The ventral tegmental area dopamine to lateral amygdala projection supports cocaine cue associative learning.

Learning and memory mechanisms are critically involved in drug craving and relapse. Environmental cues paired with repeated drug use acquire incentive value such that exposure to the cues alone can trigger craving and relapse. The amygdala, particularly the lateral amygdala (LA), underlies cue-related learning processes that assign valence to environmental stimuli including drug-paired cues. Evidence suggests that the ventral tegmental area (VTA) dopamine (DA) projection to the LA participates in encoding reinforcing effects that act as a US in conditioned cue reward-seeking as DA released in the amygdala is important for emotional and behavioral functions. Here we used chemogenetics to manipulate these VTA DA inputs to the LA to determine the role of this projection for acquisition of drug-cue associations and reinstatement of drug-seeking. We found inhibiting DA input to the LA during cocaine self-administration slowed acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with DA input to the LA had no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Overall, we show that manipulation of projections underlying DA signaling in the LA may be useful for developing therapeutic interventions for substance use disorders.

Sex- and age-dependent effects of chronic corticosterone exposure on depressive-like, anxiety-like, and fear-related behavior: Role of amygdala glutamate receptors in the rat.

Persistent glucocorticoid elevation consistent with chronic stress exposure can lead to psychopathology, including mood and anxiety disorders. Women and stress-exposed adolescents are more likely to be diagnosed with mood disorders, suggesting that sex and age are important factors in determining vulnerability, though much remains to be determined regarding the mechanisms underlying this risk. Thus, the aim of the present experiments was to use the chronic corticosterone (CORT) exposure paradigm, a model of depression-like behavior that has previously been established primarily in adult males, to determine the mood-related effects of CORT in female and adolescent rats. Depression- and anxiety-like effects in adulthood were determined using the sucrose preference (SPT), the forced swim test (FST), the elevated plus maze, and fear conditioning. Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) glutamate receptor subunit levels were then measured. In a subsequent experiment, adult male and female rats were tested for the effects of pharmacological activation (via AMPA) or inhibition (via NBQX) of AMPA receptors in the BLA on behavior in the FST. Overall, females showed reduced anxiety- and depressive-like behaviors relative to males. However, females treated with CORT in adolescence, but not adulthood, had increased immobility in the FST, indicative of depression-like behavior. In contrast, CORT did not alter behavior in adolescent-treated males, though the previously reported depression-like effect of adult CORT exposure was observed. Control females had higher expression of the AMPA receptor subunits GluA1 and GluA2/3 selectively in the BLA relative to males. Adolescent CORT treatment, however, decreased BLA GluA1 and GluA2/3 expression in females, but increased expression in males, consistent with the direction of depression-like behavioral effects. Male and female rats also demonstrated opposing patterns of response to BLA AMPA receptor modulation in the FST, with AMPA infusion magnifying the sex difference of decreased immobility in females. Overall, these experiments show that increased glutamate receptor function in the BLA may decrease the risk of developing depressive-like behavior, further supporting efforts to target glutamatergic receptors for the treatment of stress-related psychiatric disorders. These findings also support further focus on sex as a biological variable in neuropsychiatric research.

Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia.

BACKGROUND: The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. METHODS: We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). RESULTS: In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor ß sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. CONCLUSION: Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

Valence encoding in the amygdala influences motivated behavior.

The amygdala is critical for emotional processing and motivated behavior. Its role in these functions is due to its processing of the valence of environmental stimuli. The amygdala receives direct sensory input from sensory thalamus and cortical regions to integrate sensory information from the environment with aversive and/or appetitive outcomes. As many reviews have discussed the amygdala's role in threat processing and fear conditioning, this review will focus on how the amygdala encodes positive valence and the mechanisms that allow it to distinguish between stimuli of positive and negative valence. These findings are also extended to consider how valence encoding populations in the amygdala contribute to local and long-range circuits including those that integrate environmental cues and positive valence. Understanding the complexity of valence encoding in the amygdala is crucial as these mechanisms are implicated in a variety of disease states including anxiety disorders and substance use disorders.

Metformin reduces neuroinflammation and improves cognitive functions after traumatic brain injury.

Within the brain, traumatic brain injury (TBI) alters synaptic plasticity and increases neuroinflammation and neuronal death. Yet, there lacks effective TBI treatments providing pleiotropic beneficial effects on these diverse cellular processes necessary for functional recovery. Here, we show the diabetes drug, metformin, significantly improves cognitive functions after controlled cortical impact (CCI) injury in mice, showing improved spatial learning and nest building. Furthermore, injured animals treated with metformin exhibit increased ramification of microglia processes, indicating reduced neuroinflammation. Finally, metformin treatment in vitro increased neuronal activation of partitioning defective 1 (Par1), a family of Ser/Thr kinases playing a key role in synaptic plasticity and neuroinflammation. These results suggest metformin is a promising therapeutic agent for targeting multiple cellular processes necessary for functional TBI recovery.

Effects of short-term clomipramine on anxiety-like behavior, cellular metabolism, and oxidative stress in primary fibroblast cells of male and female rats.

Anxiety is the most prevalent mental disorder among adults in the United States and females tend to have significantly higher rates of anxiety compared with men. Common treatments for anxiety include usage of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, however, sex differences in the efficacy of these drugs exist. In this study, we were interested in determining if acutely manipulating serotonin mechanisms at the whole-animal level affects cellular metabolism and oxidative stress in primary fibroblast cells from clomipramine-treated Sprague-Dawley rats. Our groups included a female and male control group that was injected with a saline solution, a female and male group that was injected with a low dosage of clomipramine, and a female and male group of rats that were injected with a high dosage of clomipramine. We then compared cellular oxygen consumption rates, rates of glycolysis and oxidative stress parameters in primary fibroblasts grown from each of the groups described above. We found that clomipramine-treated rats had significantly lower rates of glycolysis and glycolytic capacity, regardless of sex. Coupling efficiency was significantly higher in male rats compared with female rats across treatment groups. Our data suggest that in female rats reduced glutathione (GSH) is nonsignificantly reduced, yet lipid peroxidation (LPO) damage still accumulates, meaning that enzymatic antioxidants may be acting to reduce any continual increases in LPO damage. This is a metabolically costly process that may be happening because of our drug treatments. Our results provide further evidence of sex differences in the behavioral and metabolic responses to short-term clomipramine treatment. Continued investigation into these sex differences may reveal their potential for improving our understanding of how different therapeutic interventions may be better suited for treating males and females.

Cornual placenta accreta managed by postpartum total laparoscopic hysterectomy.

The patient presented here delivered at 32 weeks' gestation after expectant management of spontaneous preterm membrane rupture. She had an unusually located placenta accreta at the left cornu that required a hysterectomy for treatment. The type of abnormal placentation and the laparoscopic approach to her surgery were unique features of her care.

Outcomes of child sexual abuse as predictors of later sexual victimization.

The association between a history of child sexual abuse (CSA) and specific negative outcomes (attachment, feelings of power, and self-esteem) was explored as was the relationship between those negative outcomes and sexual victimization during the first semester of college. Two groups of freshman college women (67 who had experienced CSA and 55 who had not) completed measures of attachment, feelings of power, and self-esteem at the beginning of their freshman year of college. At the end of their first semester of college, participants (n = 93) provided information about whether they had been sexually assaulted during their first semester of college. The results indicated that participants in the CSA group did not differ on reported attachment anxiety, attachment avoidance, feelings of power, or self-esteem as compared to the control group. However, participants in the CSA group were more like to be sexually victimized during their first semester of college. Finally, logistic regression indicated that the negative outcomes of CSA were significantly related to sexual victimization during the first semester of college, with attachment anxiety playing an important role. Theoretical and practical implications of the findings are discussed.