Transcending the amyloid-beta dominance paradigm in Alzheimer's disease: An exploration of behavioural, metabolic, and gut microbiota phenotypes in 5xFAD mice.

The amyloid cascade hypothesis is widely accepted as an explanation for the neuropathological changes in Alzheimer's disease (AD). However, the role of amyloid-beta (Aß) as the sole cause of these changes is being questioned. Using the 5xFAD mouse model of AD, we investigated various factors contributing to neuropathology, including genetic load (heterozygous (HTZ) versus homozygous (HZ) condition), behavioural phenotype, neuropathology markers, metabolic physiology, and gut microbiota composition at early (5 months of age) and late (12 months of age) stages of disease onset, and considering both sexes. At 5 months of age, both HTZ and HZ mice exhibited hippocampal alterations associated with Aß accumulation, leading to increased neuroinflammation and disrupted PI3K-Akt pathway. However, only HZ mice showed cognitive impairment in the Y-maze and Morris water maze tests, worsening with age. Dysregulation of both insulin and insulin secretion-regulating GIP peptide were observed at 5 months of age, disappearing later. Circulating levels of metabolic-regulating hormones, such as Ghrelin and resisting helped to differentiates HTZ mice from HZ mice. Differences between HTZ and HZ mice were also observed in gut microbiota composition, disrupted intestinal barrier proteins, and increased proinflammatory products in the intestine. These findings suggest that cognitive impairment in 5xFAD mice may not solely result from Aß aggregation. Other factors, including altered PI3K-Akt signalling, disrupted insulin-linked metabolic pathways, and changes in gut microbiota, contribute to disease progression. Targeting Aß deposition alone may not suffice. Understanding AD pathogenesis and its multiple contributing factors is vital for effective therapies.

Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice.

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.

Long-term consequences of alcohol use in early adolescent mice: Focus on neuroadaptations in GR, CRF and BDNF.

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a 5-week two-bottle choice protocol (postnatal day [pd]21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals' age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation and cognition.

Remote memory of drug experiences coexists with cognitive decline and abnormal adult neurogenesis in an animal model of cocaine-altered cognition.

Cocaine addiction is a chronic disorder in which the person loses control over drug use. The past memories of the stimuli associated with the drug are a relevant clinical problem, since they trigger compulsive drug-seeking and drug-taking habits. Furthermore, these persistent drug-related memories seemingly coexist with cognitive decline that predicts worse therapeutic output. Here, we use a new animal model of cocaine-altered cognition that allowed to observe these events in the same individual and study their relationship. Mice were chronically administered cocaine in a conditioned place preference (CPP) apparatus for 14 days, and control mice received saline. After 28 days of cocaine withdrawal, animals were tested for retrieval of remote drug-associated memory as well as for cognitive performance in a battery of tests, including novel object and place recognition and spatial memory. The cocaine-withdrawn mice showed persistent CPP memory while impaired in the cognitive tasks, displaying deficits in reference memory acquisition and working memory. However, the CPP expression was not associated with the defective cognitive performance, indicating that they were concomitant but independent occurrences. After completion of the experiment, adult hippocampal neurogenesis (AHN) was studied as a relevant neurobiological correlate due to its potential role in both learning and drug addiction. Results suggested a preserved basal AHN in the cocaine-withdrawn mice but an aberrant learning-induced regulation of these neurons. This paradigm may be useful to investigate maladaptive cognition in drug addiction as well as related therapies.

Where to place the rewards? Exploration bias in mice influences performance in the classic hole-board spatial memory test.

The classic hole-board paradigm (a square arena with 16 holes arranged equidistantly in a 4 × 4 pattern) assesses both exploration and spatial memory in rodents. For spatial memory training, food rewards are hidden in a fixed set of holes. The animal must not visit (i.e. nose-poke) the holes that are never baited (reference memory; RM) nor re-visit a baited hole within a session (working memory; WM). However, previous exploratory bias may affect performance during reward searching. During habituation sessions with either all holes rewarded or all holes empty, mice intrinsically preferred poking peripheral holes (especially those located in the maze's corners) over centre holes. During spatial memory training, mice progressively shifted their hole pokes and staying time to the central area that contained hidden rewards, while mice exposed to the empty apparatus still preferred the periphery. A group of pseudotrained mice, for whom rewards were located randomly throughout the maze, also increased their central preference. Furthermore, reward location influenced memory measures. Most repeated pokes (WM-errors) were scored in the locations that were most intrinsically appealing to mice (i.e. the corner and wall-baited holes), supporting a strong influence of previous exploratory bias. Regarding RM, finding rewards located in the centre holes, which were initially less preferred, entailed more difficulty and required more trials to learn. This outcome was confirmed by a second experiment that varied the pattern of rewarded holes, as well as the starting positions. Therefore, reward location is a relevant aspect to consider when designing a hole-board memory task.

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory.

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 -receptor-deficient mice were acutely infused with LPA, which revealed that LPA1 -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.

Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

Involvement of IGF-II receptors in the antioxidant and neuroprotective effects of IGF-II on adult cortical neuronal cultures.

Insulin-like growth factor-II (IGF-II) is a naturally occurring peptide that exerts known pleiotropic effects ranging from metabolic modulation to cellular development, growth and survival. IGF-II triggers its actions by binding to and activating IGF (IGF-I and IGF-II) receptors. In this study, we assessed the neuroprotective effect of IGF-II on corticosterone-induced oxidative damage in adult cortical neuronal cultures and the role of IGF-II receptors in this effect. We provide evidence that treatment with IGF-II alleviates the glucocorticoid-induced toxicity to neuronal cultures, and this neuroprotective effect occurred due to a decrease in reactive oxygen species (ROS) production and a return of the antioxidant status to normal levels. IGF-II acts via not only the regulation of synthesis and/or activity of antioxidant enzymes, especially manganese superoxide dismutase, but also the restoration of mitochondrial cytochrome c oxidase activity and mitochondrial membrane potential. Although the antioxidant effect of IGF-I receptor activation has been widely reported, the involvement of the IGF-II receptor in these processes has not been clearly defined. The present report is the first evidence describing the involvement of IGF-II receptors in redox homeostasis. IGF-II may therefore contribute to the mechanisms of neuroprotection by acting as an antioxidant, reducing the neurodegeneration induced by oxidative insults. These results open the field to new pharmacological approaches to the treatment of diseases involving imbalanced redox homeostasis. In this study, we demonstrated that the antioxidant effect of IGF-II is at least partially mediated by IGF-II receptors.

Voluntary exercise followed by chronic stress strikingly increases mature adult-born hippocampal neurons and prevents stress-induced deficits in 'what-when-where' memory.

We investigated whether voluntary exercise prevents the deleterious effects of chronic stress on episodic-like memory and adult hippocampal neurogenesis. After bromodeoxyuridine (BrdU) administration, mice were assigned to receive standard housing, chronic intermittent restraint stress, voluntary exercise or a combination of both (stress starting on the seventh day of exercise). Twenty-four days later, mice were tested in a 'what-when-where' object recognition memory task. Adult hippocampal neurogenesis (proliferation, differentiation, survival and apoptosis) and c-Fos expression in the hippocampus and extra-hippocampal areas (medial prefrontal cortex, amygdala, paraventricular hypothalamic nucleus, accumbens and perirhinal cortex) were assessed after behavior. Chronic intermittent restraint stress impaired neurogenesis and the 'when' memory, while exercise promoted neurogenesis and improved the 'where' memory. The 'when' and 'where' memories correlated with c-Fos expression in CA1 and the dentate gyrus, respectively. Furthermore, analysis suggested that each treatment induced a distinct pattern of functional connectivity among the areas analyzed for c-Fos. In the animals in which stress and exercise were combined, stress notably reduced the amount of voluntary exercise performed. Nevertheless, exercise still improved memory and counteracted the stress induced-deficits in neurogenesis and behavior. Interestingly, compared with the other three treatments, the stressed exercising animals showed a larger increase in cell survival, the maturation of new neurons and apoptosis in the dentate gyrus, with a considerable increase in the number of 24-day-old BrdU+cells that differentiated into mature neurons. The interaction between exercise and stress in enhancing the number of adult-born hippocampal neurons supports a role of exercise-induced neurogenesis in stressful conditions.

Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis.

Cocaine-related contextual cues are a recurrent source of craving and relapse. Extinction of cue-driven cocaine seeking remains a clinical challenge, and the search for adjuvants is ongoing. In this regard, combining physical and cognitive training is emerging as a promising strategy that has shown synergistic benefits on brain structure and function, including enhancement of adult hippocampal neurogenesis (AHN), which has been recently linked to reduced maintenance of maladaptive drug seeking. Here, we examined whether this behavioral approach disrupts cocaine-context associations via improved AHN. To this aim, C57BL/6J mice (N = 37) developed a cocaine-induced conditioned place preference (CPP) and underwent interventions consisting of exercise and/or spatial working memory training. Bromodeoxyuridine (BrdU) was administered during early running sessions to tag a subset of new dentate granule cells (DGCs) reaching a critical window of survival during spatial learning. Once these DGCs became functionally mature (∼ 6 weeks-old), mice received extinction training before testing CPP extinction and reinstatement. We found that single and combined treatments accelerated CPP extinction and prevented reinstatement induced by a low cocaine priming (2 mg/kg). Remarkably, the dual-intervention mice showed a significant decrease of CPP after extinction relative to untreated animals. Moreover, combining the two strategies led to increased number and functional integration of BrdU+ DGCs, which in turn maximized the effect of spatial training (but not exercise) to reduce CPP persistence. Together, our findings suggests that sequencing physical and cognitive training may redound to decreased maintenance of cocaine-context associations, with multi-level stimulation of AHN as a potential underlying mechanism.

Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice.

The present study was designed to investigate the effect of pharmacological inhibition of endocannabinoid degradation on behavioural actions of the dopamine D2/D3 receptor agonist quinpirole in male C57Bl/6J mice. In addition, we studied the effects of endocannabinoid degradation inhibition on both cocaine-induced psychomotor activation and behavioural sensitization. We analysed the effects of inhibition of the two main endocannabinoid degradation enzymes: fatty acid amide hydrolase (FAAH), using inhibitor URB597 (1 mg/kg); monoacylglycerol lipase (MAGL), using inhibitor URB602 (10 mg/kg). Administration of quinpirole (1 mg/kg) caused a temporal biphasic response characterized by a first phase of immobility (0-50 min), followed by enhanced locomotion (next 70 min) that was associated with the introduction of stereotyped behaviours (stereotyped jumping and rearing). Pretreatment with both endocannabinoid degradation inhibitors did not affect the hypoactivity actions of quinpirole. However, this pretreatment resulted in a marked decrease in quinpirole-induced locomotion and stereotyped behaviours. Administration of FAAH or MAGL inhibitors did not attenuate the acute effects of cocaine. Furthermore, these inhibitors did not impair the acquisition of cocaine-induced behavioural sensitization or the expression of cocaine-induced conditioned locomotion. Only MAGL inhibition attenuated the expression of an already acquired cocaine-induced behavioural sensitization. These results suggest that pharmacological inhibition of endocannabinoid degradation might exert a negative feedback on D2/D3 receptor-mediated hyperactivity. This finding might be relevant for therapeutic approaches for either psychomotor disorders (dyskinesia, corea) or disorganized behaviours associated with dopamine-mediated hyperactivity.

Unveiling the Secrets of the Stressed Hippocampus: Exploring Proteomic Changes and Neurobiology of Posttraumatic Stress Disorder.

Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number of other psychopathologies. PTSD is a very heterogeneous disorder with different subtypes that depend on, among other factors, the type of stressor that provokes it. However, the neurobiological mechanisms are poorly understood. The study of early stress responses may hint at the way PTSD develops and improve the understanding of the neurobiological mechanisms involved in its onset, opening the opportunity for possible preventive treatments. Proteomics is a promising strategy for characterizing these early mechanisms underlying the development of PTSD. The aim of the work was to understand how exposure to acute and intense stress using water immersion restraint stress (WIRS), which could be reminiscent of natural disaster, may induce several PTSD-associated symptoms and changes in the hippocampal proteomic profile. The results showed that exposure to WIRS induced behavioural symptoms and corticosterone levels reminiscent of PTSD. Moreover, the expression profiles of hippocampal proteins at 1 h and 24 h after stress were deregulated in favour of increased inflammation and reduced neuroplasticity, which was validated by histological studies and cytokine determination. Taken together, these results suggest that neuroplastic and inflammatory dysregulation may be a therapeutic target for the treatment of post-traumatic stress disorders.

When is adult hippocampal neurogenesis necessary for learning? evidence from animal research.

The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.

Do changes in microglial status underlie neurogenesis impairments and depressive-like behaviours induced by psychological stress? A systematic review in animal models.

Stress may have a negative effect on mental health and is the primary environmental risk factor in the aetiology of depression. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The hippocampus is a target structure of the adverse effects of stress, and hippocampal neurogenesis plays a crucial role. However, we do not know the mechanisms by which stress impacts neurogenesis. Recent studies indicate that changes in neuroinflammation, primarily via microglial cells, may play an essential role in this process. However, the relationship between stress, microglial changes, and alterations in neurogenesis and their involvement in the development of depression is poorly characterized. For this reason, this systematic review aims to synthesise and evaluate current studies that have investigated the relationship between these variables. Taken together, the revised data, although not entirely conclusive, seem to suggest that microglial changes induced by psychological stress regulate neurogenesis and in turn may be responsible for the development of depressive-like behaviours, but other factors that influence these stressful experiences should not be dismissed.

Persistent changes in exploration and hyperactivity coexist with cognitive impairment in mice withdrawn from chronic cocaine.

Repeated cocaine exposure induces lasting neurobehavioral adaptations such as cognitive decline in animal models. However, persistent changes in spontaneous -unconditioned- motor and exploratory responses are scarcely reported. In this study, mice were administered with cocaine (20 mg/kg/day) or vehicle for 12 consecutive days. After 24 days of drug abstinence, a behavioral assessment was carried out in drug-free conditions and in unfamiliar environments (i.e. no cocaine-associated cues were presented). The cocaine-withdrawn mice showed cognitive deficits in spontaneous alternation behavior and place recognition memory. Importantly, they also displayed hyperlocomotion, increased rearing activity and altered exploratory patterns in different tasks. In the forced swimming test, they were more active (struggled/climbed more) when trying to escape from the water albeit showing normal immobility behavior. In conclusion, in addition to cognitive deficits, chronic cocaine in rodents may induce long-lasting alterations in exploratory activity and psychomotor activation that are triggered even in absence of drug-related stimuli.

Insulin-like growth factor II prevents oxidative and neuronal damage in cellular and mice models of Parkinson's disease.

Oxidative distress and mitochondrial dysfunction, are key factors involved in the pathophysiology of Parkinson's disease (PD). The pleiotropic hormone insulin-like growth factor II (IGF-II) has shown neuroprotective and antioxidant effects in some neurodegenerative diseases. In this work, we demonstrate the protective effect of IGF-II against the damage induced by 1-methyl-4-phenylpyridinium (MPP+) in neuronal dopaminergic cell cultures and a mouse model of progressive PD. In the neuronal model, IGF-II counteracts the oxidative distress produced by MPP + protecting dopaminergic neurons. Improved mitochondrial function, increased nuclear factor (erythroid-derived 2)-like2 (NRF2) nuclear translocation along with NRF2-dependent upregulation of antioxidative enzymes, and modulation of mammalian target of rapamycin (mTOR) signalling pathway were identified as mechanisms leading to neuroprotection and the survival of dopaminergic cells. The neuroprotective effect of IGF-II against MPP + -neurotoxicity on dopaminergic neurons depends on the specific IGF-II receptor (IGF-IIr). In the mouse model, IGF-II prevents behavioural dysfunction and dopaminergic nigrostriatal pathway degeneration and mitigates neuroinflammation induced by MPP+. Our work demonstrates that hampering oxidative stress and normalising mitochondrial function through the interaction of IGF-II with its specific IGF-IIr are neuroprotective in both neuronal and mouse models. Thus, the modulation of the IGF-II/IGF-IIr signalling pathway may be a useful therapeutic approach for the prevention and treatment of PD.

Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis.

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.

Plasma Concentrations of Lysophosphatidic Acid and Autotaxin in Abstinent Patients with Alcohol Use Disorder and Comorbid Liver Disease.

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX-LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX-LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX-LPA axis and AUD or liver disease. LPA and ATX were log10-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F(1,131) = 10.677, p = 0.001) and higher ATX (F(1,131) = 8.327, p = 0.005) concentrations than control subjects; patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, p < 0.05) than patients with AUD but not liver disease; significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, p < 0.05); and the severity of AUD with ATX (rho = -0.33, p < 0.05)); and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, p < 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX-LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases.