC-derived neurons. Second, we address the remaining challenges for cellular replacement therapies in cortical brain injuries, focusing on electrophysiological properties, functional integration and therapeutic effects of the transplanted neurons.

While the neurobiology of simple and habitual choices is relatively well known, our current understanding of goal-directed choices and planning in the brain is still limited. Theoretical work suggests that goal-directed computations can be productively associated to modelbased (reinforcement learning) computations, yet a detailed mapping between computational processes and neuronal circuits remains to be fully established. Here we report a computational analysis that aligns Bayesian nonparametrics and model-based reinforcement learning (MB-RL) to the functioning of the hippocampus (HC) and the ventral striatum (vStr)-a neuronal circuit that increasingly recognized to be an appropriate model system to understand goal-directed (spatial) decisions and planning mechanisms in the brain. We test the MB-RL agent in a contextual conditioning task that depends on intact hippocampus and ventral striatal (shell) function and show that it solves the task while showing key behavioral and neuronal signatures of the HC-vStr circuit. Our simulations also explore the benefits of biological forms of look-ahead prediction (forward sweeps) during both learning and control. This article thus contributes to fill the gap between our current understanding of computational algorithms and biological realizations of (model-based) reinforcement learning.