Perinatal Western-style diet exposure associated with decreased microglial counts throughout the arcuate nucleus of the hypothalamus in Japanese macaques.

Perinatal exposure to a high-fat, high-sugar Western-style diet (WSD) is associated with altered neural circuitry in the melanocortin system. This association may have an underlying inflammatory component, as consumption of a WSD during pregnancy can lead to an elevated inflammatory environment. Our group previously demonstrated that prenatal WSD exposure was associated with increased markers of inflammation in the placenta and fetal hypothalamus in Japanese macaques. In this follow-up study, we sought to determine whether this heightened inflammatory state persisted into the postnatal period, as prenatal exposure to inflammation has been shown to reprogram offspring immune function and long-term neuroinflammation would present a potential means for prolonged disruptions to microglia-mediated neuronal circuit formation. Neuroinflammation was approximated in 1-yr-old offspring by counting resident microglia and peripherally derived macrophages in the region of the hypothalamus examined in the fetal study, the arcuate nucleus (ARC). Microglia and macrophages were immunofluorescently stained with their shared marker, ionized calcium-binding adapter molecule 1 (Iba1), and quantified in 11 regions along the rostral-caudal axis of the ARC. A mixed-effects model revealed main effects of perinatal diet (P = 0.011) and spatial location (P = 0.003) on Iba1-stained cell count. Perinatal WSD exposure was associated with a slight decrease in the number of Iba1-stained cells, and cells were more densely located in the center of the ARC. These findings suggest that the heightened inflammatory state experienced in utero does not persist postnatally. This inflammatory response trajectory could have important implications for understanding how neurodevelopmental disorders progress.NEW & NOTEWORTHY Prenatal Western-style diet exposure is associated with increased microglial activity in utero. However, we found a potentially neuroprotective reduction in microglia count during early postnatal development. This trajectory could inform the timing of disruptions to microglia-mediated neuronal circuit formation. Additionally, this is the first study in juvenile macaques to characterize the distribution of microglia along the rostral-caudal axis of the arcuate nucleus of the hypothalamus. Nearby neuronal populations may be greater targets during inflammatory insults.

Perinatal Western-style diet alters serotonergic neurons in the macaque raphe nuclei.

Introduction: The neurotransmitter serotonin is a key regulator of neurotransmission, mood, and behavior and is essential in neurodevelopment. Dysfunction in this important neurotransmitter system is connected to behavioral disorders such as depression and anxiety. We have previously shown that the developing serotonin system is sensitive to perinatal exposure to Western-style diet (WSD). Methods: To advance our hypothesis that perinatal WSD has a long-term impact on the serotonergic system, we designed a fluorescent immunohistochemistry experiment using antibodies against tryptophan hydroxylase 2 (TPH2) and vesicular glutamate transporter 3 (VGLUT3) to probe protein expression in the raphe subnuclei in 13-month-old Japanese macaques (Macaca fuscata; n = 22). VGLUT3 has been shown to be coexpressed in TPH2+ cells in the dorsal raphe (DR) and median raphe nucleus (MnR) of rodent raphe nuclei and may provide information about the projection site of serotonergic fibers into the forebrain. We also sought to improve scientific understanding of the heterogeneity of the serotonin production center for the central nervous system, the midbrain raphe nuclei. Results: In this immunohistochemical study, we provide the most detailed characterization of the developing primate raphe to date. We utilize multi-level modeling (MLM) to simultaneously probe the contribution of WSD, offspring sex, and raphe anatomical location, to raphe neuronal measurements. Our molecular and morphological characterization revealed that the 13-month-old macaque DR is remarkably similar to that of adult macaques and humans. We demonstrate that vesicular glutamate transporter 3 (VGLUT3), which rodent studies have recently shown can distinguish raphe populations with distinct projection targets and behavioral functions, likewise contributes to the heterogeneity of the primate raphe. Discussion: This study provides evidence that perinatal WSD has a long-term impact on the density of serotonin-producing neurons, potentially limiting serotonin availability throughout the brain. Due to the critical involvement of serotonin in development and behavior, these findings provide important insight into the mechanisms by which maternal nutrition and metabolic state influence offspring behavioral outcomes. Finally, these findings could inform future research focused on designing therapeutic interventions to optimize neural development and decrease a child's risk of developing a mental health disorder.

Maternal Interleukin-6 Is Associated With Macaque Offspring Amygdala Development and Behavior.

Human and animal cross-sectional studies have shown that maternal levels of the inflammatory cytokine interleukin-6 (IL-6) may compromise brain phenotypes assessed at single time points. However, how maternal IL-6 associates with the trajectory of brain development remains unclear. We investigated whether maternal IL-6 levels during pregnancy relate to offspring amygdala volume development and anxiety-like behavior in Japanese macaques. Magnetic resonance imaging (MRI) was administered to 39 Japanese macaque offspring (Female: 18), providing at least one or more time points at 4, 11, 21, and 36 months of age with a behavioral assessment at 11 months of age. Increased maternal third trimester plasma IL-6 levels were associated with offspring's smaller left amygdala volume at 4 months, but with more rapid amygdala growth from 4 to 36 months. Maternal IL-6 predicted offspring anxiety-like behavior at 11 months, which was mediated by reduced amygdala volumes in the model's intercept (i.e., 4 months). The results increase our understanding of the role of maternal inflammation in the development of neurobehavioral disorders by detailing the associations of a commonly examined inflammatory indicator, IL-6, on amygdala volume growth over time, and anxiety-like behavior.

Scale (in)variance in a unified diffusion model of decision making and timing.

Weber's law is the canonical scale-invariance law in psychology: when the intensities of 2 stimuli are scaled by any value k, the just-noticeable-difference between them also scales by k. A diffusion model that approximates a spike-counting process accounts for Weber's law (Link, 1992), but there exist surprising corollaries of this account that have not yet been described or tested. We show that (a) this spike-counting diffusion model predicts time-scale invariant decision time distributions in perceptual decision making, and time-scale invariant response time (RT) distributions in interval timing; (b) for 2-choice perceptual decisions, the model predicts equal accuracy but faster responding for stimulus pairs with equally scaled-up intensities; (c) the coefficient of variation (CV) of decision times should remain constant across average intensity scales, but should otherwise decrease as a specific function of stimulus discriminability and speed-accuracy trade-off; and (d) for timing tasks, RT CVs should be constant for all durations, and RT skewness should always equal 3 times the CV. We tested these predictions using visual, auditory and vibrotactile decision tasks and visual interval timing tasks in humans. The data conformed closely to the predictions in all modalities. These results support a unified theory of decision making and timing in terms of a common, underlying spike-counting process, compactly represented as a diffusion process.

Speed accuracy trade-off under response deadlines.

Perceptual decision making has been successfully modeled as a process of evidence accumulation up to a threshold. In order to maximize the rewards earned for correct responses in tasks with response deadlines, participants should collapse decision thresholds dynamically during each trial so that a decision is reached before the deadline. This strategy ensures on-time responding, though at the cost of reduced accuracy, since slower decisions are based on lower thresholds and less net evidence later in a trial (compared to a constant threshold). Frazier and Yu (2008) showed that the normative rate of threshold reduction depends on deadline delays and on participants' uncertainty about these delays. Participants should start collapsing decision thresholds earlier when making decisions under shorter deadlines (for a given level of timing uncertainty) or when timing uncertainty is higher (for a given deadline). We tested these predictions using human participants in a random dot motion discrimination task. Each participant was tested in free-response, short deadline (800 ms), and long deadline conditions (1000 ms). Contrary to optimal-performance predictions, the resulting empirical function relating accuracy to response time (RT) in deadline conditions did not decline to chance level near the deadline; nor did the slight decline we typically observed relate to measures of endogenous timing uncertainty. Further, although this function did decline slightly with increasing RT, the decline was explainable by the best-fitting parameterization of Ratcliff's diffusion model (Ratcliff, 1978), whose parameters are constant within trials. Our findings suggest that at the very least, typical decision durations are too short for participants to adapt decision parameters within trials.