- Drugs, sleep, and the addicted brain. [Review]
- NNeuropsychopharmacology 2019 Jul 16
- Alec Coppen. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 15
- Sleep and neurological autoimmune diseases. [Review]
- NNeuropsychopharmacology 2019 Jul 14
- Neurological autoimmune diseases are characterized by an inappropriate immune response that by mistake targets the nervous system. As a result, patients experiment a number of neurological manifestat…
Neurological autoimmune diseases are characterized by an inappropriate immune response that by mistake targets the nervous system. As a result, patients experiment a number of neurological manifestations that may include insomnia, excessive daytime sleepiness, cataplexy, central hypoventilation, and REM sleep behavior disorder. Polysomnographic evaluation may reveal disorganized sleep architecture involving both NREM and REM sleep, and REM sleep intrusions into wakefulness. The study of sleep disorders in the setting of autoimmune diseases (e.g., narcolepsy, anti-IgLON5 disease, paraneoplastic neurological syndromes) shows that an abnormal immune-mediated (humoral or cellular) response target the neuronal structures (e.g., brainstem, hypothalamus) and neurotransmitters systems (e.g., hypocretin) that regulate sleep resulting in sleep impairment. It is a window to examine the link between the autoimmune system and the sleep regulation at the molecular, cellular, and anatomic level.
- Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 09
- Human genetic variation in the nicotinic receptor gene cluster CHRNA5/A3/B4, in particular the non-synonymous and frequent CHRNA5 variant rs16969968 (α5SNP), has an important consequence on smoking b…
Human genetic variation in the nicotinic receptor gene cluster CHRNA5/A3/B4, in particular the non-synonymous and frequent CHRNA5 variant rs16969968 (α5SNP), has an important consequence on smoking behavior in humans. A number of genetic association studies have additionally implicated the CHRNA5 gene in addictions to other drugs, and also body mass index (BMI). Here, we model the α5SNP, in a transgenic rat line, and establish its role in alcohol dependence, and feeding behavior. Rats expressing the α5SNP consume more alcohol, and exhibit increased relapse to alcohol seeking after abstinence. This high-relapsing phenotype is reflected in altered activity in the insula, linked to interoception, as established using c-Fos immunostaining. Similarly, relapse to food seeking is increased in the transgenic group, while a nicotine treatment reduces relapse in both transgenic and control rats. These findings point to a general role of this human polymorphism in reward processing, and multiple addictions other than smoking. This could pave the way for the use of medication targeting the nicotinic receptor in the treatment of alcohol use and eating disorders, and comorbid conditions in smokers.
- Evidence for a sex-specific contribution of polygenic load for anorexia nervosa to body weight and prefrontal brain structure in nonclinical individuals. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 08
- Genetic predisposition and brain structural abnormalities have been shown to be involved in the biological underpinnings of anorexia nervosa (AN). Prefrontal brain regions are suggested to contribute…
Genetic predisposition and brain structural abnormalities have been shown to be involved in the biological underpinnings of anorexia nervosa (AN). Prefrontal brain regions are suggested to contribute through behavioral inhibition mechanisms to body weight. However, it is unknown if and to which extent biological correlates for AN might be present in individuals without clinical AN symptomatology. We therefore investigated the contribution of polygenic load for AN on body weight and prefrontal brain structure in a sample of n = 380 nonclinical individuals. A polygenic score (PGS) reflecting the individual genetic load for the trait of anorexia nervosa was calculated. Structural MRI data were acquired and preprocessed using the cortical parcellation stream of FreeSurfer. We observed a significant PGS × sex interaction effect on body mass index (BMI), which was driven by a negative correlation between PGS and BMI in female participants. Imaging analyses revealed significant interaction effects of sex × PGS on surface area of the lateral orbitofrontal cortex (OFC), the pars orbitalis (PO), the rostral middle frontal gyrus (RMF) and the pars triangularis (PT) of the left frontal cortex. The interaction effects were driven by positive correlations between PGS and prefrontal surface areas in female participants and negative correlations in male participants. We furthermore found sex-specific associations between BMI and left RMF surface area as well as between BMI and left PO and left RMF thickness. Our findings demonstrate a sex-specific association between polygenic load for AN, BMI, and prefrontal brain structure in nonclinical individuals. Hence, this study identifies structural abnormalities associated with polygenic load for AN and BMI in brain regions deeply involved in behavioral inhibition and impulse regulation as candidate brain regions for future research.
- Association of childhood traumatization and neuropsychiatric outcomes with altered plasma micro RNA-levels. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 08
- Childhood traumatization (CT) is associated with the development of several neuropsychiatric disorders in later life. Experimental data in animals and observational data in humans revealed evidence f…
Childhood traumatization (CT) is associated with the development of several neuropsychiatric disorders in later life. Experimental data in animals and observational data in humans revealed evidence for biological alterations in response to CT that may contribute to its long-term consequences. This includes epigenetic changes in miRNA levels that contribute to complex alterations of gene expression. We investigated the association between CT and 121 miRNAs in a target sample of N = 150 subjects from the general population and patients from the Department of Psychiatry. We hypothesized that CT exhibits a long-term effect on miRNA plasma levels. We supported our findings using bioinformatics tools and databases. Among the 121 miRNAs 22 were nominally significantly associated with CT and four of them (let-7g-5p, miR-103a-3p, miR-107, and miR-142-3p) also after correction for multiple testing; most of them were previously associated with Alzheimer's disease (AD) or depression. Pathway analyses of target genes identified significant pathways involved in neurodevelopment, inflammation and intracellular transduction signaling. In an independent general population sample (N = 587) three of the four miRNAs were replicated. Extended analyses in the general population sample only (N = 687) showed associations of the four miRNAs with gender, memory, and brain volumes. We gained increasing evidence for a link between CT, depression and AD through miRNA alterations. We hypothesize that depression and AD not only share environmental factors like CT but also biological factors like altered miRNA levels. This miRNA pattern could serve as mediating factor on the biological path from CT to adult neuropsychiatric disorders.
- Effects of hydrocortisone on autobiographical memory retrieval in patients with posttraumatic stress disorder and borderline personality disorder: the role of childhood trauma. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 06
- In a previous study, we found that patients with posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) showed better autobiographical memory (AM) retrieval after hydrocortiso…
In a previous study, we found that patients with posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) showed better autobiographical memory (AM) retrieval after hydrocortisone administration than after placebo administration. Here we investigate the neural correlates of AM retrieval after hydrocortisone administration in patients with PTSD or BPD. We recruited 78 female participants for this placebo-controlled crossover study: 40 healthy controls, 20 patients with PTSD, and 18 patients with BPD (all without medication). All participants received an oral placebo or 10 mg hydrocortisone in a randomized order before performing an AM task. Neural activity was monitored during the task by functional magnetic resonance imaging. Neural activation did not differ between the three groups during AM retrieval, neither in the placebo condition nor after hydrocortisone intake. Multiple regression analysis revealed that Childhood Trauma Questionnaire scores correlated positively with hydrocortisone effects on activation in the anterior medial prefrontal cortex (amPFC), ventrolateral prefrontal cortex (vlPFC), posterior cingulate cortex (PCC), angular gyrus, and cerebellum. These results suggest that hydrocortisone-induced neural activation pattern during AM retrieval is related to childhood trauma. Previously described effects in the hippocampus, which were absent in the current study, might be related to PTSD caused by trauma in adulthood. The effects of hydrocortisone on brain activation and how these effects are influenced by childhood trauma, trauma in adulthood, and PTSD symptoms should be determined in future studies.
- Experimental design and analysis for consideration of sex as a biological variable. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 05
- Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 05
- Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is i…
Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.
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- Striatum-related functional activation during reward- versus punishment-based learning in psychosis risk. [Journal Article]
- NNeuropsychopharmacology 2019 Jul 04
- Psychosis is strongly related to increased striatal dopamine. However, the neural consequences of increased striatal dopamine in psychosis risk are still not fully understood. Consistent with an incr…
Psychosis is strongly related to increased striatal dopamine. However, the neural consequences of increased striatal dopamine in psychosis risk are still not fully understood. Consistent with an increase in striatal dopamine, in previous research, psychosis risk has been associated with neural EEG evidence of a greater response to unexpected reward than unexpected punishment feedback on a reversal-learning task. However, previous research has not directly examined whether psychosis risk is associated with altered striatal activation when receiving unexpected feedback on this task. There were two groups of participants: an antipsychotic medication-naive psychosis risk group (n = 21) who had both (a) extreme levels of self-reported psychotic-like beliefs and experiences and (b) interview-rated current-attenuated psychotic symptoms; and a comparison group (n = 20) who had average levels of self-reported psychotic-like beliefs and experiences. Participants completed a reversal-leaning task during fMRI scanning. As expected, in both ROI and whole-brain analyses, the psychosis risk group exhibited greater striatal activation (for whole-brain analyses, the peak was located in the right caudate) to unexpected reward than unexpected punishment feedback relative to the comparison group. These results indicate that psychosis risk is associated with a relatively increased neural sensitivity to unexpected reward than unexpected punishment outcomes and appears consistent with increased striatal dopamine. The results may help us better understand and detect striatal dysfunction in psychosis risk.