Brief exposure to enriched environment rapidly shapes the glutamate synapses in the rat brain: A metaplastic fingerprint.

Environmental enrichment (EE) has been shown to produce beneficial effects in addiction disorders; however, due to its configurational complexity, the underlying mechanisms are not yet fully elucidated. Recent evidence suggests that EE, acting as a metaplastic agent, may affect glutamatergic mechanisms underlying appetitive memory and, in turn, modulate reward-seeking behaviours: here, we have investigated such a possibility following a brief EE exposure. Adult male Sprague-Dawley rats were exposed to EE for 22 h and the expression of critical elements of the glutamate synapse was measured 2 h after the end of EE in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (Hipp) brain areas, which are critical for reward and memory. We focused our investigation on the expression of NMDA and AMPA receptor subunits, their scaffolding proteins SAP102 and SAP97, vesicular and membrane glutamate transporters vGluT1 and GLT-1, and critical structural components such as proteins involved in morphology and function of glutamatergic synapses, PSD95 and Arc/Arg3.1. Our findings demonstrate that a brief EE exposure induces metaplastic changes in glutamatergic mPFC, NAc and Hipp. Such changes are area-specific and involve postsynaptic NMDA/AMPA receptor subunit composition, as well as changes in the expression of their main scaffolding proteins, thus influencing the retention of such receptors at synaptic sites. Our data indicate that brief EE exposure is sufficient to dynamically modulate the glutamatergic synapses in mPFC-NAc-Hipp circuits, which may modulate rewarding and memory processes.

Hybrid reference-based Video Source Identification.

Millions of users share images and videos generated by mobile devices with different profiles on social media platforms. When publishing illegal content, they prefer to use anonymous profiles. Multimedia Forensics allows us to determine whether videos or images have been captured with the same device, and thus, possibly, by the same person. Currently, the most promising technology to achieve this task exploits unique traces left by the camera sensor into the visual content. However, image and video source identification are still treated separately from one another. This approach is limited and anachronistic, if we consider that most of the visual media are today acquired using smartphones that capture both images and videos. In this paper we overcome this limitation by exploring a new approach that synergistically exploits images and videos to study the device from which they both come. Indeed, we prove it is possible to identify the source of a digital video by exploiting a reference sensor pattern noise generated from still images taken by the same device. The proposed method provides performance comparable with or even better than the state-of-the-art, where a reference pattern is estimated from video frames. Finally, we show that this strategy is effective even in the case of in-camera digitally stabilized videos, where a non-stabilized reference is not available, thus solving the limitations of the current state-of-the-art. We also show how this approach allows us to link social media profiles containing images and videos captured by the same sensor.

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats.

Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24 h before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24 h and 7 d after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK-801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24 h after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation.

A New Dataset for Source Identification of High Dynamic Range Images.

Digital source identification is one of the most important problems in the field of multimedia forensics. While Standard Dynamic Range (SDR) images are commonly analyzed, High Dynamic Range (HDR) images are a less common research subject, which leaves space for further analysis. In this paper, we present a novel database of HDR and SDR images captured in different conditions, including various capturing motions, scenes and devices. As a possible application of this dataset, the performance of the well-known reference pattern noise-based source identification algorithm was tested on both kinds of images. Results have shown difficulties in source identification conducted on HDR images, due to their complexity and wider dynamic range. It is concluded that capturing conditions and devices themselves can have an impact on source identification, thus leaving space for more research in this field.

Ecocebo: How the interaction between environment and drug effects may improve pharmacotherapy outcomes.

This narrative review describes the research on the effects of the association between environmental context and medications, suggesting the benefit of specific design interventions in adjunction to pharmacotherapy. The literature on Evidence-Based Design (EBD) studies and Neuro-Architecture show how contact with light, nature, and specific physical features of urban and interior architecture may enhance the effects of analgesic, anxiolytics, and antidepressant drugs. This interaction mirrors those already known between psychedelics, drugs of abuse, and setting. Considering that the physical feature of space is a component of the complex placebo configuration, the aim is to highlight those elements of built or natural space that may help to improve drug response in terms of efficacy, tolerability, safety, and compliance. Ecocebo, the integration of design approaches such as EBD and Neuro-Architecture may thus contribute to a more efficient, cost-sensitive, and sustainable pharmacotherapy.

The effects of virtual reality environmental enrichments on craving to food in healthy volunteers.

RATIONALE: Environmental enrichment (EE) is a non-pharmacological approach that has been shown to be effective in reducing food-taking in rats. Studies in human volunteers are still in their infancy, given the difficulty to translate the complexity of EE in clinical practice. Virtual reality (VR) is a promising methodological approach, but no study has yet applied it to model and test EE in humans. OBJECTIVES: The present study is the first to assess the effects of virtual EE on craving for palatable food. METHODS: Eighty-one healthy volunteers (43 women) were divided into three groups: (i) exposure to a virtual EE (VR-EE), (ii) exposure to a virtual neutral environment (VR-NoEE), and (iii) without exposure to VR (No VR). Craving for palatable food at basal level and evoked by neutral and palatable food images was assessed before and after the VR simulation. Behavior during VR exposure and subjective measures related to the experience were also collected. RESULTS: VR-EE group showed a significantly greater decrease in pre-post craving difference compared to No VR for all assessments and at basal level compared to VR-NoEE. Interestingly, an inverse correlation between craving and deambulation in the VR simulation emerged in VR-EE group only. CONCLUSIONS: The study highlighted the feasibility of exposing human subjects to an EE as a virtual simulation. Virtual EE induced effects on basal craving for food that suggest the potential for further improvements of the protocol to extend its efficacy to palatable food cues.

PRNU-Based Video Source Attribution: Which Frames Are You Using?

Photo Response Non-Uniformity (PRNU) is reputed the most successful trace to identify the source of a digital video. However, its effectiveness is mainly limited by compression and the effect of recently introduced electronic image stabilization on several devices. In the last decade, several approaches were proposed to overcome both these issues, mainly by selecting those video frames which are considered more informative. However, the two problems were always treated separately, and the combined effect of compression and digital stabilization was never considered. This separated analysis makes it hard to understand if achieved conclusions still stand for digitally stabilized videos and if those choices represent a general optimum strategy to perform video source attribution. In this paper, we explore whether an optimum strategy exists in selecting frames based on their type and their positions within the groups of pictures. We, therefore, systematically analyze the PRNU contribute provided by all frames belonging to either digitally stabilized or not stabilized videos. Results on the VISION dataset come up with some insights into optimizing video source attribution in different use cases.

Glutamate receptors and metaplasticity in addiction.

Chronic drug use is a neuroadaptive disorder characterized by strong and persistent plasticity in the mesocorticolimbic reward system. Long-lasting effects of drugs of abuse rely on their ability to hijack glutamate receptor activity and long-term synaptic plasticity processes like long-term potentiation and depression. Importantly, metaplasticity-based modulation of synaptic plasticity contributes to durable neurotransmission changes in mesocorticolimbic pathways including the ventral tegmental area and the nucleus accumbens, causing 'maladaptive' drug memory and higher risk for drug-seeking relapse. On the other hand, drug-induced metaplasticity can make appetitive memories more malleable to modification, offering a potential target mechanism for intervention. Here we review the literature on the role of glutamate receptors in addiction-related metaplasticity phenomena.

Metaplastic Effects of Ketamine and MK-801 on Glutamate Receptors Expression in Rat Medial Prefrontal Cortex and Hippocampus.

Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients' refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on relevant brain areas for mood disorders. The aim of the present study was to investigate the molecular changes occurring at glutamatergic synapses 24 h after ketamine or MK-801 treatment in the rat medial prefrontal cortex (mPFC) and hippocampus (Hipp). In particular, we analyzed the levels of the glutamate transporter-1 (GLT-1), NMDA receptors, AMPA receptors subunits, and related scaffolding proteins. In the homogenate, we found a general decrease of protein levels, whereas their changes in the post-synaptic density were more complex. In fact, ketamine in the mPFC decreased the level of GLT-1 and increased the level of GluN2B, GluA1, GluA2, and scaffolding proteins, likely indicating a pattern of enhanced excitability. On the other hand, MK-801 only induced sparse changes with apparently no correlation to functional modification. Differently from mPFC, in Hipp, both substances reduced or caused no changes of glutamate receptors and scaffolding proteins expression. Ketamine decreased NMDA receptors while increased AMPA receptors subunit ratios, an effect indicative of permissive metaplastic modulation; conversely, MK-801 only decreased the latter, possibly representing a blockade of further synaptic plasticity. Taken together, these findings indicate a fine tuning of glutamatergic synapses by ketamine compared to MK-801 both in the mPFC and Hipp.

Protocols for instrumental memory reconsolidation in rodents: A methodological review.

BACKGROUND: Memory reconsolidation enables the update of a previously consolidated memory trace after its reactivation. Although Pavlovian memory reconsolidation has been widely demonstrated, instrumental memory reconsolidation is still debated. Early studies suggested that instrumental memories did not undergo reconsolidation and therefore could not be disrupted, whereas other authors suggested that these memories are just more resistant to destabilization and reconsolidation in comparison to Pavlovian memories. AIM AND RESULTS: The present paper reviews the behavioral protocols used to investigate appetitive instrumental memory reconsolidation in rodents and describes in detail the specific methods used for memory retrieval, with a critical analysis of the different experimental parameters. CONCLUSIONS: The modalities under which the reconsolidation of appetitive (sucrose or drugs of abuse) instrumental memories occurs have been explored and partially elucidated. Further investigations are recommended on the boundary conditions that constrain instrumental memory reactivation.

A Survey of Deep Learning-Based Source Image Forensics.

Image source forensics is widely considered as one of the most effective ways to verify in a blind way digital image authenticity and integrity. In the last few years, many researchers have applied data-driven approaches to this task, inspired by the excellent performance obtained by those techniques on computer vision problems. In this survey, we present the most important data-driven algorithms that deal with the problem of image source forensics. To make order in this vast field, we have divided the area in five sub-topics: source camera identification, recaptured image forensic, computer graphics (CG) image forensic, GAN-generated image detection, and source social network identification. Moreover, we have included the works on anti-forensics and counter anti-forensics. For each of these tasks, we have highlighted advantages and limitations of the methods currently proposed in this promising and rich research field.

The metaplastic effects of ketamine on sucrose renewal and contextual memory reconsolidation in rats.

Metaplastic effects of the NMDARs blocker ketamine at the neural and behavioural levels have been described as potential mechanisms underlying the beneficial effects in treatment-resistant depression. However, ketamine effects on addictive behaviours are still unexplored. In the present study, we investigated the effects of ketamine given under a "metaplasticity-inducing dose regimen" on sucrose-related renewal and contextual memory reconsolidation in rats. After a molecular analysis of ketamine modulation of GluN2B, GluA1 and mGluR5 receptors levels in nucleus accumbens, hippocampus and amygdala, two behavioural models were used to investigate ketamine effects: i) context-induced renewal of sucrose-seeking, and ii) sucrose memory reconsolidation. Ketamine was administrated 24 h before the renewal test or the retrieval. At the molecular level, ketamine i) decreased GluN2B, GluA1 and mGluR5 receptors in hippocampus, ii) decreased GluA1 and mGluR5 but increased GluN2B in nucleus accumbens and iii) increased GluN2B and mGluR5 in amygdala. At the behavioural level, ketamine given prior to renewal significantly inhibited responding compared to vehicle, while no significant effects were observed on reconsolidation of contextual memory. In conclusion, the molecular analysis of ketamine metaplastic effects in key brain areas suggest a possible involvement of glutamatergic receptors in the inhibition of sucrose renewal but not of contextual memory reconsolidation. The inhibition of renewal could be correlated to hippocampal and accumbal decreased levels of GluA1 and mGluR5, whereas, the lack of effect on contextual memory reconsolidation could be correlated to decreased GluN2B expression in hippocampus, landmark of destabilization-insensitive state.

Reconsolidation of sucrose instrumental memory in rats: The role of retrieval context.

Memory reconsolidation enables the update of a previously consolidated memory trace after its reactivation. Although Pavlovian memory reconsolidation has been widely demonstrated, instrumental memory reconsolidation is still debated. The most critical issue on instrumental memory reconsolidation findings have mainly been linked to the presence of specific boundary conditions for reactivation, for instance contextual parameters. In this study, we investigated the role of the spatial context on molecular markers of sucrose instrumental memory reactivation. Following withdrawal, rats previously conditioned to sucrose self-administration underwent either instrumental memory retrieval or no-retrieval in the conditioned context (Context A, AA condition) or in a modified version of the conditioned context (Context B, AB condition). Two hours later, the level of GluA1 and GluN2B receptors, Zif268 and phosphorylated-rpS6 (rpS6P) was measured in key brain areas for memory reactivation. Retrieval in Context A significantly increased GluA1Rs and GluN2BRs in amygdala compared to no-retrieval, indicating that memory successfully reactivated and destabilized. Moreover, Zif268 level was significantly increased after retrieval in Context A in the nucleus accumbens shell, central and basolateral amygdala but not in the hippocampus, while retrieval in Context B significantly increased Zif268 level in all brain areas. On the other hand, rpS6P level was increased in the nucleus accumbens shell and central amygdala, but decreased in the hippocampus, after retrieval in Context A, while retrieval in Context B did not change rpS6P level in brain areas, except for a small but significant decrease in hippocampus. While the increase of Zif268 level indicated that memory reactivation has been triggered in both the conditions, the lack of change in rpS6P levels after retrieval in Context B - in particular in the central amygdala - suggests that the reconsolidation process could not occur after memory reactivation in a context different from the conditioned one.

Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine.

RATIONALE: Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. OBJECTIVE: Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. RESULTS: We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. CONCLUSIONS: Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.

Ketamine Self-Administration Elevates αCaMKII Autophosphorylation in Mood and Reward-Related Brain Regions in Rats.

Modulation of αCaMKII expression and phosphorylation is a feature shared by drugs of abuse with different mechanisms of action. Accordingly, we investigated whether αCaMKII expression and activation could be altered by self-administration of ketamine, a non-competitive antagonist of the NMDA glutamate receptor, with antidepressant and psychotomimetic as well as reinforcing properties. Rats self-administered ketamine at a sub-anesthetic dose for 43 days and were sacrificed 24 h after the last drug exposure; reward-related brain regions, such as medial prefrontal cortex (PFC), ventral striatum (vS), and hippocampus (Hip), were used for the measurement of αCaMKII-mediated signaling. αCaMKII phosphorylation was increased in these brain regions suggesting that ketamine, similarly to other reinforcers, activates this kinase. We next measured the two main targets of αCaMKII, i.e., GluN2B (S1303) and GluA1 (S831), and found increased activation of GluN2B (S1303) together with reduced phosphorylation of GluA1 (S831). Since GluN2B, via inhibition of ERK, regulates the membrane expression of GluA1, we measured ERK2 phosphorylation in the crude synaptosomal fraction of these brain regions, which was significantly reduced suggesting that ketamine-induced phosphorylation of αCaMKII promotes GluN2B (S1303) phosphorylation that, in turn, inhibits ERK 2 signaling, an effect that results in reduced membrane expression and phosphorylation of GluA1. Taken together, our findings point to αCaMKII autophosphorylation as a critical signature of ketamine self-administration providing an intracellular mechanism to explain the different effects caused by αCaMKII autophosphorylation on the post-synaptic GluN2B- and GluA1-mediated functions. These data add ketamine to the list of drugs of abuse converging on αCaMKII to sustain their addictive properties.

Ketamine Self-Administration Reduces the Homeostasis of the Glutamate Synapse in the Rat Brain.

Ketamine is a non-competitive antagonist of the NMDA glutamate receptor with psychotomimetic and reinforcing properties, although recent work has pointed out its antidepressant action following acute exposure. Our aim was to investigate the expression of crucial components of the glutamate synapse following chronic ketamine self-administration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. Rats self-administered ketamine at a sub-anesthetic dose for 5-6 weeks and were sacrificed 24 h after the last drug exposure. We found a general downregulation of glutamate receptor expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of NMDA receptor subunits, whereas AMPA receptor protein levels were reduced in Hip; of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC and Hip, respectively. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in these brain regions. These findings reveal a dynamic impairment of glutamate homeostasis in the mPFC and Hip that may represent a signature of long-term exposure to ketamine S/A. Further, this decrement, similarly observed in humans and animal models of schizophrenia may represent a specific feature of the human disease endophenotype.