Maternal and Early Postnatal Immune Activation Produce Dissociable Effects on Neurotransmission in mPFC-Amygdala Circuits.

Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including autism spectrum disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors, and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12.5 to produce maternal immune activation (MIA). Male offspring received either vehicle or lipopolysaccharide, which simulates a bacterial infection, on postnatal day 9 to produce postnatal immune activation (PIA). We then used optogenetics to address the possibility that early developmental immune activation causes persistent alterations in the flow of signals within the mPFC to basolateral amygdala (BLA) pathway, a circuit implicated in ASD. We found that our MIA regimen produced increases in synaptic strength in glutamatergic projections from the mPFC to the BLA. In contrast, our PIA regimen produced decreases in feedforward GABAergic inhibitory postsynaptic responses resulting from activation of local circuit interneurons in the BLA by mPFC-originating fibers. Both effects were seen together when the regimens were combined. Changes in the balance between excitation and inhibition were differentially translated into the modified spike output of BLA neurons. Our findings raise the possibility that prenatal and postnatal immune activation may affect different cellular targets within brain circuits that regulate some of the core behavioral signs of conditions such as ASD.SIGNIFICANCE STATEMENT Immune system activation during prenatal and early postnatal development may contribute to the development of autism spectrum disorder (ASD). Combining optogenetic approaches and behavioral assays that reflect core features of ASD (anxiety, decreased social interactions), we uncovered mechanisms by which the ASD-associated behavioral impairments induced by immune activation could be mediated at the level of interactions within brain circuits implicated in control of emotion and motivation (mPFC and BLA, specifically). Here, we present evidence that prenatal and postnatal immune activation can have different cellular targets in the brain, providing support to the notion that the etiology of ASD may be linked to the excitation/inhibition imbalance in the brain affecting the signal flow within relevant behavior-driving neural microcircuits.

N-Methyl-d-aspartate receptor co-agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse.

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR-/- mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR-/- mice, cocaine-induced increases in DA and glutamate release were blunted. γ-Amino-butyric acid efflux was unaffected in the SR-/- mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction.

Chronic opioid use after coronary bypass surgery.

BACKGROUND: Opioid dependence has become a major health care issue. Pain management of invasive surgical procedures with opioids may potentially contribute to this epidemic. We sought to determine the association of opioid-prescribing patterns with chronic opioid use. METHODS: We retrospectively reviewed all patients undergoing isolated coronary artery bypass graft (CABG) procedures during 2016 at a single institution. Prescribing patterns and medication usage were compared between opioid-naïve and opioid-exposed patients (patients with reported opioid use within 30 days prior to surgery). Chronic opioid dependence was defined as opioid usage beyond 90 days after discharge. RESULTS: We included 284 opioid-naïve and 46 opioid-exposed patients. Although overall prescribing patterns were similar between groups, a higher proportion of opioid-exposed patients were prescribed a total dose >150 mg of oxycodone per discharge prescription (15.2% vs 4.9%; P = 0.024), and had a higher proportion of refills within 30 days (28.3% vs 10.9%; relative risk [RR] 3.2 [95% confidence interval (CI): 1.5-6.8]; all P < 0.05). The incidence of chronic opioid dependence was higher among opioid-exposed patients compared to opioid-naïve patients (21.7% vs 3.2%; RR 8.5 [95%CI: 3.2-22.3]; P = 0.001). CONCLUSIONS: Ongoing opioid use 3 months after CABG is present in 21.7% of opioid-exposed patients and 3.2% of opioid-naïve patients. These preliminary findings highlight the burden of prescribing patterns on the overall opioid epidemic and the need to develop alternative pain management strategies.

Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system.

Accumulating evidence indicates that kappa-opioid receptors (KORs) and their endogenous ligand, dynorphin (DYN), can play important roles in regulating the effects of stress. Here, we examined the role of KOR systems in the molecular and behavioral effects of acute (1-day) and chronic (10-day) social defeat stress (SDS) in mice. We found that acute SDS increased DYN mRNA levels within the nucleus accumbens, a key element of brain dopamine (DA) systems. In contrast, chronic SDS produced long-lasting decreases in DYN mRNA levels. We then examined whether disruption of KOR function would affect development of SDS-induced depressive-like behaviors, as measured in the intracranial self-stimulation and social interaction tests. Ablation of KORs from DA transporter-expressing neurons delayed the development of SDS-induced anhedonia in the intracranial self-stimulation test, suggesting increased stress resilience. However, administration of the long-lasting KOR antagonist JDTic (30 mg/kg, intraperitoneally) before the SDS regimen did not affect anhedonia, suggesting that disruption of KOR function outside DA systems can oppose stress resilience. Social avoidance behavior measured after the 10-day SDS regimen was not altered by ablation of KORs in DA transporter-expressing neurons or by JDTic administration before testing. Our findings indicate that KORs expressed in DA systems regulate the effects of acute, but not chronic, social stress.

Neural targets in the study and treatment of social cognition in autism spectrum disorder.

The purpose of this chapter is to present results from recent research on social cognition in autism spectrum disorder (ASD). The clinical phenomenology and neuroanatomical circuitry of ASD are first briefly described. The neuropharmacology of social cognition in animal models of ASD and humans is then addressed. Next, preclinical and clinical research on the neurohormone oxytocin is reviewed. This is followed by a presentation of results from preclinical and clinical studies on the excitatory amino acid glutamate. Finally, the role of neuroinflammation in ASD is addressed from the perspectives of preclinical neuroscience and research involving humans with ASD.

Sex-based differences in mitral valve Re-operation after mitral valve repair: Truth or myth?

BACKGROUND: Outcomes after mitral valve (MV) repair are known to be worse in women. Less is known about sex-based differences in MV repair durability. METHODS: All adult patients undergoing MV repair from 2002 to 2016 were reviewed. Of 2463 cases, 947 (39%) were women. Re-operation risk was defined as any intervention for repair failure or MV disease progression. Median follow-up was 8.2 years. RESULTS: Women were older with higher STS-risk scores and were more likely to have rheumatic disease (RHD). Operative mortality was clinically higher in women (2.7% vs 1.7%; P = 0.09). Although women had significantly higher 10-year re-operation risk (7% vs 4%), adjusted longitudinal analysis showed that this was associated with RHD in women (HR 4.04; P = 0.001). Female sex alone was not a significant predictor (P = 0.21). CONCLUSIONS: Re-operation following MV repair was infrequent. Women had increased re-operation risk that was largely attributable to their worse preoperative profiles rather than female sex alone.

Outcomes After Tricuspid Valve Repair With Ring Versus Suture Bicuspidization Annuloplasty.

BACKGROUND: Ring annuloplasty (Ring) and suture bicuspidization annuloplasty (Suture-bicuspidization) are 2 techniques for tricuspid valve repair. With the emergence of transcatheter tricuspid valve repair technologies that mimic these conventional surgical techniques, we compared their midterm outcomes and longitudinal echocardiographic profiles. METHODS: From 2002 to 2016, 650 patients underwent tricuspid valve repair (324 Ring and 326 Suture-bicuspidization) for primary or functional tricuspid regurgitation (TR). Concomitant aortic valve, mitral valve, or coronary artery bypass graft procedures were included but tricuspid valve replacement, concomitant aortic procedures, heart transplantation or ventricular assist device placement procedures were excluded. Tricuspid valve event-free survival was estimated using Kaplan-Meier competing risk analysis. Freedom from TR recurrence (defined as at least moderate TR) and freedom from tricuspid valve reoperation were also assessed. RESULTS: There were no statistical differences in terms of age, gender, and most baseline comorbidities (P > .05). In-hospital outcomes also did not significantly differ between groups (P > .05). However, Suture-bicuspidization was associated with significantly lower tricuspid valve event-free survival, and freedom from TR recurrence and tricuspid valve reoperation compared with Ring at 1, 5, and 8 years (all P < .05). After adjusting for significant confounders, Suture-bicuspidization continued to be associated with significantly decreased tricuspid valve event-free survival (hazard ratio = 2.13; 95% confidence interval, 1.3-3.4). CONCLUSIONS: The superiority of Ring over Suture-bicuspidization annuloplasty for tricuspid valve repair appeared to be evident in terms of event-free survival and freedom from tricuspid valve insufficiency and reoperation. These findings raise concern in the context of emerging transcatheter technologies that mimic the bicuspidization technique.

Cardiac Surgery in Patients With Opioid Use Disorder: An Analysis of 1.7 Million Surgeries.

BACKGROUND: Adverse repercussions associated with the current opioid epidemic have been documented in many surgical specialties. This study evaluated the impact of opioid use disorder (OUD) on in-hospital cardiac surgery outcomes by using a large national database. METHODS: Using the National Inpatient Sample, this study isolated patients undergoing coronary artery bypass grafting, valve repair, or valve replacement from 2009 to 2014. Patients were stratified by OUD status. Multivariable analysis was performed to evaluate the association between opioid use and postoperative outcomes. Patients were further stratified by surgery type. RESULTS: Overall, 1,743,161 patients underwent cardiac surgery, and 6960 patients had OUD (0.4%). Mean age was 47.2 and 65.8 years among those with and without OUD, respectively. Although in-hospital mortality did not differ among these groups, patients with OUD had a significantly higher incidence of stroke (8.3% vs 2.8%) and acute kidney injury (21.4% vs 16.2%), longer hospital stays (18 days vs 10 days), and higher hospitalization costs ($81,238 vs $58,654; all P < .01). However, after adjusting for patient and hospital-level factors, OUD was associated only with a longer hospital length of stay (2.2 days; 95% confidence interval, 1.19 to 3.20) compared with non-opioid users. CONCLUSIONS: OUD among cardiac surgery patients is associated with prolonged hospitalization and increased risk of postoperative morbidity, mainly driven by the patient's preoperative risk factors. Strategies to minimize these risk factors at the prehospitalization level is warranted to curb the opioid epidemic and improve overall outcomes in this vulnerable population.

Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice.

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. Here we examined the effects of early-life immune system activation (EIA)-comprising regimens of prenatal, early postnatal, or combined ("two-hit") immune activation-on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C) on gestational day 12.5 to produce maternal immune activation (MIA). Some offspring also received lipopolysaccharide (LPS) on postnatal day 9 to produce postnatal immune activation (PIA). EIA produced disruptions in social behavior and increases in repetitive behaviors that were larger in males than in females. Ultrasonic vocalizations (USVs) were altered in both sexes. Molecular studies revealed that EIA also produced prominent sex-specific changes in inflammation-related gene expression in the brain. Whereas both sexes showed increases in pro-inflammatory factors, as reflected by levels of mRNA and protein, expression of anti-inflammatory factors was decreased in males but increased in females. Our findings demonstrate that EIA can produce sex-specific behavioral effects and immune responses in the brain, and identify molecular processes that may contribute to resilience in females.

Toward an immune-mediated subtype of autism spectrum disorder.

A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immune-modulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.