ABSTRACT
OBJECTIVE: Anorexia nervosa (AN) is characterized by hyperactivation of the hypothalamic-pituitary-adrenal axis and cognitive deficits. However, little is known about the rapid non-genomic stress response involvement. This study investigates the molecular, structural and behavioral signatures of the anorexic phenotype induction in female rats on stress-related mechanisms in the hippocampus. METHOD: Female adolescent rats, exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, were sacrificed in the acute phase of the pathology (postnatal day [P]42) or following a 7-day recovery period (P49). RESULTS: ABA rats, in addition to body weight loss and increased wheel activity, alter their pattern of activity over days, showing increased food anticipatory activity, a readout of their motivation to engage in intense physical activity. Corticosterone plasma levels were enhanced at P42 while reduced at P49 in ABA rats. In the membrane fraction of the hippocampus, we found reduced glucocorticoid receptor levels together with reduced expression of caldesmon, n-cadherin and neuroligin-1, molecular markers of cytoskeletal stability and glutamatergic homeostasis. Accordingly, structural analyses revealed reduced dendritic spine density, a reduced number of mushroom-shaped spines, together with an increased number of thin-shaped spines. These events are paralleled by impairment in spatial memory measured in the spatial order object recognition test. These effects persisted even when body weight of ABA rats was restored. DISCUSSION: Our findings indicate that ABA induction orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.
Subject(s)
Hippocampus , Animals , Female , Hippocampus/metabolism , Rats , Spatial Memory/physiology , Anorexia/metabolism , Anorexia/physiopathology , Anorexia/pathology , Corticosterone/blood , Stress, Psychological/physiopathology , Stress, Psychological/metabolism , Memory Disorders/physiopathology , Memory Disorders/pathology , Rats, Wistar , Receptors, Glucocorticoid/metabolism , Anorexia Nervosa/metabolism , Anorexia Nervosa/physiopathology , Anorexia Nervosa/pathology , Disease Models, AnimalABSTRACT
Introduction: Early social environment, either positive or negative, shapes the adult brain. Communal nesting (CN), a naturalistic setting in which 2-3 females keep their pups in a single nest sharing care-giving behavior, provides high level of peer interaction for pups. Early social isolation (ESI) from dam and siblings represents, instead, an adverse condition providing no peer interaction. Methods: We investigated whether CN (enrichment setting) might influence the response to ESI (impoverishment setting) in terms of social behavior and glutamate system in the medial prefrontal cortex (mPFC) of adult and adolescent male and female rats. Results: Pinning (a rewarding component of social play behavior) was significantly more pronounced in males than in females exposed to the combination of CN and ESI. CN sensitized the glutamate synapse in the mPFC of ESI-exposed male, but not female, rats. Accordingly, we observed (i) a potentiation of the glutamatergic neurotransmission in the mPFC of both adolescent and adult males, as shown by the recruitment of NMDA receptor subunits together with increased expression/activation of PSD95, SynCAM 1, Synapsin I and αCaMKII; (ii) a de-recruiting of NMDA receptors from active synaptic zones of same-age females, together with reduced expression/activation of the above-mentioned proteins, which might reduce the glutamate transmission. Whether similar sex-dependent glutamate homeostasis modulation occurs in other brain areas remains to be elucidated. Discussion: CN and ESI interact to shape social behavior and mPFC glutamate synapse homeostasis in an age- and sex-dependent fashion, suggesting that early-life social environment may play a crucial role in regulating the risk to develop psychopathology.
ABSTRACT
Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.
Subject(s)
Anorexia , Hippocampus , Janus Kinase 2 , Leptin , Receptors, Leptin , STAT3 Transcription Factor , Signal Transduction , Animals , Female , Janus Kinase 2/metabolism , STAT3 Transcription Factor/metabolism , Hippocampus/metabolism , Leptin/blood , Anorexia/etiology , Anorexia/metabolism , Rats , Receptors, Leptin/metabolism , Anorexia Nervosa/metabolism , Anorexia Nervosa/blood , Disease Models, Animal , Adaptation, PhysiologicalABSTRACT
Any deviation from the programmed processes of brain development may modify its formation and functions, thereby precipitating pathological conditions, which often become manifest in adulthood. Exposure to a challenge during crucial periods of vulnerability, such as adolescence, may reveal molecular changes preceding behavioral outcomes. Based on a previous study showing that prenatal fluoxetine (FLX) leads to the development of an anhedonic-like behavior in adult rats, we aimed to assess whether the same treatment regimen (i.e., fluoxetine during gestation; 15 mg/kg/day) influences the ability to respond to acute restraint stress (ARS) during adolescence. We subjected the rats to a battery of behavioral tests evaluating the development of various phenotypes (cognitive deficit, anhedonia, and anxiety). Furthermore, we carried out molecular analyses in the plasma and prefrontal cortex, a brain region involved in stress response, and whose functions are commonly altered in neuropsychiatric conditions. Our findings confirm that prenatal manipulation did not affect behavior in adolescent rats but impaired the capability to respond properly to ARS. Indeed, we observed changes in several molecular key players of the hypothalamic pituitary adrenal axis, particularly influencing genomic effects mediated by the glucocorticoid receptor. This study highlights that prenatal FLX exposure influences the ability of adolescent male rats to respond to an acute challenge, thereby altering the functionality of the hypothalamic-pituitary-adrenal axis, and indicates that the prenatal manipulation may prime the response to challenging events during this critical period of life.
Subject(s)
Fluoxetine , Prenatal Exposure Delayed Effects , Female , Pregnancy , Rats , Animals , Male , Humans , Fluoxetine/pharmacology , Selective Serotonin Reuptake Inhibitors , Hypothalamo-Hypophyseal System , Receptors, Glucocorticoid , Pituitary-Adrenal System , Prefrontal Cortex , Stress, Psychological , Corticosterone/pharmacologyABSTRACT
Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned- and conditioned-morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion-specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac-1 and RhoA mRNA levels as pro-plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro-plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine-tolerance plasticity in the hippocampus.
Subject(s)
Brain-Derived Neurotrophic Factor , Hippocampus , Male , Animals , Rats , Morphine/pharmacology , Neurogenesis , Neuronal Plasticity , RNA, MessengerABSTRACT
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.
Subject(s)
Glutamic Acid , Receptors, AMPA , Rats , Animals , Male , Glutamic Acid/metabolism , Rats, Sprague-Dawley , Receptors, AMPA/metabolism , N-Methylaspartate/pharmacology , Synapses/physiology , Nucleus Accumbens , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
BACKGROUND: Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. METHODS: To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. RESULTS: Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. LIMITATIONS: Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. CONCLUSIONS: Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.
Subject(s)
Brain-Derived Neurotrophic Factor , Imipramine , Humans , Rats , Female , Animals , Imipramine/pharmacology , Imipramine/therapeutic use , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Mania/metabolism , Depression , Proto-Oncogene Proteins c-akt/metabolism , Antidepressive Agents/pharmacology , Hippocampus/metabolismABSTRACT
Introduction: Early social isolation (ESI) disrupts neurodevelopmental processes, potentially leading to long-lasting emotional and cognitive changes in adulthood. Communal nesting (CN), i.e., the sharing of parental responsibilities between multiple individuals in a nest, creates a socially enriching environment known to impact social and anxiety-related behaviors. Methods: This study examines the effects of (i) the CN condition and of (ii) ESI during the 3rd week of life (i.e., pre-weaning ESI) on motor, cognitive, and emotional domains during adolescence and adulthood in male and female rats reared in the two different housing conditions, as well as (iii) the potential of CN to mitigate the impact of ESI on offspring. Results: We found that in a spontaneous locomotor activity test, females exhibited higher activity levels compared to males. In female groups, adolescents reared in standard housing (SH) condition spent less time in the center of the arena, suggestive of increased anxiety levels, while the CN condition increased the time spent in the center during adolescence, but not adulthood, independently from ESI. The prepulse inhibition (PPI) test showed a reduced PPI in ESI adolescent animals of both sexes and in adult males (but not in adult females), with CN restoring PPI in males, but not in adolescent females. Further, in the marble burying test SH-ESI adolescent males exhibited higher marble burying behavior than all other groups, suggestive of obsessive-compulsive traits. CN completely reversed this stress-induced effect. Interestingly, ESI and CN did not have a significant impact on burying behavior in adult animals of both sexes. Discussion: Overall, our findings (i) assess the effects of ESI on locomotion, sensorimotor gating, and compulsive-like behaviors, (ii) reveal distinct vulnerabilities of males and females within these domains, and (iii) show how early-life social enrichment may successfully counteract some of the behavioral alterations induced by early-life social stress in a sex-dependent manner. This study strengthens the notion that social experiences during early-life can shape emotional and cognitive outcomes in adulthood, and points to the importance of social enrichment interventions for mitigating the negative effects of early social stress on neurodevelopment.
ABSTRACT
BACKGROUND: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities. OBJECTIVE: In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure. RESULTS: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors. CONCLUSION: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.
ABSTRACT
Poor knowledge about psychiatric disorders often results in similar diagnoses for patients with different symptoms, thus limiting the effectiveness of the available medications. As suggested by several lines of evidence, to improve these shortcomings, it is essential to identify biomarkers associated with specific symptoms and to stratify patients into more homogeneous populations taking a further step toward personalized medicine. Here, we aimed to associate specific behavioral phenotypes with specific molecular alterations by employing an animal model based on the pharmacological manipulation of the serotonergic system, which mimics a condition of vulnerability to develop psychiatric disorders. In particular, we treated female and male rats with fluoxetine (FLX 15 mg/kg dissolved in drinking water) during prenatal or early postnatal life, and we evaluated different pathological-like phenotypes (cognitive deficit, anhedonia, and anxiety) by exposing the rats to a battery of behavioral tests during adolescence and adulthood. In addition, we carried out molecular analyses on specific brain areas and in the blood. Our results showed that perinatal FLX administration determined age- and sex-dependent effects, with males being more sensitive to prenatal manipulation and manifesting anhedonic-like behavior and females to early postnatal exposure, exhibiting cognitive deficits and a less anxious phenotype. Furthermore, we identified, peripherally and centrally, biological functions altered by perinatal serotonin modulation regardless of the timing of exposure and sex, and other pathways specific for the pathological-like phenotypes. The results presented here provide new insights into potential biomarkers associated with specific behavioral phenotypes that may be useful for broadening knowledge about psychiatric conditions.
Subject(s)
Prenatal Exposure Delayed Effects , Selective Serotonin Reuptake Inhibitors , Pregnancy , Rats , Male , Humans , Animals , Female , Selective Serotonin Reuptake Inhibitors/pharmacology , Fluoxetine , Brain , Anxiety/drug therapy , Biomarkers , Cognition , Behavior, AnimalABSTRACT
Prenatal alcohol exposure (PAE) affects neuronal networks and brain development causing a range of physical, cognitive and behavioural disorders in newborns that persist into adulthood. The array of consequences associated with PAE can be grouped under the umbrella-term 'fetal alcohol spectrum disorders' (FASD). Unfortunately, there is no cure for FASD as the molecular mechanisms underlying this pathology are still unknown. We have recently demonstrated that chronic EtOH exposure, followed by withdrawal, induces a significant decrease in AMPA receptor (AMPAR) expression and function in developing hippocampus in vitro. Here, we explored the EtOH-dependent pathways leading to hippocampal AMPAR suppression. Organotypic hippocampal slices (2 days in cultures) were exposed to EtOH (150 mM) for 7 days followed by 24 h EtOH withdrawal. Then, the slices were analysed by means of RT-PCR for miRNA content, western blotting for AMPA and NMDA related-synaptic proteins expression in postsynaptic compartment and electrophysiology to record electrical properties from CA1 pyramidal neurons. We observed that EtOH induces a significant downregulation of postsynaptic AMPA and NMDA subunits and relative scaffolding protein expression and, accordingly, a decrease of AMPA-mediated neurotransmission. Simultaneously, we found that chronic EtOH induced-upregulation of miRNA 137 and 501-3p and decreased AMPA-mediated neurotransmission are prevented by application of the selective mGlu5 antagonist MPEP during EtOH withdrawal. Our data indicate mGlu5 via miRNA137 and 501-3p expression as key factors in the regulation of AMPAergic neurotransmission that may contribute, at least in part, to the pathogenesis of FASD.
Subject(s)
Fetal Alcohol Spectrum Disorders , MicroRNAs , Prenatal Exposure Delayed Effects , Infant, Newborn , Humans , Female , Pregnancy , Ethanol/pharmacology , Ethanol/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism , N-Methylaspartate/pharmacology , Up-Regulation , Fetal Alcohol Spectrum Disorders/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Prenatal Exposure Delayed Effects/metabolism , Hippocampus/metabolism , Receptors, AMPA/genetics , Receptors, AMPA/metabolism , MicroRNAs/genetics , MicroRNAs/metabolismABSTRACT
In humans, cocaine abuse during adolescence poses a significant risk for developing cognitive deficits later in life. Among the regions responsible for cognitive processes, the medial prefrontal cortex (mPFC) modulates temporal order information via mechanisms involving the mammalian-target of rapamycin (mTOR)-mediated pathway and protein synthesis regulation. Accordingly, our goal was to study the effect of repeated cocaine exposure during both adolescence and adulthood on temporal memory by studying the mTOR pathway in the mPFC. Adolescent or adult rats underwent repeated cocaine injections for 15 days and, after two weeks of withdrawal, engaged in the temporal order object recognition (TOOR) test. We found that repeated cocaine exposure during adolescence impaired TOOR performance, while control or adult-treated animals showed no impairments. Moreover, activation of the mTOR-S6-eEF2 pathway following the TOOR test was diminished only in the adolescent cocaine-treated group. Notably, inhibition of the mTOR-mediated pathway by rapamycin injection impaired TOOR performance in naïve adolescent and adult animals, revealing this pathway to be a critical component in regulating recency memory. Our data indicate that withdrawal from cocaine exposure impairs recency memory via the dysregulation of protein translation mechanisms, but only when cocaine is administered during adolescence.
Subject(s)
Cocaine , Humans , Rats , Animals , Adolescent , Cocaine/pharmacology , Sirolimus/pharmacology , Memory , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Prefrontal Cortex/metabolism , Mammals/metabolismABSTRACT
BACKGROUND AND PURPOSE: Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure. EXPERIMENTAL APPROACH: Male CD-1 mice were injected with vehicle, JWH-018 (6 mg·kg-1 ), the CB1 -antagonist NESS-0327 (1 mg·kg-1 ) or co-administration of NESS-0327 and JWH-018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH-018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their main synthetic and degrading enzymes in the striatum and hippocampus. KEY RESULTS: The repeated treatment with JWH-018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH-018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH-018, reduced hippocampal CB1 receptor density and induced a long-term alteration in AEA and 2-AG levels and their degrading enzymes, FAAH and MAGL, in the striatum. CONCLUSION AND IMPLICATIONS: Our findings suggest that repeated administration of a high dose of JWH-018 leads to the manifestation of psychotic-like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.
Subject(s)
Cannabinoids , Cognitive Dysfunction , Mice , Male , Animals , Endocannabinoids/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Receptors, N-Methyl-D-Aspartate , Cannabinoids/pharmacology , Neuronal Plasticity , Receptor, Cannabinoid, CB1/metabolismABSTRACT
Brain metabolism is a fundamental process involved in the proper development of the central nervous system and in the maintenance of the main higher functions in humans. As consequence, energy metabolism imbalance has been commonly associated to several mental disorders, including depression. Here, by employing a metabolomic approach, we aimed to establish if differences in energy metabolite concentration may underlie the vulnerability and resilience in an animal model of mood disorder named chronic mild stress (CMS) paradigm. In addition, we have investigated the possibility that modulation of metabolite concentration may represent a pharmacological target for depression by testing whether repeated treatment with the antidepressant venlafaxine may normalize the pathological phenotype by acting at metabolic level. The analyses were conducted in the ventral hippocampus (vHip) for its key role in the modulation of anhedonia, a core symptom of patients affected by depression. Interestingly, we showed that a shift from glycolysis to beta oxidation seems to be responsible for the vulnerability to chronic stress and that vHip metabolism contributes to the ability of the antidepressant venlafaxine to normalize the pathological phenotype, as shown by the reversal of the changes observed in specific metabolites. These findings may provide novel perspectives on metabolic changes that could serve as diagnostic markers and preventive strategies for the early detection and treatment of depression as well as for the identification of potential drug targets.
Subject(s)
Antidepressive Agents , Glucose , Rats , Animals , Humans , Venlafaxine Hydrochloride/pharmacology , Rats, Wistar , Glucose/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Antidepressive Agents/metabolism , Anhedonia/physiology , Hippocampus , Stress, Psychological/metabolism , Depression/drug therapy , Depression/metabolism , Disease Models, AnimalABSTRACT
Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1.
Subject(s)
Acetylcysteine , Genes, Immediate-Early , Animals , Male , Rats , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Antidepressive Agents/therapeutic use , Rats, Wistar , Venlafaxine Hydrochloride/pharmacology , Venlafaxine Hydrochloride/therapeutic useABSTRACT
Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT-/-) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.
Subject(s)
Dopamine Plasma Membrane Transport Proteins , Receptors, AMPA , Rats , Animals , Receptors, AMPA/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology , Dopamine/metabolism , Receptors, Dopamine/metabolism , Prefrontal Cortex/metabolismABSTRACT
Stress is a major precipitating factor for psychiatric disorders and its effects may depend on its duration and intensity. Of note, there are differences in individual susceptibility to stress, with some subjects displaying vulnerability and others showing resistance. Furthermore, the ability to react to stressful-life events can alter the response to a subsequent new stressor. Hence, we investigated whether the vulnerability and resilience to the chronic mild stress (CMS) paradigm, in terms of the hedonic phenotype, are paralleled by a different response when facing a novel acute challenge. Specifically, rats submitted to CMS were stratified based on their sucrose intake into vulnerable (anhedonic rats showing reduce intake of sucrose) and resilient (rats not showing the anhedonic-like behavior) subgroups and then further exposed to an acute restraint stress (ARS). Then, neuronal activation was investigated by measuring the gene expression of early immediate (IEG) genes such as Arc and Cfos and early response (ERG) genes, such as Gadd45ß, Sgk1, Dusp1, and Nr4a1, in brain regions that play a crucial role in the stress response. We found that resilient rats preserve the ability to increase ERG expression following the ARS selectively in the ventral hippocampus. Conversely, such ability is lost in vulnerable rats. Interestingly, the recovery from the anhedonic phenotype observed in vulnerable rats after 3 weeks of rest from the CMS procedure also parallels the restoration of the ability to adequately respond to the challenge. In conclusion, these findings support the role of the ventral subregion of the hippocampus in the management of both chronic and acute stress response and point to this brain subregion as a critical target for a potential therapeutic strategy aimed at promoting stress resilience.
Subject(s)
Anhedonia , Hippocampus , Rats , Animals , Anhedonia/physiology , Rats, Wistar , Hippocampus/metabolism , Brain/metabolism , Sucrose/metabolism , Sucrose/pharmacology , Stress, Psychological/drug therapy , Disease Models, AnimalABSTRACT
Social and emotional experiences differently shape individual's neurodevelopment inducing substantial changes in neurobiological substrates and behavior, particularly when they occur early in life. In this scenario, the present study was aimed at (i) investigating the impact of early social environments on emotional reactivity of adolescent male and female rats and (ii) uncovering the underlying molecular features, focusing on the cortical endocannabinoid (eCB) and glucocorticoid systems. To this aim, we applied a protocol of environmental manipulation based on early postnatal socially enriched or impoverished conditions. Social enrichment was realized through communal nesting (CN). Conversely, an early social isolation (ESI) protocol was applied (post-natal days 14-21) to mimic an adverse early social environment. The two forms of social manipulation resulted in specific behavioral and molecular outcomes in both male and female rat offspring. Despite the combination of CN and ESI did not affect emotional reactivity in both sexes, the molecular results reveal that the preventive exposure to CN differently altered mRNA and protein expression of the main components of the glucocorticoid and eCB systems in male and female rats. In particular, adolescent females exposed to the combination of CN and ESI showed increased corticosterone levels, unaltered genomic glucocorticoid receptor, reduced cannabinoid receptor type-1 and fatty acid amide hydrolase protein levels, suggesting that the CN condition evokes different reorganization of these systems in males and females.
ABSTRACT
Introduction: Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a pathological fear of gaining weight, excessive physical exercise, and emotional instability. Since the amygdala is a key region for emotion processing and BDNF has been shown to play a critical role in this process, we hypothesized that alteration in the amygdalar BDNF system might underline vulnerability traits typical of AN patients. Methods: To this end, adolescent female rats have been exposed to the Activity-Based Anorexia (ABA) protocol, characterized by the combination of caloric restriction and intense physical exercise. Results: The induction of the anorexic phenotype caused hyperactivity and body weight loss in ABA animals. These changes were paralleled by amygdalar hyperactivation, as measured by the up-regulation of cfos mRNA levels. In the acute phase of the pathology, we observed reduced Bdnf exon IX, exon IV, and exon VI gene expression, while mBDNF protein levels were enhanced, an increase that was, instead, uncoupled from its downstream signaling as the phosphorylation of TrkB, Akt, and S6 in ABA rats were reduced. Despite the body weight recovery observed 7 days later, the BDNF-mediated signaling was still downregulated at this time point. Discussion: Our findings indicate that the BDNF system is downregulated in the amygdala of adolescent female rats under these experimental conditions, which mimic the anorexic phenotype in humans, pointing to such dysregulation as a potential contributor to the altered emotional processing observed in AN patients. In addition, since the modulation of BDNF levels is observed in other psychiatric conditions, the persistent AN-induced changes of the BDNF system in the amygdala might contribute to explaining the onset of comorbid psychiatric disorders that persist in patients even beyond recovery from AN.
ABSTRACT
Stress-related mental disorders encompass a plethora of pathologies that share the exposure to a negative environment as trigger for their development. The vulnerability to the effects of a negative environment is not equal to all but differs between individuals based on the genetic background makeup. Here, to study the molecular mechanisms potentially underlying increased threat anticipation, we employed an animal model showing this symptom (5-HTT knockout rats) which we exposed to Pavlovian fear conditioning (FC). We investigated the role of mitochondria, taking advantage of the recent evidence showing that the dynamic of these organelles is dysregulated after stress exposure. Behavioral experiments revealed that, during the second day of extinction of the FC paradigm, 5-HTT knockout (5-HTT-/-) animals showed a lack of fear extinction recall. From a mechanistic standpoint, we carried out our molecular analyses on the amygdala and prefrontal cortex, given their role in the management of the fear response due to their tight connection. We demonstrated that mitochondrial dynamics are impaired in the amygdala and prefrontal cortex of 5-HTT-/- rats. The dissection of the potential contributing factors revealed a critical role in the mechanisms regulating fission and fusion that are dysregulated in transgenic animals. Furthermore, mitochondrial oxidative phosphorylation, mitochondrial biogenesis, and the production of antioxidant enzymes were altered in these brain regions in 5-HTT-/- rats. In summary, our data suggest that increased extracellular 5-HT levels cause an unbalance of mitochondrial functionality that could contribute to the reduced extinction recall of 5-HTT-/- rats, pointing out the role of mitochondrial dynamics in the etiology of psychiatric disorders. Our findings, also, provide some interesting insights into the targeted development of drugs to treat such disorders.