Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning.

Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC.SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus-reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards.

Trajectory analyses of virologic outcomes reflecting community-based HIV treatment in Washington DC 1994-2012.

BACKGROUND: Effective treatment of HIV since 1996 has reduced morbidity and mortality through virologic suppression. Combination antiretroviral therapy (cART) has been recognized as key to the prevention of drug resistance and the transmission of infection. We used eighteen years of virologic outcomes in a long-standing cohort of women to describe longitudinal viral load trajectories; and examine factors associated with sustained viremia and mortality. METHODS: We analyzed data from DC WIHS women with > four semiannual visits using a group-based logistic trajectory analysis approach to identify patterns of HIV RNA detection (>80 copies/mL or lower assay limit, and >1000 copies/mL). We verified findings using cumulative viral load suppression-years, explored group characteristics using generalized linear modeling with generalized estimating equations for repeated measures, and examined survival using the Kaplan-Meier and Cox proportional hazard analyses. RESULTS: 329 women contributed 6633 visits between 1994 and 2012 and demonstrated high, moderate, and low probability patterns of HIV RNA detection (>80 copies/mL) in 40.7, 35.6, and 23.7% of participant visits, respectively. Analysis of cumulative years of viral load suppression supported these observations. Kaplan-Meier survival analysis demonstrated high mortality of 31.1% with sustained viremia, but no significant difference in mortality between intermittent viremia and non-viremia patterns, 6.9 and 4.9% respectively. Mortality was associated with higher age, lower CD4+ T lymphocyte count, and sustained viremia by Cox multivariate analysis. CONCLUSIONS: This ecologic study demonstrates the effectiveness of viral suppression, and conversely the association between viremia and mortality. In community delivery of cART for HIV care, distinct patterns of sustained viremia, intermittent viremia, and non-viremia were identified over nearly 18 years in the DC WIHS, capturing the dynamics and complexity of sustaining long-term HIV care. Persistent viremia was associated with lower CD4s and mortality, but surprisingly mortality was not different between continuous suppression and intermittent viremia. Classification of long-term virologic patterns such as these observed HIV treatment "careers" may provide a suitable framework to identify modifiable factors associated with treatment resilience and failure. Both individual and population interventions are needed to reduce transmission, prevent the emergence of drug resistance, and improve outcomes of community ART programs.

Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function.

Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring.

Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chow-fed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas NPY(1) receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85alpha) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85alpha expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity.