Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent adaptations within brain ...reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of gamma-aminobutyric acidergic striatal projection neurons (SPNs) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D1 receptor) and indirect (D2 receptor) SPN pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA, which mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto direct and indirect SPN pathways by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type–specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtype and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses, as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction.
Memory consolidation refers to a slow process that stabilises a memory trace after initial acquisition of novel events. The consolidation theory posits that once a memory is stored in the brain, it ...remains fixed for the lifetime of the memory. However, compelling evidence has suggested that upon recall, memories can re-enter a state of transient instability, requiring further stabilisation to be available once again for recall. Since its rehabilitation in the past ten years, this process of reconsolidation of memory after recall stimulated intense debates in the field of cognitive neuroscience. In this review we compile this plentiful literature with a particular emphasis on some of the key questions that have emerged from the reconsolidation theory. We focus on tracing the characterisation of the boundary conditions that constrain the occurrence of memory reconsolidation. We also discuss accumulating evidence supporting the idea that reconsolidation, as implied by its definition, is not a mere repetition of consolidation. We review seminal studies that uncovered specific mechanisms recruited during reconsolidation that are not always crucially involved in consolidation. We next address the physiological significance of reconsolidation since several lines of evidence support the idea that reconsolidation, as opposed to consolidation, may offer a unique opportunity to update memories. We finally discuss recent evidence for or against the potential that the process of memory reconsolidation offers for ongoing efforts to develop novel strategies to combat pathogenic memories.
Huntington's disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin's gene. The associated neurodegeneration mainly affects ...the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.
Over the past few years multiple studies have attempted to uncover molecular signatures of memory reconsolidation when compared to consolidation. In the present study we used immunocytochemical ...detection of the MAPK/ERK1/2 pathway, to track activated neuronal circuits in the hippocampus and amygdala recruited during the consolidation and reconsolidation of a contextual fear conditioning (CFC) memory. We report selective differences in magnitude and temporal dynamics of activated ERK1/2 signalling in different subregions of these two structures between the post-training and post-retrieval periods, except in the dentate gyrus, where the patterns of activation were similar. We then focused on this brain area to dissect out the patterns of downstream ERK1/2 signalling components, including the phosphorylation of MSK-1 and histone H3 on ser10, along with the induction of the Immediate Early Genes (IEGs) Arc/Arg3.1, c-Fos and Zif268/Egr1 following CFC training and retrieval. We found that the completion of the nucleosomal response as well as the induction of IEGs shorter during the reconsolidation period as compared to consolidation. Our results shed new light on the cellular mechanisms underlying the consolidation and reconsolidation processes engaged following CFC training and retrieval and further extend the notion that memory reconsolidation is not mechanistically a repetition of consolidation. In addition, we provide evidence that the strength of a previously established CFC memory is characterized by distinct patterns of ERK1/2 activation in different hippocampal and amygdalar subfields upon CFC memory recall. Our results emphasize the differences between consolidation and reconsolidation processes in relation to contextual fear memories.
The capacity to remember our past experiences and organize our future draws on a number of cognitive processes that allow our brain to form and store neural representations that can be recalled and ...updated at will. In the brain, these processes require mechanisms of neural plasticity in the activated circuits, brought about by cellular and molecular changes within the neurons activated during learning. At the cellular level, a wealth of experimental data accumulated in recent years provides evidence that signaling from synapses to nucleus and the rapid regulation of the expression of immediate early genes encoding inducible, regulatory transcription factors is a key step in the mechanisms underlying synaptic plasticity and the modification of neural networks required for the laying down of memories. In the activated neurons, these transcriptional events are thought to mediate the activation of selective gene programs and subsequent synthesis of proteins, leading to stable functional and structural remodeling of the activated networks, so that the memory can later be reactivated upon recall. Over the past few decades, novel insights have been gained in identifying key transcriptional regulators that can control the genomic response of synaptically activated neurons. Here, as an example of this approach, we focus on one such activity-dependent transcription factor, Zif268, known to be implicated in neuronal plasticity and memory formation. We summarize current knowledge about the regulation and function of Zif268 in different types of brain plasticity and memory processes.
Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain ...cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington's disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington's disease.
Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by ...the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.
Compelling evidence points to the existence of independent cellular processes involved in the consolidation and reconsolidation of memory. For instance, a double dissociation has been reported ...between hippocampal Extracellular-Regulated Kinase-1/2 (ERK1/2) activity being necessary for contextual fear conditioning (CFC) consolidation but not reconsolidation. Conversely, hippocampal expression of the immediate early gene Zif268 is necessary for CFC reconsolidation but not consolidation. Since we previously reported that ERK1/2 controls the transcription of Zif268 in the hippocampus, we examined the precise role of ERK1/2 activity and Zif268 gene expression dosage in CFC memory processing. For this, we first assessed performance of Zif268 homozygous and heterozygous mutant mice in a CFC paradigm. Whereas Zif268-/- mice displayed a deficit of both consolidation and reconsolidation, Zif268+/- mice displayed a selective deficit of reconsolidation only, therefore pointing to the relationship between Zif268 gene expression dosage and CFC memory processing. Zif268 gene expression dosage interfered with the reconsolidation process if and only if CFC memory was relatively recently encoded and directly reactivated. Furthermore, CFC memory strengthening previously reported to involve Zif268 expression in the hippocampus was spared in Zif268+/- mice. Finally, blocking ERK1/2 activity prior to CFC retrieval prevented the deficit of reconsolidation observed in Zif268+/- mice. Collectively, these results highlight a tight relationship between Zif268 gene expression dosage and CFC memory processing. They also suggest that ERK1/2 activity upon CFC memory recall is necessary for its retrieval, a prerequisite for its reactivation and subsequent reconsolidation.
Various experimental models are used to study brain development and degeneration. They range from whole animal models, which preserve anatomical structures but strongly limit investigations at the ...cellular level, to dissociated cell culture systems that allow detailed observation of cell phenotypes but lack the highly ordered physiological neuron connection architecture. We describe here a platform comprising independent cell culture chambers separated by an array of "axonal diodes". This array involves asymmetric micro-channels, imposing unidirectional axon connectivity with 97% selectivity. It allows the construction of complex, oriented neuronal networks not feasible with earlier platforms. Different neuronal subtypes could be co-cultivated for weeks, and sequential seeding of different cell populations reproduced physiological network development. To illustrate possible applications, we created and characterized a cortico-striatal oriented network. Functional synaptic connections were established. The activation of striatal differentiation by cortical axons, and the synchronization of neural activity were demonstrated. Each neuronal population and subcompartment could be chemically addressed individually. The directionality of neural pathways being a key feature of the nervous system organization, the axon diode concept brings in a paradigmatic change in neuronal culture platforms, with potential applications for studying neuronal development, synaptic transmission and neurodegenerative disorder such as Alzheimer and Parkinson diseases at the sub-cellular, cellular and network levels.
Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this ...context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca2+ signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.
•5-HT signaling controls t-LTD in striatal projection neurons of the direct pathway•5-HT signaling shapes dendritic Ca2+ signals•5-HT-mediated regulation of t-LTD biases thalamostriatal synapses•Gating of t-LTD requires dampened activity of the 5-HT4R subtype, which modulates BK channel function
Cavaccini and Gritti et al. combine chemogenetic and optogenetic approaches to show that serotonergic signaling provides a control mechanism of synaptic plasticity at thalamic inputs to the striatum.
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