Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology

Background The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. Methods We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. Results High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. Conclusions This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. Graphical abstract

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a Pilot Investigation

Objective: Outcome processing, the ability to learn from feedback, is an important component of adaptive behavior and rehabilitation. Evidence from healthy adults implicates the striatum and dopamine in outcome processing. Animal research shows that damage to dopaminergic pathways in the brain can lead to a disruption of dopamine tone and transmission. Such evidence thus suggests that persons with TBI experience deficits in outcome processing. However, no research has directly investigated outcome processing and associated neural mechanisms in TBI. Here, we examine outcome processing in individuals with TBI during learning. Given that TBI negatively impacts striatal and dopaminergic systems, we hypothesize that individuals with TBI exhibit deficits in learning from outcomes. Methods: To test this hypothesis, individuals with moderate-to-severe TBI and healthy adults were presented with a declarative paired-associate word learning task. Outcomes indicating performance accuracy were presented immediately during task performance and in the form of either monetary or performance-based feedback. Two types of feedback provided the opportunity to test whether extrinsic and intrinsic motivational aspects of outcome presentation play a role during learning and outcome processing. Results: Our results show that individuals with TBI exhibited impaired learning from feedback compared to healthy participants. Additionally, individuals with TBI exhibited increased activation in the striatum during outcome processing. Conclusions: The results of this study suggest that outcome processing and learning from immediate outcomes is impaired in individuals with TBI and might be related to inefficient use of neural resources during task performance as reflected by increased activation of the striatum.

Relationships Between Iron Status, Cognitive Performance, and Smoking Cessation

Objectives Smoking cessation research suggests that women are more likely than men to respond to financial incentives to quit smoking, despite having lower rates of smoking cessation overall. Animal models suggest that iron deficiency, which is more prevalent in women, may alter dopaminergic pathways involved in both reward processing and addiction. The present study examines the extent to which iron status impacts ability to quit smoking and performance on a battery of cognitive tasks, including tasks assessing learning and decision-making which depend on the integrity of the dopaminergic pathways. Methods Participants were recruited from a local smoking cessation clinic and followed for 6 months as they received counseling to quit smoking. Visits included a baseline appointment, as well as 1- and 6-month follow up visits. At each appointment, participants performed cognitive tests, including the serial reaction time task (SRT) and probabilistic selection task (PST), with concurrent EEG, then gave a small sample of blood. Smoking behavior was examined using time to relapse (TTR), which was the week (1–26) in which the participant relapsed, if relapse occurred. Iron status variables of interest were hemoglobin (Hb) and percentile of the NHANES III age- and race-adjusted distributions of serum ferritin (sFtP). Correlations examined the associations between iron status variables and reaction times (RTs) on the SRT and PST, choice behavior on PST, and TTR. Results TTR was positively related to sFtP (r = 0.79, P < .005). Regarding the cognitive measures, there was a nonlinear relationship between sFtP and RT for the SRT task: participants with sFtP at or below the 45th percentile had a negative relationship with RT, while those with sFtP above the 55th percentile had a positive one. Hb was negatively correlated with learning from negative consequences in the PST. In addition, RTs for high-conflict choices and correct responses had a nonlinear relationship with sFtP like that found with the SRT. Conclusions Variations in iron affect smoking cessation as well as cognitive performance. Being low in iron may represent an additional burden to a woman who attempts to quit smoking. Funding Sources TSET Health Promotion Research Center - Oklahoma Tobacco Settlement Endowment Trust (TSET; Grant # r21–02) and NCI Support Grant P30CA225520.

Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways

Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidence suggests that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood, and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and mesocortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of activity-dependent markers pERK and c-fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Our results show that social stress decreases the density of TH+ dopaminergic axonal projections in the deep layers of the mPFC in susceptible but not resilient male and female mice. Consistently, our analyses suggest that pERK expression is decreased in the mPFC but increased in the NAc following CSDS in males and females, with no change in c-fos expression in both sexes. Overall, our findings indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity in males and females.

Subcortical Structures and Creative Divergent Thinking: A Resting-State functional MRI Analysis

This study aimed to testify whether spontaneous fluctuations in the subcortex contribute to creative divergent thinking. Individuals at high- and low levels of creativity were recruited and the resting-state fMRI data was collected. Seed-wise and dynamic functional connectivity (FC) were used to identify differences between the two groups. The topological properties of the subcortical network were measured, and their relationship with performance of creative divergent thinking was calculated using brain-behaviour correlation analyses. The results revealed higher FC between the putamen, pallidum, and thalamus in high creativity group (HCG) compared to low creativity group (LCG) within the subcortex. Whole-brain FC results showed stronger connection across subcortical (i.e., the thalamus and pallidum) and cerebral regions (i.e., the insula, middle frontal gyrus, and middle temporal gyrus) in HCG compared to LCG. In addition, the subcortical FC demonstrated a positive correlation with performance of creative thinking across the pallidum, putamen, and thalamus. Our findings may provide novel insights into the relationship between creative divergent thinking and the activities of the subcortex. It is likely that not only fronto-striatal dopaminergic pathways, but also “motor” pathways, are involved in creative thinking processing.

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

Dopamine is an essential neurotransmitter, which functions are mediated by five G protein-coupled receptors, dopamine D1 to D5 receptors (D1R-D5R) in mammals. Among them, D1R is the most abundantly expressed dopamine receptor in the CNS and is the central receptor mediating excitatory dopamine signaling in multiple dopaminergic pathways. Dysregulation of D1R signaling has been directly linked to Parkinson’s disease (PD), schizophrenia, and drug abuse. Due to its fundamental functions in human diseases, D1R has long been the subject of intensive drug development effort toward the treatment of neuropsychiatric diseases. Here, we report the structures of D1R-Gs complex bound to endogenous agonist dopamine and synthetic agonist SKF81297, both with positive allosteric modulator LY3154207. These structures reveal the basis of dopamine recognition, the binding and potential allosteric regulation of DRD1 PAM LY3154207, and provide structural templates for design of subtype-selective D1R ligand for drug discovery targeting DRD1 for treating various CNS diseases.

Stress-induced Alterations of Mesocortical and Mesolimbic Dopaminergic Pathways

Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidences suggest that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and cortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of the activity-dependent markers pERK and c-Fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We showed that social stress decreases the density of dopaminergic axonal projections to the mPFC but not to the NAc in susceptible and resilient mice. This was accompanied by sex-specific alterations of pERK and c-Fos expression in the VTA of susceptible but not resilient mice. Our results indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity differently in males and females.