oxytocin and Cognitive-Dysfunction

The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment.

Topics: Cognitive Dysfunction; Humans; Metabolic Syndrome; Oxytocin; Psychotic Disorders; Schizophrenia

Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.

Topics: Amenorrhea; Animals; Anorexia Nervosa; Autocrine Communication; Bone and Bones; Bone Density; Breast Neoplasms; Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus; Estrogens; Female; Humans; Male; Osteoporosis, Postmenopausal; Oxytocin; Paracrine Communication; Sex Characteristics

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

Topics: Animals; Arginine Vasopressin; Brain; Cognitive Dysfunction; Humans; Mental Disorders; Oxytocin

While there is growing interest in the potential for intranasal oxytocin (IN-OT) to improve social cognition and neurocognition (ie, nonsocial cognition) in schizophrenia, the extant literature has been mixed. Here, we perform a Bayesian meta-analysis of the efficacy of IN-OT to improve areas of social and neurocognition in schizophrenia. A systematic search of original research publications identified randomized controlled trials (RCTs) of IN-OT as a treatment for social and neurocognitive deficits in schizophrenia for inclusion. Standardized mean differences (SMD) and corresponding variances were used in multilevel Bayesian models to obtain meta-analytic effect-size estimates. Across a total of 12 studies (N = 273), IN-OT did not improve social cognition (SMD = 0.07, 95% credible interval [CI] = [-0.06, 0.17]) or neurocognition (SMD = 0.12, 95% CI = [-0.12, 0.34]). There was moderate between study heterogeneity for social cognition outcomes (τs= 0.12). Moderator analyses revealed that IN-OT had a significantly larger effect on high-level social cognition (ie, mentalizing and theory of mind) compared to low-level social cognition (ie, social cue perception) (b = 0.19, 95% CI = [0.05, 0.33]). When restricting our analysis to outcomes for high-level social cognition, there was a significant effect of IN-OT (SMD = 0.20, 95 % CI = [0.05, 0.33]) but the effect was not robust to sensitivity analyses. The present analysis indicates that IN-OT may have selective effects on high-level social cognition, which provides a more focused target for future studies of IN-OT.

Topics: Administration, Intranasal; Adult; Bayes Theorem; Cognitive Dysfunction; Humans; Multilevel Analysis; Outcome Assessment, Health Care; Oxytocin; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Social Perception; Theory of Mind

Schizophrenia is a chronic multifactorial disorder. Over the last years, there has been a growing interest in cognitive deficits in schizophrenia, which is considered by many as the core abnormality of the disease. In the systematic review we focus on the social cognition and its correlation with the neuropeptide oxytocin, which is shown to be involved in the emotion recognizing processes, in the trust behavior and many other aspects of social functioning. The systematic review was performed in order to summarize the data on the liaison of oxytocin with the social cognition impairment in schizophrenia patients. Oxytocin is assumed to be a potential therapeutic agent for schizophrenia, with a special link to social cognitive functions. The oxytocinergic system is a promising neuromodulator of emotion recognition that may have the potential to normalize the social dysfunction seen in schizophrenia. Further studies are required to provide more data on the correlations between oxytocin and socialcognition as well as other schizophrenia symptoms.

Topics: Cognition; Cognitive Dysfunction; Humans; Oxytocin; Schizophrenia; Schizophrenic Psychology; Social Perception; Theory of Mind

Negative symptoms and cognitive impairments tend to co-occur in people with schizophrenia. If their association with each other is due, in part, to shared pathophysiology, then this suggests that a single drug could potentially be effective for both domains. The current study was designed to examine this hypothesis.. Fifty-eight participants with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision schizophrenia or schizoaffective disorder entered into a 6-week double-blind, placebo-controlled, double-dummy, randomized clinical trial of intranasal oxytocin and galantamine. Seventeen participants were randomized to intranasal oxytocin, 20 were randomized to galantamine, and 21 were randomized to placebo. The Scale for the Assessment of Negative Symptoms total score was used to assess change in negative symptoms (the primary outcome measure for oxytocin). The MATRICS Consensus Cognitive Battery composite score was used to assess cognition (the primary outcome measure for galantamine).. There were no significant group differences for negative symptoms (oxytocin vs placebo: F2,47.4 = 0.19, P = 0.83; galantamine vs placebo: F2,52.5 = 0.41, P = 0.67). There were no significant group differences for cognitive impairments (galantamine vs placebo: t40 = 0.71, P = 0.48; oxytocin vs placebo: t40 = 0.50, P = 0.62). There were also no significant group differences for the functional capacity or ancillary symptom measures.. The lack of an efficacy signal for either compound precluded our ability to test whether pharmacological treatment pathways for negative symptoms and cognitive impairments overlap or are independent.

Topics: Administration, Intranasal; Adult; Cognitive Dysfunction; Double-Blind Method; Female; Galantamine; Humans; Male; Middle Aged; Nootropic Agents; Oxytocics; Oxytocin; Pessimism; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Whether there is a relationship between oxytocin (OXT) use in labor and the risk of autism (ASD), and the nature of such relationship, is unclear. By integrating genetic and clinical data in a sample of 176 ASD participants, we tested the hypothesis that OXT is a marker for abnormal prenatal development which leads to impairments in the process of labor. OXT-exposed ASD had more obstetric complications (P = 0.031), earlier onset of symptoms (P = 0.027), poorer cognitive development (P = 0.011), higher mutation burden across neurodevelopment genes (P = 0.020; OR = 5.33) and lower transmission of polygenic risk for ASD (P = 0.0319), than non-exposed ASD. OXT seems to constitute a risk indicator rather than a risk factor for ASD, which is relevant for diagnostic and genetic counselling.

Topics: Autism Spectrum Disorder; Autistic Disorder; Cognition; Cognitive Dysfunction; Female; Humans; Oxytocin; Pregnancy

Traumatic brain injury (TBI) is a major risk factor to develop epilepsy and cognitive impairments. Neuropeptide oxytocin has been previously evidenced to produce antiepileptic effects. However, the involvement of central oxytocin in TBI-induced epileptic status and cognitive dysfunctions is not fully elucidated. In this study, we aim to investigate the role of oxytocin on a TBI model followed by seizure induction to clarify whether the epilepsy and cognitive deficits could be mitigated by oxytocin. TBI was established by weight drop and epileptic behaviors were induced by pentylenetetrazole (PTZ) injection in mice. Moreover, oxytocin was microinjected into the medial prefrontal cortex (mPFC) to observe the effects on the epilepsy and cognition. The blood-brain barrier (BBB) function and the neuroinflammation were measured by Evans Blue staining and enzyme-linked immunosorbent assays, respectively. Mice exposed to TBI demonstrate increased vulnerability to PTZ-mediated seizures and cognitive disturbances with a decrease in peripheral and brain oxytocin levels. Additionally, TBI reduces oxytocin, disrupts the BBB permeability and triggers neuroinflammation in mPFC in PTZ-treated mice. Intra-mPFC oxytocin simultaneously mitigates epilepsy and cognitive impairments. Finally, oxytocin restores BBB integrity and reduces mPFC inflammation in PTZ-treated TBI mice. These findings showed that intra-mPFC oxytocin suppressed the seizure vulnerability and cognitive deficits in TBI mice. The normalization of BBB integrity and inhibition of neuroinflammation may be involved in the antiepileptic and cognition-improved effects of oxytocin, suggesting that targeting inflammatory procedure in mPFC may decrease the risk to develop epilepsy and cognitive impairments in individuals previously experienced TBI.

Topics: Animals; Anticonvulsants; Brain Injuries, Traumatic; Cognitive Dysfunction; Disease Models, Animal; Epilepsy; Mice; Neuroinflammatory Diseases; Oxytocin; Pentylenetetrazole; Prefrontal Cortex; Seizures

Thyroid hormones play an essential role in metabolism regulation and circadian rhythm control. Recent studies approved their role in normal development and healthy function of central nervous system (CNS). The thyroid gland is a component of the hypothalamic-pituitary-thyroid axis disrupted during thyrotoxicosis and hypothyroidism, two main clinical conditions that induce more liability against dementia-related disease.. In the first step, this study evaluated the circular level of neuropeptide Y (NPY), leptin, oxytocin, and vasopressin in hyperthyroidism and hypothyroidism patients. In the second step, we investigated neurological and cognitive abnormalities by assessment of the hallmark proteins and peptides such as amyloid β (Aβ) variants, glycogen synthase kinase 3β (GSK-3β), and tau protein in thyroid-deficient samples.. The results show increased content of leptin hormone in patients with hypothyroidism who also manifested high levels of vasopressin. Underactivation and overactivation of the thyroid gland are accompanied by reduced circular oxytocin. We may conclude that thyroid deficiency is associated with neurohormone dysregulation. Interestingly, both patient groups exhibited significant increases in Aβ40 and Aβ42 levels relative to the control group, which was also accompanied by the rise in GSK-3β; this might be interpreted as cholinergic system dysfunction and cognitive impairment. The results revealed tau content increased considerably in thyrotoxicosis but did not change significantly in hypothyroidism compared to the control group.. Therefore, our results have shown that thyroid gland dysfunction is a risk factor for cognitive impairment, mainly through neuroendocrine dysregulation. This study provides a relationship between hyperthyroidism/hypothyroidism and biomarkers of neurological abnormalities in blood serum.

Topics: Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Glycogen Synthase Kinase 3 beta; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Oxytocin; Thyrotoxicosis

Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K

Topics: Animals; Brain Injuries; Chlorides; Cognitive Dysfunction; Cranial Irradiation; DNA Damage; Hippocampus; Humans; Mice; Neuroprotective Agents; Oxytocin; Quality of Life; Symporters

Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition.. We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay.. We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002).. This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Topics: Cognitive Dysfunction; Emotions; Humans; Huntington Disease; Oxytocin

Oxytocin is a neuropeptide hormone that plays an important role in social bonding and behavior. Recent studies indicate that oxytocin could be involved in the regulation of neurological disorders. However, its role in modulating cognition in Alzheimer's disease (AD) has never been explored. Hence, the present study aims to investigate the potential of chronic intranasal oxytocin in halting memory impairment & AD pathology in aluminum chloride-induced AD in female rats. Morris water maze was used to assess cognitive dysfunction in two-time points throughout the treatment period. In addition, neuroprotective effects of oxytocin were examined by assessing hippocampal acetylcholinesterase activity, β-amyloid 1-42 protein, and Tau levels. In addition, ERK1/2, GSK3β, and caspase-3 levels were assessed as chief neurobiochemical mediators in AD. Hippocampi histopathological changes were also evaluated. These findings were compared to the standard drug galantamine alone and combined with oxytocin. Results showed that oxytocin restored cognitive functions and improved animals' behavior in the Morris test. This was accompanied by a significant decline in acetylcholinesterase activity, 1-42 β-amyloid and Tau proteins levels. Hippocampal ERK1/2 and GSK3β were also reduced, exceeding galantamine effects, thus attenuating AD pathological hallmarks formation. Determination of caspase-3 revealed low cytoplasmic positivity, indicating the ceasing of neuronal death. Histopathological examination confirmed these findings, showing restored hippocampal cells structure. Combined galantamine and oxytocin treatment showed even better biochemical and histopathological profiles. It can be thus concluded that oxytocin possesses promising neuroprotective potential in AD mediated via restoring cognition and suppressing β-amyloid, Tau accumulation, and neuronal death.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Caspase 3; Cognitive Dysfunction; Disease Models, Animal; Female; Galantamine; Glycogen Synthase Kinase 3 beta; MAP Kinase Signaling System; Oxytocin; Rats; tau Proteins

In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than are recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD. Here, we found that both aging and traumatic brain injury-associated dementia increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus. Further, age-related increases in hippocampal PDE11A4 mRNA and protein were conserved in mice, as was the increased vulnerability of associative versus recognition memories to ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) ectopically accumulated in the membrane fraction and filamentous structures we term "ghost axons." These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the punctate accumulation of PDE11A4. In contrast, PDE11A4-pS162 caused dispersal. Importantly, preventing age-related increases in PDE11 expression via genetic deletion protected mice from ARCD of short-term and remote long-term associative memory (aLTM) in the social transmission of food preference assay, albeit at the expense of recent aLTM. Further, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice caused aging-like impairments in CREB function and remote social-but not non-social-LTMs. RNA sequencing and phosphoproteomic analyses of VHIPP identified cGMP-PKG-as opposed to cAMP-PKA-as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD. Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Animals; Cholinergic Agents; Cognitive Dysfunction; Endocannabinoids; Exoribonucleases; Hippocampus; Humans; Mice; Oxytocin; RNA, Messenger

Learning and memory impairment manifests years before the onset of motor impairments in Huntington's disease (HD). Oxytocin (OXT), as a neurohypophyseal neuropeptide has a key role in both learning and memory. Hence, we investigated possible protective effect of OXT on instrumental fear conditioning memory impairment by 3-Nitropropionic acid (3-NP) induced HD, considering sex and prenatal stress effects. Pregnant Wistar rats were exposed to restraint stress for 45 min three times a day, from the gestational day 8 to parturition. 3-NP was injected intraperitoneally (20 mg/kg) for 5-7 days after OXT (10 μg/μl. icv) injection in the male and female offspring rats respectively. One day after the last 3-NP injection, the rotarod and passive avoidance task were conducted. As the key molecular determinants in metabolism and memory processes, we measured the activity of acetylcholinesterase (AChE) and the amount of receptor interacting protein3 (RIP3) in the hippocampus, prefrontal cortex, striatum and amygdala using spectrophotometry and western blotting respectively. Besides, the activity of glutamate dehydrogenase was measured (GDH) as a chain between metabolism and memory formation. The results indicated that OXT improved learning and memory impairment caused by 3-NP or prenatal stress in both sexes. It was along with a significant decrease in the level of RIP3, AChE and GDH activities. However, in the presence of prenatal stress, the OXT could improve 3-NP induced learning and memory impairments just in female rats. So it could be suggested as an effective neurotherapeutic agent in diseases such as HD, but its sex and context dependency should be considered carefully.

Topics: Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Conditioning, Operant; Disease Models, Animal; Fear; Female; Huntington Disease; Male; Neurotoxins; Nitro Compounds; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Propionates; Rats; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Sex Characteristics; Stress, Psychological

Intranasal administration of the neuropeptide oxytocin (OT) has yielded inconsistent effects on social cognition and general cognition in individuals with schizophrenia (SZ). Few studies have examined whether endogenous peripheral OT levels are also associated with social and general cognition in SZ. The current study examined whether plasma OT levels are associated with performance on a higher-order social cognition measure (i.e., a task that requires inferential processes and knowledge not directly presented in social stimuli), as well as domains of general cognition. Participants included 30 individuals with SZ and 21 demographically matched healthy controls (CN). The MATRICS Consensus Cognitive Battery was administered to assess neuropsychological impairment in relation to 7 domains (processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, and social cognition). Plasma OT levels were measured via radioimmunoassay. SZ had significantly lower endogenous OT levels and poorer MCCB performance on all 7 domains than CN. In CN and SZ, lower endogenous OT was associated with poorer social cognition. In SZ, lower endogenous OT was also associated with poorer processing speed and working memory. The significant association between OT and social cognition in both CN and SZ highlights the importance of endogenous OT levels as a biological predictor of social cognition, irrespective of clinical status. Significant associations between plasma OT and general neurocognition may reflect either an anxiolytic effect of plasma OT that results in better neurocognitive performance, or OT's action on dopamine and enhancement of dopamine tone that results in improved cognition.

Topics: Adult; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Oxytocin; Psychotic Disorders; Schizophrenia; Social Perception; Theory of Mind