ABSTRACT
Real-life decisions are often repeated. Whether considering taking a job in a new city, or doing something mundane like checking if the stove is off, decisions are frequently revisited even if no new information is available. This mode of behavior takes a particularly pathological form in obsessive-compulsive disorder (OCD), which is marked by individuals' redeliberating previously resolved decisions. Surprisingly, little is known about how information is transferred across decision episodes in such circumstances, and whether and how such transfer varies in OCD. In two experiments, data from a repeated decision-making task and computational modeling revealed that both implicit and explicit memories of previous decisions affected subsequent decisions by biasing the rate of evidence integration. Further, we replicated previous work demonstrating impairments in baseline decision-making as a function of self-reported OCD symptoms, and found that information transfer effects specifically due to implicit memory were reduced, offering computational insight into checking behavior.
Subject(s)
Decision Making/physiology , Memory/physiology , Obsessive-Compulsive Disorder/physiopathology , Adult , Female , Humans , Male , Models, Theoretical , Obsessive Behavior/metabolism , Obsessive Behavior/physiopathologyABSTRACT
Noncanonical poly(A) polymerases are frequently tethered to mRNA 3' untranslated regions and regulate poly(A) tail length and resulting translation. In the brain, one such poly(A) polymerase is Gld2, which is anchored to mRNA by the RNA-binding protein CPEB1 to control local translation at postsynaptic regions. Depletion of CPEB1 or Gld2 from the mouse hippocampus results in a deficit in long-term potentiation (LTP), but only depletion of CPEB1 alters animal behaviour. To test whether a related enzyme, Gld4, compensates for the lack of Gld2, we separately or simultaneously depleted both proteins from hippocampal area CA1 and again found little change in animal behaviour, but observed a deficit in LTP as well as an increase in long-term depression (LTD), two forms of protein synthesis-dependent synaptic plasticity. RNA-seq data from Gld2, Gld4, and Gld2/Gld4-depleted hippocampus show widespread changes in steady state RNA levels, alternative splicing, and alternative poly(A) site selection. Many of the RNAs subject to these alterations encode proteins that mediate synaptic function, suggesting a molecular foundation for impaired synaptic plasticity.
Subject(s)
CA1 Region, Hippocampal/metabolism , Long-Term Potentiation/genetics , Polynucleotide Adenylyltransferase/genetics , RNA Processing, Post-Transcriptional , Transcription Factors/genetics , mRNA Cleavage and Polyadenylation Factors/genetics , 3' Untranslated Regions , Animals , Avoidance Learning/physiology , CA1 Region, Hippocampal/pathology , Gene Expression Regulation , Injections, Intraventricular , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Neuronal Plasticity , Obsessive Behavior/genetics , Obsessive Behavior/metabolism , Obsessive Behavior/physiopathology , Polynucleotide Adenylyltransferase/antagonists & inhibitors , Polynucleotide Adenylyltransferase/metabolism , Protein Biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Transcription, Genetic , mRNA Cleavage and Polyadenylation Factors/antagonists & inhibitors , mRNA Cleavage and Polyadenylation Factors/metabolismABSTRACT
Accumbal dopamine plays an important role in physiological responses and diseases such as schizophrenia, Parkinson's disease, and depression. Since the nucleus accumbens contains different neurotransmitters, it is important to know how they interact with dopaminergic function: this is because modifying accumbal dopamine has far-reaching consequences for the treatment of diseases in which accumbal dopamine is involved. This review provides a summary of these interactions, and our current knowledge about them are as follows: A) AMPA receptors are required for dopamine-dependent behavior and vice versa; NMDA receptors modulate the activity at the level of AMPA and/or dopamine D1 receptors. B) GABA(A), but not GABA(B), receptors inhibit dopamine-dependent behavior. C) Nicotinic receptors are required for dopamine-dependent behavior, whereas muscarinic receptors inhibit dopamine-dependent behavior. D) α-Adrenoceptors inhibit dopamine-dependent behavior in contrast to ß-adrenoceptors, which potentiate this behavior. E) µ- and δ2-opioid receptors elicit behavior that requires an intact dopaminergic function and δ2-opioid receptors modulate dopamine-dependent behavior. F) Orexin 2 receptors play an important, modifying role in dopamine-dependent behavior. G) Somatostatin receptors potentiate dopamine-dependent behavior. It is suggested that modulation of the above-mentioned non-dopaminergic receptors provide new tools to control physiological functions as well as diseases mediated by accumbal dopamine.
Subject(s)
Dopamine/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nucleus Accumbens/metabolism , Obsessive Behavior/metabolism , Receptors, Neurotransmitter/metabolism , Animals , Behavior, Animal/drug effects , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Neurons/drug effects , Nucleus Accumbens/drug effects , Obsessive Behavior/drug therapy , Rats , Receptors, Neurotransmitter/agonists , Receptors, Neurotransmitter/antagonists & inhibitorsABSTRACT
OBJECTIVE: To investigate the regional metabolite abnormalities and changes after treatment in patients with OCD with autogenous and reactive obsessions. METHOD: We assessed right anterior cingulate cortex (ACC) and amygdala-hippocampal region (Am + Hpp) N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr) concentrations and NAA/Cr and Cho/Cr ratios using single-voxel proton magnetic resonance spectroscopy in 15 patients with autogenous obsessions (OCD-A), 15 patients with reactive obsessions (OCD-R) and 15 healthy controls (HC). Measurements were repeated after 16 weeks of fluoxetine treatment. RESULTS: Baseline ACC NAA/Cr ratios of both OCD groups were significantly lower than HC. OCD-A group had significantly lower baseline NAA/Cr ratios in the Am + Hpp than other groups. These differences were more likely to be explained by higher Cr levels in ACC. We found no significant differences and changes for Cho levels and Cho/Cr ratios between groups and within groups. Significant increase in NAA/Cr ratios of OCD-A group found in the Am + Hpp was more likely to be explained by increased NAA levels. No significant changes were found in ACC NAA/Cr ratios. CONCLUSION: While disturbed energy metabolism in ACC might reflect a common pathology in patients with OCD regardless of symptom dimension, alterations in mesiotemporal lobe are more likely for autogenous obsessions.
Subject(s)
Fluoxetine/pharmacokinetics , Limbic System , Obsessive-Compulsive Disorder/drug therapy , Obsessive-Compulsive Disorder/metabolism , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Choline/metabolism , Creatine/metabolism , Diagnostic and Statistical Manual of Mental Disorders , Drug Monitoring/methods , Female , Fluoxetine/administration & dosage , Humans , Limbic System/drug effects , Limbic System/metabolism , Magnetic Resonance Spectroscopy , Male , Middle Aged , Obsessive Behavior/drug therapy , Obsessive Behavior/metabolism , Obsessive-Compulsive Disorder/psychology , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Treatment OutcomeABSTRACT
Both animal and human studies suggest that volume-regulating hormones could play a role in alcohol dependence as well as in alcohol craving. The role of the volume-regulating hormones, renin, aldosterone, and the N-terminal pro B-type natriuretic peptide (NT-proBNP) in alcohol craving was therefore evaluated in the present study. Twenty-five actively drinking alcohol-dependent patients satisfied the inclusion criteria and were enrolled into the study. The volume-regulating hormones, renin, aldosterone, and the NT-proBNP, and craving measurements--Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS)--were performed at baseline and after 12 weeks. Sixteen patients remained totally abstinent for the entire 12 weeks and were available for the second assessments. At baseline, no correlations between hormones and craving scores were found with either the 25 patients initially enrolled or the 16 abstinent patients. At 12 weeks, a significant increase of renin and a significant decrease of aldosterone were observed. Aldosterone showed a significant direct correlation with the obsessive OCDS subscore (r=0.59, P=.016) and a trend toward a significant direct correlation with the PACS score (r=0.48, P=.057). Renin demonstrated a significant direct correlation with the obsessive OCDS subscore (r=0.51, P=.041) and with the PACS score (r=0.56, P=.025). The NT-proBNP never correlated with craving measurements. In conclusion, the renin-aldosterone axis could play a role in craving in medium-term abstinent patients and thereby leading to the hypothesis that alcohol craving could be influenced by the fluid volume intake.
Subject(s)
Alcoholism/metabolism , Aldosterone/blood , Behavior, Addictive/metabolism , Obsessive Behavior/metabolism , Renin-Angiotensin System , Renin/blood , Temperance , Alcoholism/psychology , Alcoholism/therapy , Baclofen/therapeutic use , Counseling , Female , Humans , Longitudinal Studies , Male , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Pilot Projects , Psychiatric Status Rating Scales , Self-Help Groups , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Overcommitment (OC) is a pattern of excessive striving. In reaction to work stress, OC has been associated with higher sympathetic nervous system activation and cortisol release, but data on neuroendocrine reactivity to standardized stressors are scarce. We investigated whether OC is associated with differential levels of the stress hormones norepinephrine and cortisol in response to acute psychosocial stress. METHODS: Fifty-eight medication-free non-smoking men aged between 20 and 65 years (mean+/-S.E.M.: 36.3+/-1.8) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We assessed OC as well as a variety of psychological control variables including vital exhaustion, perfectionism, chronic stress, and cognitive stress appraisal. Moreover, we measured plasma norepinephrine as well as salivary cortisol before and after stress and several times up to 60 min thereafter. RESULTS: Higher OC was associated with lower baseline norepinephrine levels (r = -0.37, p < 0.01). General linear models controlling for age, BMI, and mean arterial blood pressure revealed that higher overcommitment was associated with lower norepinephrine and cortisol levels before and after stress (p's < 0.02) as well as with lower norepinephrine stress reactivity (p = 0.02). Additional controlling for the potential psychological confounders vital exhaustion, perfectionism, chronic stress, and depression confirmed lower norepinephrine levels before and after stress (p < 0.01) as well lower norepinephrine stress reactivity (p = 0.02) with increasing OC. Higher OC independently explained 13% of the total norepinephrine stress response (beta = -0.46, p < 0.01, R(2) change = 0.13). CONCLUSIONS: Our findings suggest blunted increases in norepinephrine following stress with increasing OC potentially mirroring blunted stress reactivity of the sympathetic nervous system.
Subject(s)
Behavior, Addictive/metabolism , Norepinephrine/blood , Obsessive Behavior/metabolism , Stress, Psychological/metabolism , Workload/psychology , Adaptation, Physiological , Adult , Area Under Curve , Behavior, Addictive/psychology , Heart Rate , Humans , Hydrocortisone/metabolism , Linear Models , Male , Obsessive Behavior/psychology , Reference Values , Saliva/metabolism , Statistics as TopicABSTRACT
BACKGROUND: Asperger syndrome (AS; an autistic disorder) is associated with impaired social skills and obsessional/repetitive behavior. Patients with autism have significant abnormalities in the frontal lobe and frontoparietal connectivity. Nobody has examined the relationship between abnormalities in the frontal and parietal lobes and clinical symptoms in people with AS. METHODS: We used in vivo proton magnetic resonance spectroscopy to examine neuronal integrity of the medial prefrontal and parietal lobes in 14 non-learning-disabled adults with AS and 18 control subjects (of similar sex, age, and IQ). We obtained measures of the prefrontal lobe in 11, the parietal lobe in 13, and both lobes in 10 subjects with AS. We measured concentrations and ratios of N-acetylaspartate (NAA), creatine and phosphocreatine (Cr + PCr), and choline (Cho). Levels of NAA, Cr + PCr, and Cho are indicators of neuronal density and mitochondrial metabolism, phosphate metabolism, and membrane turnover. Frontal metabolite levels were correlated with scores on the Yale-Brown Obsessive Compulsive Scale and the Autism Diagnostic Interview. RESULTS: Subjects with AS had a significantly higher prefrontal lobe concentration of NAA (z = -3.1; P =.002), Cr + PCr (z = -2.2; P =.03), and Cho (z = -2.9; P =.003). Increased prefrontal NAA concentration was significantly correlated with obsessional behavior (tau = 0.67; P =.005); increased prefrontal concentration of Cho, with social function (tau = 0.72; P =.02). We found no significant differences in parietal lobe metabolite concentrations. CONCLUSION: Subjects with AS have abnormalities in neuronal integrity of the prefrontal lobe, which is related to severity of clinical symptoms.